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Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants

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Let’s acknowledge the biggest killer of women (and men)

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Risk factors for MI are more potent in women, finds study

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• Peer review
• Elizabeth R C Millett , epidemiologist 1 ,
• Sanne A E Peters , research fellow in epidemiology, and associate professor 1 2 ,
• Mark Woodward , professor of statistics and epidemiology , professor of medical statistics, and adjunct professor of epidemiology 1 3 4
• 1 The George Institute for Global Health, University of Oxford, Oxford OX1 2BQ, UK
• 2 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
• 3 The George Institute for Global Health, University of New South Wales, Newtown, NSW, Australia
• 4 Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA
• Correspondence to: S A E Peters sanne.peters{at}georgeinstitute.ox.ac.uk
• Accepted 25 September 2018

Objectives To investigate sex differences in risk factors for incident myocardial infarction (MI) and whether they vary with age.

Design Prospective population based study.

Setting UK Biobank.

Participants 471 998 participants (56% women; mean age 56.2) with no history of cardiovascular disease.

Main outcome measure Incident (fatal and non-fatal) MI.

Results 5081 participants (1463 (28.8%) of whom were women) had MI over seven years’ mean follow-up, resulting in an incidence per 10 000 person years of 7.76 (95% confidence interval 7.37 to 8.16) for women and 24.35 (23.57 to 25.16) for men. Higher blood pressure indices, smoking intensity, body mass index, and the presence of diabetes were associated with an increased risk of MI in men and women, but associations were attenuated with age. In women, systolic blood pressure and hypertension, smoking status and intensity, and diabetes were associated with higher hazard ratios for MI compared with men: ratio of hazard ratios 1.09 (95% confidence interval 1.02 to 1.16) for systolic blood pressure, 1.55 (1.32 to 1.83) for current smoking, 2.91 (1.56 to 5.45) for type 1 diabetes, and 1.47 (1.16 to 1.87) for type 2 diabetes. There was no evidence that any of these ratios of hazard ratios decreased with age (P>0.2). With the exception of type 1 diabetes, the incidence of MI was higher in men than in women for all risk factors.

Conclusions Although the incidence of MI was higher in men than in women, several risk factors were more strongly associated with MI in women compared with men. Sex specific associations between risk factors and MI declined with age, but, where it occurred, the higher relative risk in women remained. As the population ages and the prevalence of lifestyle associated risk factors increase, the incidence of MI in women will likely become more similar to that in men.

Introduction

Coronary heart disease (CHD) has been the leading cause of mortality worldwide for over 25 years, 1 2 and was estimated to be the cause of 17% of deaths globally in 2016. 3 Death rates from CHD are considerably lower in women than in men at younger ages, but often converge with increasing age. Male-to-female coronary mortality rate ratios are typically around 4 to 5 in middle age (30-64) and 2 thereafter (65-89). 4 In the INTERHEART case-control study, women had their first myocardial infarction (MI) on average nine years later than men. 5 In addition to later presentation, men and women can have different symptoms, treatments, and outcomes of MI, some of which may be because of the effects and prevalence of risk factors. Several large scale meta-analyses have compared the sex specific associations between risk factors and CHD. Key findings from these analyses are that, compared with men, women had a higher ratio of relative risk of CHD: 44% higher if they had diabetes 6 and 25% higher if they were current smokers. 7 However, these meta-analyses included studies performed over an extensive time scale, with heterogeneous study populations, and with varying sets of adjustment for potential confounders. Importantly, the analyses were unable to reliably explore whether the identified sex differences in relative risk were consistent with age, or to compare the sex differences for different risk factors on an equal basis. In addition, the analyses could not make comparisons on the absolute scale.

To obtain comparably adjusted results, overall and within age groups, we used the UK Biobank to investigate the sex differences in risk factors for MI and how these may vary with age.

The UK Biobank is a large prospective study of 502 628 participants recruited between 2006 and 2010. 8 Participants aged between 40 and 69 were invited to attend one of 22 centres for a baseline assessment, where informed consent was obtained, a touchscreen questionnaire was completed, a face-to-face interview was conducted, and a range of physical measurements were taken. Participants gave details of their medical history, regular use of any drugs, and their lifestyle factors, such as smoking status. Baseline data are linked to hospital admissions data (hospital episode statistics admitted patient care activity (HES, England), the general/acute inpatient and day case dataset (SMR01, Scotland) and the patient episode database for Wales (PEDW)) and Office for National Statistics (ONS) mortality records, which enable long term follow-up of participants and their health outcomes.

Participants who subsequently withdrew from the study (n=64) and those with a history of cardiovascular disease (self reported or hospital admission diagnosis of MI, angina, or stroke before the date of the baseline assessment, n=30 566) were excluded from the current analyses.

Measurement of risk factors

We investigated six risk factors: blood pressure, smoking status, diabetes mellitus, body mass index, atrial fibrillation, and socioeconomic status. For blood pressure, the mean of two sitting systolic and diastolic blood pressure measurements, taken at baseline using the Omron HEM-7015IT digital blood pressure monitor (Omron Healthcare), was calculated. Blood pressure was categorised using American Heart Association (AHA) 2017 guidelines (normal: systolic blood pressure <120 mm Hg and diastolic blood pressure <80 mm Hg; elevated: systolic blood pressure 120-129 mm Hg and diastolic blood pressure <80 mm Hg; stage 1 hypertension: systolic blood pressure 130-139 mm Hg or diastolic blood pressure 80-89 mm Hg; and stage 2 hypertension: systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg). 9 We further categorised AHA stages into eight groups according to reported use of antihypertensive drugs. Smoking status was self reported and included the daily cigarette consumption of current smokers. Self reported diabetes was categorised as type 1 if participants were aged less than 30 when the disease was diagnosed and they were using insulin, and type 2 otherwise. Participants with type 2 diabetes were further classified according to self reported treatment. Body mass index was calculated by dividing a participant’s weight in kilograms, measured using the Tanita BC-418 MA body composition analyser (Tanita Corporation of America), by the square of his or her standing height in metres, measured using a Seca 202 height measure (SECA, Germany). Overweight was defined as a body mass index of at least 25 kg/m 2 and less than 30 kg/m 2 ; obesity was defined as a body mass index of 30 kg/m 2 or higher. A history of atrial fibrillation was self reported. Socioeconomic status was determined using the postcode based Townsend deprivation index and categorised into thirds using national cut-off points (high: <–2.08; middle ≥–2.08 to <1.40; low ≥1.40).

The study endpoint was the incidence of fatal or non-fatal MI, defined using an algorithm developed by UK Biobank. 10 Linking with relevant hospital admissions data (HES, SMR01, and PEDW) and ONS enabled UK Biobank to identify the date of the first known MI after the date of baseline assessment by using codes I21, I22, I23, I24.1 or I25.2 from the 10th edition of the International Classification of Diseases. Follow-up for all participants started at inclusion in the UK Biobank and ended on 31 March 2016, or when the first fatal or non-fatal MI occurred.

Statistical analyses

Baseline characteristics for women and men are presented as number (percentage) for categorical variables, mean (standard deviation) for approximately symmetrical continuous variables, and median (interquartile range) for asymmetrical continuous variables. The incidence of MI was estimated separately for women and men. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals for MI comparing women with men, adjusted for age, systolic blood pressure, body mass index, smoking status, and diabetes. These analyses were further stratified by age in five year groups.

To estimate the hazard ratios for MI for each risk factor, we used Cox regression models, with interaction terms between each variable and sex. All models were adjusted for age and other variables specified a priori, which varied across risk factors. In addition to age, we adjusted systolic blood pressure, diabetes, and socioeconomic status for each other as well as for smoking status, body mass index, use of lipid lowering drugs, and antihypertensive drugs. Atrial fibrillation was similarly adjusted for these eight variables. Diastolic blood pressure and AHA hypertension stages were adjusted for the same variables as systolic blood pressure, except when AHA hypertension stage was further categorised by use of antihypertensive drugs, in which case adjustment for antihypertensive drugs was clearly inappropriate. The models for smoking variables included socioeconomic status, and the models for body mass index included smoking status and socioeconomic status. We decided not to adjust body mass index for systolic blood pressure because systolic blood pressure is thought to be a mediating factor and our goal was to examine the independent effects of sex on risk factor associations with MI.

The interaction term of each risk factor with sex was used to obtain the women-to-men relative hazard ratio for each risk factor. This ratio should be interpreted as a measure of interaction (in a statistical sense) or effect modification (in a clinical sense). We used a likelihood ratio test to check for deviation from the linear trend for the ratio of hazard ratios for categories of daily cigarette consumption.

Missing data can be a source of bias. We determined the percentage of missing data for each variable used in this study. We ran a sensitivity analysis for any variable for which more than 5% of the data were missing by performing 20 iterations of a multiple imputation using chained equations and including sex interactions in the imputation model. 11 When less than 5% of data for a risk factor or potential confounder of interest was missing, participants with missing data were not included in the relevant model.

To investigate whether sex differences in risk factors differed by age group (<50, 50-59, and ≥60), we added a three way interaction between sex, age group, and the risk factor of interest to the models. Age group was subsequently included as a linear term to produce Wald test P values for trend among women and men and in the interaction for the ratio of hazard ratios. Because the UK Biobank cohort is comparatively socially advantaged (and healthy) compared with the UK population in general, we investigated whether there was evidence of heterogeneity in the effects of risk factors according to socioeconomic status. Therefore, we ran additional subgroup analyses for participants at or above, and below the national median Townsend deprivation index score (−0.56).

We also looked at sex differences on the absolute scale, which are less likely to be relevant than relative risks for application in other populations, but should be considered when making clinical decisions. We evaluated sex differences on the absolute scale as unadjusted and adjusted rates per 10 000 person years by sex and their women-to-men difference of differences, estimated using Poisson regression models. Adjustments were the same as those used in the Cox models.

Analyses were performed using Stata version 14.2.

Patient and public involvement

No patients were involved in setting the research question or the outcome measures, and they were not involved in developing plans for the design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. We have no plans to disseminate the results of the research to study participants or the relevant patient community.

Table 1 presents the baseline characteristics of 471 998 participants with no history of cardiovascular disease included in these analyses. The proportion of women was 56% and the mean age at study baseline was 56 (standard deviation 8) in both sexes. At baseline, a lower percentage of women than men had diabetes or atrial fibrillation, or were taking lipid lowering or blood pressure lowering drugs. Overall, women had slightly lower blood pressure and were less likely to have ever smoked than men.

Characteristics of women and men without a history of cardiovascular disease who participated in the UK Biobank. Values are numbers (percentages) unless stated otherwise

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After a mean follow-up of seven years, 5081 first MI events were recorded (1463 (28.8%) in women) (table 1). Models adjusted for multiple variables showed that the rate of MI in women was less than half that in men (hazard ratio 0.37; 95% confidence interval 0.35 to 0.40). The lower risk of MI in women compared with men was apparent across all age groups, but attenuated slightly with increasing age, from 0.27 (0.18 to 0.41) among those aged less than 45, to 0.45 (0.40 to 0.50) among those aged 65 and over (supplementary table 1).

Blood pressure

Rising values of all blood pressure indices were associated with a higher risk of MI in both sexes after adjusting for confounding variables ( fig 1 ). Compared with normal blood pressure, the risk of MI increased with AHA hypertension stage in both sexes and was consistently higher among women than men. The women-to-men ratio of hazard ratios for elevated blood pressure was 1.83 (95% confidence interval 1.33 to 2.52), whereas for stage 1 and stage 2 hypertension the ratios were both about 1.5 ( fig 2 ). We also considered the effects of higher blood pressure on MI according to antihypertensive drug use. The hazard ratios for MI were higher for participants taking drugs than for those not taking drugs for each AHA stage and in both sexes (supplementary table 2). This increase was more pronounced in women. For example, comparing participants with elevated blood pressure taking antihypertensive drugs with those with normal blood pressure not taking antihypertensive drugs, the hazard ratio was 3.65 (2.44 to 5.44) in women and 1.75 (1.26 to 2.44) in men (ratio of hazard ratios 2.08, 95% confidence interval 1.24 to 3.50) (supplementary table 2).

Adjusted hazard ratios for association between risk factors and incident myocardial infarction by sex. Horizontal lines indicate corresponding 95% confidence intervals around hazard ratios. All models were adjusted for age. Additionally, systolic blood pressure, diabetes, and socioeconomic status were adjusted for each other as well as smoking status, body mass index, lipid lowering drugs, and antihypertensive drugs. Atrial fibrillation was similarly adjusted for these eight variables. Diastolic blood pressure and American Heart Association hypertension stages were adjusted for the same variables as systolic blood pressure. Models for smoking variables included socioeconomic status, and models for body mass index contained smoking status and socioeconomic status

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Adjusted women-to-men ratios of hazard ratios for association between risk factors and incident myocardial infarction. Horizontal lines indicate corresponding 95% confidence intervals around ratio of hazard ratios. All models were adjusted for age. Additionally, systolic blood pressure, diabetes, and socioeconomic status were adjusted for each other as well as smoking status, body mass index, lipid lowering drugs, and antihypertensive drugs. Atrial fibrillation was similarly adjusted for these eight variables. Diastolic blood pressure and American Heart Association hypertension stages were adjusted for the same variables as systolic blood pressure. Models for smoking variables included socioeconomic status, and models for body mass index contained smoking status and socioeconomic status

Smoking status

Compared with never smoking, current and former smoking were each associated with an increased risk of MI in both sexes, but with larger hazard ratios in women than men. For current smokers, the hazard ratios were 3.46 (95% confidence interval 3.02 to 3.98) in women and 2.23 (2.03 to 2.44) in men (fig 1) (ratio of hazard ratios 1.55, 95% confidence interval 1.32 to 1.83; fig 2). Greater smoking intensity was associated with a higher risk of MI in both sexes, but especially among women. The women to men ratio of hazard ratios increased with cigarette consumption (with evidence of non-linearity, P=0.006; fig 2).

Type 1 and 2 diabetes

Compared with people without diabetes, women with type 1 diabetes had more than eight times the risk of MI (hazard ratio 8.18, 95% confidence interval 5.20 to 12.86; fig 1), almost three times the hazard ratio in men (2.81, 1.82 to 4.33; fig 1; ratio of hazard ratios 2.91, 1.56 to 5.45; fig 2). Type 2 diabetes was associated with an increased risk of MI in both sexes; the hazard ratio was 1.96 (1.60 to 2.41) in women and 1.33 (1.18 to 1.51) in men (fig 1); the ratio of hazard ratios was 1.47 (1.16 to 1.87; fig 2). When analysing the type of treatment given to people with type 2 diabetes, there was still an excess risk in women compared with men (supplementary table 3). Hazard ratios for both sexes and the women-to-men ratio were greater when insulin use was reported.

Body mass index

The risk of MI rose with increasing body mass index, and with being overweight or obese (compared with normal weight) for both sexes ( fig 1 ). However, there was no evidence of any difference by sex (ratio of hazard ratios 0.97 (95% confidence interval 0.91 to 1.03) for every 5 kg/m 2 additional body mass index, 0.89 (0.76 to 1.03) for overweight, and 0.93 (0.79 to 1.09) for obese; fig 2).

Atrial fibrillation

The hazard ratio for MI associated with atrial fibrillation was 1.54 (95% confidence interval 0.89 to 2.66) in women and 1.35 (1.04 to 1.77) in men (fig 1); there was no evidence of a sex difference (ratio of hazard ratios 1.14, 95% confidence interval 0.62 to 2.09; fig 2).

Socioeconomic status

Compared with high socioeconomic status, women with a low socioeconomic status had a hazard ratio for MI of 1.27 (95% confidence interval 1.11 to 1.46); the equivalent hazard ratio in men was 1.12 (1.03 to 1.22) (fig 1). For each unit increase in the Townsend deprivation index score (moving from higher to lower socioeconomic status), women had 3% (hazard ratio 1.03, 1.02 to 1.05) higher risk of MI compared with a 2% (1.02, 1.01 to 1.03) higher risk in men. There was some evidence that this risk was slightly higher among women than men (ratio of hazard ratios 1.02, 1.00 to 1.04).

Confounding and modification by age

The results from the age adjusted analyses were generally similar to the multiple adjusted analyses (supplementary table 4). The sex specific hazard ratios for stage 1 and 2 hypertension, current smokers, diabetes, and socioeconomic status were slightly higher than those that were further adjusted, as were the ratios of hazard ratios for current smokers, diabetes, atrial fibrillation, and the lowest third category of socioeconomic status.

In both sexes, the hazard ratios for systolic blood pressure, diastolic blood pressure, hypertension stage 2, and high smoking intensity decreased with increasing age ( fig 3 ). Type 2 diabetes was associated with a higher risk of MI in those aged less than 50 (women: hazard ratio 3.73 (95% confidence interval 1.93 to 7.20); men: 2.18 (1.43 to 3.31); fig 3), while the 50-59 and 60 and older age groups had similarly increased risks of around 90% in women and 30% in men. For none of the risk factors investigated was there evidence that the women-to-men ratio of hazard ratios differed by age group ( fig 4 and supplementary table 5).

Adjusted hazard ratios for association between risk factors and incident myocardial infarction by age group and sex. Horizontal lines indicate corresponding 95% confidence intervals around hazard ratios. Systolic blood pressure is given per 20 mm Hg and diastolic blood pressure per 10 mm Hg. Participants with stage 2 hypertension were compared with participants with normal blood pressure; current smokers were compared with never smokers; participants with diabetes were compared with those without diabetes; obesity was compared with body mass index less than 25 kg/m 2 ; and for socioeconomic status the lowest third was compared with the highest third. Models for systolic blood pressure, diabetes and socioeconomic status were adjusted for each other as well as smoking status, body mass index, lipid lowering drugs, and antihypertensive drugs. Diastolic blood pressure and American Heart Association hypertension stages were adjusted for the same variables as systolic blood pressure. Models for smoking variables included socioeconomic status, and models for body mass index contained smoking status and socioeconomic status

Adjusted women-to-men ratios of hazard ratios for association between risk factors and incident myocardial infarction by age group. Horizontal lines indicate corresponding 95% confidence intervals around ratio of hazard ratios. Systolic blood pressure is given per 20 mm Hg and diastolic blood pressure per 10 mm Hg. Participants with stage 2 hypertension were compared with participants with normal blood pressure; current smokers were compared with never smokers; participants with diabetes were compared with those without diabetes; obesity was compared with body mass index less than 25 kg/m 2 ; and for socioeconomic status the lowest third was compared with the highest third. Models for systolic blood pressure, diabetes, and socioeconomic status were adjusted for each other as well as smoking status, body mass index, lipid lowering drugs, and antihypertensive drugs. Diastolic blood pressure and American Heart Association hypertension stages were adjusted for the same variables as systolic blood pressure. Models for smoking variables included socioeconomic status, and models for body mass index contained smoking status and socioeconomic status

Modification by socioeconomic status

The only evidence of heterogeneity by socioeconomic status in the effects of sex on risk factors for MI was for former smoking versus never smoking (P=0.004, supplementary table 6). Among women with low socioeconomic status, former smokers had a 49% increased risk of MI compared with non-smokers. This increase was not present among men (hazard ratio 1.06, 95% confidence interval 0.93 to 1.22; ratio of hazard ratios 1.41, 1.11 to 1.79). There was no evidence of a sex difference in the hazard ratios comparing former with never smokers among those with high socioeconomic status (supplementary table 6).

Sex comparisons of rates of MI

Finally, we describe sex differences on the absolute scale. Incidence rates of MI per 10 000 person years were 7.76 (95% confidence interval 7.37 to 8.16) in women and 24.35 (23.57 to 25.16) in men. Type 1 diabetes was the only risk factor associated with comparable rates of MI in women and men. For all other risk factors, and for every category of these risk factors, men had higher rates of MI than women ( table 2 ; supplementary table 7). The unadjusted rates of MI were generally similar to the multiple adjusted rates, except among participants with type 1 diabetes in whom rates increased after adjustment, and among those with type 2 diabetes or atrial fibrillation in whom rates decreased after adjustment. In both sexes, multiple adjusted rates were highest among those with type 1 diabetes (women: 64.92/10 000 person years (95% confidence interval 35.88 to 93.96); men: 61.92/10 000 person years (35.17 to 88.67); table 2).

Multiple adjusted rates of myocardial infarction (per 10 000 person years) by sex, and women-to-men difference of rate differences for each risk factor

This study of 471 998 middle aged UK Biobank participants with no history of cardiovascular disease analysed the sex differences in risk factors for myocardial infarction (MI). Women who smoked more than 20 cigarettes per day had twice the relative risk of MI than equivalent men, and elevated blood pressure was associated with a more than 80% higher relative risk in women. Hypertension stages 1 and 2, smoking 10-19 cigarettes daily, and type 2 diabetes each were 40% more strongly associated with the risk of MI in women than men.

Since the sex specific relative risks attenuated with age in both sexes, our results suggest that cardiovascular risk scores should consider including age interactions for greater predictive accuracy. However, we found no evidence to suggest that the women-to-men comparisons were significantly different across age groups.

Strengths and limitations of this study

Previous studies of sex differences in MI have been restricted to a single risk factor, pooled data from disparate studies, or were based on hospital populations. In this study we analysed sex differences in MI across a range of risk factors in a general population using standardised methods on the relative and absolute scales. We also examined how age impacts sex differences in MI. The only comparable study examining a similar range of risk factors in men and women and using a standard protocol is INTERHEART. This, however, was a retrospective case-control study of patients admitted to hospital with their first acute MI, and hospital sourced controls. The study design is inferior to the UK Biobank cohort design and is more susceptible to bias. 12

Our study has limitations. Some variables had missing data but the only variable with more than 5% of data missing was the number of cigarettes smoked daily (supplementary table 8). After multiple imputation, the effects of smoking intensity, however, were not appreciably different from the complete case analysis (supplementary table 9) and we conclude that the primary results are valid. Most UK Biobank participants are white and further work is required to assess the generalisability of the results to other populations. Higher socioeconomic status was over represented in the study population, which could have limited the ability of this study to find sex differences among different socioeconomic groups. Blood samples were taken from all participants but at the time of analysis the lipid profile data were not available, preventing examination of this as a risk factor and adjusting for it as a confounder. Instead we adjusted analyses for participants’ use of lipid lowering drugs when appropriate, but residual confounding by lipid levels is possible. Diagnoses and recording of drug use at baseline relied on self report, which will have resulted in some errors. However, these errors were probably minor and may have been the same in both sexes. UK Biobank participants were aged between 40 and 70 at recruitment, and so sex differences among younger and older populations were not analysed. Whether the additional risk associated with some factors varies across a wider age range would be an interesting topic for future research.

Comparison with other studies

This study adds to the growing literature on potential sex differences in risk factors for cardiovascular disease. In a meta-analysis of more than 900 000 people, the increased risk of ischaemic heart disease with each 10 mm Hg rise in systolic blood pressure was found to be 13% in women and men. 13 There was important heterogeneity between studies, which could partly be because of different trends in blood pressure worldwide. 14 Our findings are similar to those from a recent English study of 1.25 million patients and 11 029 MI events, in which a slightly higher relative risk of MI with increasing systolic blood pressure, but not diastolic blood pressure, was found in women compared with men. 15 INTERHEART reported higher odds ratios of MI in women with hypertension than in men with hypertension (odds ratio 2.95 (95% confidence interval 2.66 to 3.28) in women and 2.32 (2.16 to 2.48) in men). 5 We found a higher relative risk of MI in women compared with men across all American Heart Association (AHA) hypertension stages, and this was most pronounced among those with elevated blood pressure. Women may be less likely to receive blood pressure lowering drugs and be less compliant with treatment, resulting in poorer blood pressure control than men. 16 Women’s longer exposure to the effects of hypertension (including before any treatment) could explain some of the higher relative risk we found in our analyses.

The INTERHEART study found that smoking accounted for around 36% of the population attributable risk of MI worldwide. 12 Both men and women who were current smokers had around three times the odds of MI compared with never smokers. There was evidence of a sex difference by former smoking status. Women who were former smokers were not found to have increased odds of MI compared with never smokers, whereas men who were former smokers had around 60% increased odds of MI compared with never smokers. 5 Our previous meta-analysis described a women to men ratio of relative risks of CHD of 1.25 (95% confidence interval 1.12 to 1.39) in current smokers compared with non-smokers, 7 which is lower than the ratio of hazard ratios of 1.55 in current smokers compared with never smokers found in the current study. In agreement with the current study, this meta-analysis found no evidence of a sex difference when comparing the risk of CHD between former smokers and never smokers. 7 INTERHEART and the Tromsø study reported an association between rising cigarette consumption and an increasing risk of MI in both sexes. 17 18 Although the Tromsø study reported no evidence of an interaction between sex and smoking intensity, the effect sizes in both studies were larger among women than men. 17 18 Our estimate of a higher relative risk in female, than male, current smokers compared with never smokers, and with increasing cigarette consumption, may be explained by differences in the duration of the tobacco epidemic worldwide; in many countries the epidemic among women is relatively recent, leading to an underestimate of women’s excess relative risk in some studies. 19 20 We have previously described how the smoking habits in UK Biobank men and women have become increasingly similar over time, 21 providing a more direct women-to-men comparison of the risk of MI associated with smoking.

The sex difference in risk of cardiovascular disease in people with diabetes has been subject to increasing interest over recent years. Pooled analyses of over 800 000 people, including over 26 000 incident CHD events, showed that women with diabetes had a 44% excess relative risk of incident CHD compared with men with diabetes. 6 INTERHEART and an Italian cohort study reported higher risks of MI in women with diabetes than in men, 5 22 whereas a meta-analysis and the China Kadoorie Biobank described an excess relative risk of mortality from CHD in women with diabetes compared with men. 23 24 In contrast, a large English cohort study of 1.9 million patients observed a slightly increased risk of non-fatal MI in women with type 2 diabetes aged less than 60 than in men of a similar age, but no differences among older age groups. 25 Exclusion of fatal MI may be partly responsible for their results, as MI mortality has been found to be higher in women than in men with diabetes. 26 Deterioration in cardiovascular risk factor levels among those with and without type 2 diabetes is greater in women than in men; therefore women with diabetes are at a disadvantage compared with men, even before their diagnosis. 27 Additionally, in the UK women with diabetes are 15% less likely than men with diabetes to meet all recommended care requirements, and might be less likely to achieve target values for treated cardiovascular risk factors. 28 29 30 The cumulative effects of these disadvantages among women throughout the trajectory of disease could explain some of the excess relative risk.

Can women “catch up” with men?

An interesting question is under what conditions would rates of MI in men and women be the same? The answer depends on many factors, including the prevalence of the risk factors for MI (see supplementary appendix). In the UK Biobank the rates of MI per 10 000 person years in women with hypertension (AHA stage 1 or 2) and diabetes (type 1 or 2) who were also current smokers was 41.76 (95% confidence interval 25.58 to 68.12) compared with 53.68 (39.95 to 72.13) in men. So even in this extreme group, defined only by risk factors for which relative risks in women exceed those in men, in our study population men still have higher rates of MI. Furthermore, few women (0.2%) and men (0.6%) had this combination of risk factors and their contribution to the overall rate of MI is inevitably small. It would take an enormous increase in the prevalence of all three risk factors for this subgroup to have even a moderate impact on the overall risk of MI in the future.

Conclusions and policy implications

Although the risk of MI is, on average, about three times higher in men than women, women tend to “catch up” to some extent if they have certain cardiovascular risk factors. Our findings suggest that clinicians should be vigilant when their female patients are elderly, smoke, have diabetes, or have high blood pressure. These findings also highlight the importance of equitable access to guideline based treatments for diabetes and hypertension, and to weight loss and smoking cessation programmes for women and men in middle and older age.

Despite the rate of MI being higher in men than women, hypertension, smoking (especially higher intensity), and type 1 and 2 diabetes confer a greater excess risk of MI in women than in men. This excess risk does not attenuate with age. In addition, a rising prevalence of lifestyle associated risk factors, coupled with the ageing population, is likely to result in women having a more similar overall rate of MI to men in the future, with a major additional burden on society and health resources.

What is already known on this topic

The incidence of myocardial infarction (MI) is lower in women than in men at younger ages, but the incidence becomes more similar with increasing age

Meta-analyses have shown sex differences in the association between several risk factors and MI, but the studies included had varying levels of adjustment for confounders and could not examine sex differences by age group

What this study adds

Hypertension, smoking, and diabetes were associated with an increased risk of MI in women and men, but with an excess relative risk in women

Although the sex specific associations between these risk factors and MI attenuated with age, the excess relative risk of MI in women did not

Women and men should receive the same access to guideline based treatments for diabetes and hypertension, and to resources to help them lose weight and stop smoking

Acknowledgments

This research has been conducted using the UK Biobank Resource (application No 2495). Permission to use the UK Biobank Resource was approved by the access subcommittee of the UK Biobank Board.

Contributors: All authors were involved in the design of the study. ERCM carried out the statistical analyses and wrote the first draft of the paper, with support from SAEP and MW. All authors contributed to further drafts and approved the final manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. ERCM is the guarantor.

Funding: SAEP is supported by a UK Medical Research Council skills development fellowship (MR/P014550/1). MW is supported by a National Health and Medical Research Council fellowship (APP108026). The funding sources had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; MW does consultancy for Amgen outside the submitted work; no other relationships or activities that could appear to have influenced the submitted work.

Ethical approval: UK Biobank has obtained Research Tissue Bank approval from its governing research ethics committee, as recommended by the National Research Ethics Service. No separate ethical approval was required. The study was conducted in accordance with the principles of the Declaration of Helsinki.

Data sharing: Researchers can apply to use the UK Biobank resource and access the data used. No additional data are available.

Transparency: The manuscript’s guarantor (ERCM) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/ .

• ↵ World Health Organization. Top 10 causes of death worldwide Geneva: WHO; 2017. www.who.int/mediacentre/factsheets/fs310/en/ .
• ↵ Institute for Health Metrics and Evaluation. GBD Compare Data Visualization Seattle, WA: IHME, University of Washington; 2016. https://vizhub.healthdata.org/gbd-compare/ .
• Naghavi M ,
• Abajobir AA ,
• Abbafati C ,
• GBD 2016 Causes of Death Collaborators
• Peters SAE ,
• Rosengren A ,
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Acute Myocardial Infarction (MI)

, MD, MS, Northwestern University Feinberg School of Medicine;

, MD, PhD, Northwestern University Feinberg School of Medicine

• Pathophysiology
• Symptoms and Signs
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Acute myocardial infarction is myocardial necrosis resulting from acute obstruction of a coronary artery. Symptoms include chest discomfort with or without dyspnea, nausea, and/or diaphoresis. Diagnosis is by electrocardiography (ECG) and the presence or absence of biomarkers. Treatment is with antiplatelets, anticoagulants, nitrates, beta-blockers, statins, and reperfusion therapy. For ST-segment-elevation myocardial infarction, emergency reperfusion is via fibrinolytic drugs, percutaneous intervention, or, occasionally, coronary artery bypass graft surgery. For non–ST-segment-elevation myocardial infarction, reperfusion is via percutaneous intervention or coronary artery bypass graft surgery.

(See also Overview of Acute Coronary Syndromes Overview of Acute Coronary Syndromes (ACS) Acute coronary syndromes result from acute obstruction of a coronary artery. Consequences depend on degree and location of obstruction and range from unstable angina to non–ST-segment elevation... read more .)

Acute MI, along with unstable angina, is considered an acute coronary syndrome Overview of Acute Coronary Syndromes (ACS) Acute coronary syndromes result from acute obstruction of a coronary artery. Consequences depend on degree and location of obstruction and range from unstable angina to non–ST-segment elevation... read more . Acute MI includes both non–ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). Distinction between NSTEMI and STEMI is vital as treatment strategies are different for these two entities.

General reference

1. Benjamin EJ, Virani SS, Callaway CW, et al . Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association [published correction appears in Circulation 2018 Mar 20;137(12 ):e493]. Circulation 2018;137(12):e67-e492. doi:10.1161/CIR.0000000000000558

Pathophysiology of Acute MI

Symptoms of ischemia

ECG changes indicative of new ischemia (significant ST/T changes or left bundle branch block Bundle Branch Block and Fascicular Block Bundle branch block is partial or complete interruption of impulse conduction in a bundle branch; fascicular block is similar interruption in a hemifascicle of the left bundle. The disorders... read more )

Development of pathologic Q waves

Imaging evidence of new loss of myocardium or new regional wall motion abnormality

Angiography or autopsy evidence of intracoronary thrombus

Slightly different criteria are used to diagnose MI during and after percutaneous coronary intervention or coronary artery bypass grafting, and as the cause of sudden death.

Type 1: Spontaneous MI caused by ischemia due to a primary coronary event (eg, plaque rupture, erosion, or fissuring; coronary dissection)

Type 2: Ischemia due to increased oxygen demand (eg, hypertension), or decreased supply (eg, coronary artery spasm or embolism, arrhythmia, hypotension)

Type 3: Related to sudden unexpected cardiac death

Type 4a: Associated with percutaneous coronary intervention (signs and symptoms of myocardial infarction with cTn values > 5 × 99th percentile URL)

Type 4b: Associated with documented stent thrombosis

Type 5: Associated with coronary artery bypass grafting (signs and symptoms of myocardial infarction with cTn values > 10 × 99th percentile URL)

Infarct location

MI affects predominantly the left ventricle (LV), but damage may extend into the right ventricle (RV) or the atria.

Right ventricular infarction usually results from obstruction of the right coronary or a dominant left circumflex artery; it is characterized by high RV filling pressure, often with severe tricuspid regurgitation Tricuspid Regurgitation Tricuspid regurgitation (TR) is insufficiency of the tricuspid valve causing blood flow from the right ventricle to the right atrium during systole. The most common cause is dilation of the... read more and reduced cardiac output.

Anterior infarcts tend to be larger and result in a worse prognosis than inferoposterior infarcts. They are usually due to left coronary artery obstruction, especially in the anterior descending artery; inferoposterior infarcts reflect right coronary or dominant left circumflex artery obstruction.

Infarct extent

Infarction may be

Nontransmural

Transmural infarcts involve the whole thickness of myocardium from epicardium to endocardium and are usually characterized by abnormal Q waves on ECG.

Nontransmural (including subendocardial) infarcts do not extend through the ventricular wall and cause only ST-segment and T-wave (ST-T) abnormalities. Subendocardial infarcts usually involve the inner one third of myocardium, where wall tension is highest and myocardial blood flow is most vulnerable to circulatory changes. These infarcts may follow prolonged hypotension.

Because the transmural depth of necrosis cannot be precisely determined clinically, infarcts are usually classified as STEMI or NSTEMI by the presence or absence of ST-segment elevation or Q waves on the ECG. Volume of myocardium destroyed can be roughly estimated by the extent and duration of creatine kinase (CK-MB) elevation or by peak levels of more commonly measured cardiac troponins.

Non–ST-segment elevation myocardial infarction (NSTEMI, subendocardial MI) is myocardial necrosis (evidenced by cardiac biomarkers Cardiac biomarkers Acute coronary syndromes result from acute obstruction of a coronary artery. Consequences depend on degree and location of obstruction and range from unstable angina to non–ST-segment elevation... read more in blood; troponin I or troponin T and CK-MB will be elevated) without acute ST-segment elevation. ECG changes such as ST-segment depression, T-wave inversion, or both may be present.

ST-segment elevation myocardial infarction (STEMI, transmural MI) is myocardial necrosis with ECG changes showing ST-segment elevation that is not quickly reversed by nitroglycerin . Troponin I or troponin T and CK-MB are elevated.

Myocardial infarction in the absence of coronary artery disease (MINOCA)

Pathophysiology references.

1. Thygesen K, Alpert JS, Jaffe AS, et al : Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol 72(18):2231–2264, 2018. doi:10.1016/j.jacc.2018.08.1038

2. Mehta SR, Eikelboom JW, Natarajan MK, et al . Impact of right ventricular involvement on mortality and morbidity in patients with inferior myocardial infarction. J Am Coll Cardiol 37(1):37–43, 2001. doi:10.1016/s0735-1097(00)01089-5

3. Tamis-Holland JE, Jneid H, Reynolds HR, et al : Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease: A scientific statement from the American Heart Association. Circulation 139:e891–e908, 2019. doi.org/10.1161/CIR.0000000000000670

Symptoms and Signs of Acute MI

Symptoms of NSTEMI and STEMI are the same. Days to weeks before the event, about two thirds of patients experience prodromal symptoms, including unstable or crescendo angina Unstable Angina Unstable angina results from acute obstruction of a coronary artery without myocardial infarction. Symptoms include chest discomfort with or without dyspnea, nausea, and diaphoresis. Diagnosis... read more , dyspnea, and fatigue.

Usually, the first symptom of infarction is deep, substernal, visceral pain, described as aching or pressure, often radiating to the back, jaw, left arm, right arm, shoulders, or all of these areas. The pain is similar to angina pectoris Symptoms and Signs Angina pectoris is a clinical syndrome of precordial discomfort or pressure due to transient myocardial ischemia without infarction. It is typically precipitated by exertion or psychologic stress... read more but is usually more severe and long-lasting; more often accompanied by dyspnea, diaphoresis, nausea, and/or vomiting; and relieved little or only temporarily by rest or nitroglycerin .

Some patients present with syncope.

In severe ischemic episodes, the patient often has significant pain and feels restless and apprehensive. Nausea and vomiting may occur, especially with inferior MI. Dyspnea and weakness due to LV failure, pulmonary edema, shock, or significant arrhythmia may dominate.

Skin may be pale, cool, and diaphoretic. Peripheral or central cyanosis may be present. Pulse may be thready, and blood pressure is variable, although many patients initially have some degree of hypertension during pain.

Symptoms and signs references

1. Parmley WW . Prevalence and clinical significance of silent myocardial ischemia. Circulation 1989;80(6 Suppl):IV68-IV73.

2. Lichtman JH, Leifheit EC, Safdar B, et al . Sex Differences in the Presentation and Perception of Symptoms Among Young Patients With Myocardial Infarction: Evidence from the VIRGO Study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients). Circulation 2018;137(8):781-790. doi:10.1161/CIRCULATIONAHA.117.031650

Diagnosis of Acute MI

Serial ECGs

Serial cardiac biomarkers

Immediate coronary angiography (unless fibrinolytics are given) for patients with STEMI or complications (eg, persistent chest pain, hypotension, markedly elevated cardiac biomarkers, unstable arrhythmias)

Delayed coronary angiography (within 24 to 48 hours) for patients with NSTEMI without complications

(See also algorithm .)

Evaluation begins with initial and serial ECG and serial measurements of cardiac biomarkers Cardiac biomarkers Acute coronary syndromes result from acute obstruction of a coronary artery. Consequences depend on degree and location of obstruction and range from unstable angina to non–ST-segment elevation... read more to help distinguish between unstable angina Unstable Angina Unstable angina results from acute obstruction of a coronary artery without myocardial infarction. Symptoms include chest discomfort with or without dyspnea, nausea, and diaphoresis. Diagnosis... read more , ST-segment elevation myocardial infarction (STEMI), and non–ST-segment elevation myocardial infarction (NSTEMI). This distinction is the center of the decision pathway because fibrinolytics Fibrinolytics Treatment of acute coronary syndromes (ACS) is designed to relieve distress, interrupt thrombosis, reverse ischemia, limit infarct size, reduce cardiac workload, and prevent and treat complications... read more benefit patients with STEMI but may increase risk for those with NSTEMI. Also, urgent cardiac catheterization is indicated for patients with acute STEMI but not generally for those with NSTEMI.

ECG Electrocardiography The standard electrocardiogram (ECG) provides 12 different vector views of the heart’s electrical activity as reflected by electrical potential differences between positive and negative electrodes... read more is the most important test and should be done as soon as possible (eg, within 10 minutes of presentation).

For STEMI, initial ECG is usually diagnostic, showing ST-segment elevation ≥ 1 mm in 2 or more contiguous leads subtending the damaged area (see figures , , , , , and ).

Acute Lateral Left ventricular Infarction (tracing obtained within a few hours of onset of illness)

Lateral left ventricular infarction (after the first 24 hours), lateral left ventricular infarction (several days later), acute inferior (diaphragmatic) left ventricular infarction (tracing obtained within a few hours of onset of illness), inferior (diaphragmatic) left ventricular infarction (after the first 24 hours), inferior (diaphragmatic) left ventricular infarction (several days later).

Pathologic Q waves are not necessary for the diagnosis. The ECG must be read carefully because ST-segment elevation may be subtle, particularly in the inferior leads (II, III, aVF); sometimes the reader’s attention is mistakenly focused on leads with ST-segment depression. If symptoms are characteristic, ST-segment elevation on ECG has a specificity of 90% and a sensitivity of 45% for diagnosing myocardial infarction. Serial tracings (obtained every 8 hours for 1 day, then daily) showing a gradual evolution toward a stable, more normal pattern or development of abnormal Q waves over a few days tends to confirm the diagnosis.

If right ventricular (RV) infarction is suspected, a 15-lead ECG is usually recorded; additional leads are placed at V4-6R (see figure ), and, to detect posterior infarction, V8 and V9.

Right Ventricular (VR) Leads VR1 Through VR6

ECG diagnosis of MI is more difficult when a left bundle branch block configuration is present because it resembles STEMI changes. ST-segment elevation concordant with the QRS complex strongly suggests MI as does > 5-mm ST-segment elevation in at least 2 precordial leads. But generally, any patient with suggestive symptoms and new-onset (or not known to be old) left bundle branch block is treated as for STEMI.

Cardiac biomarkers

Cardiac biomarkers (serum biomarkers of myocardial cell injury) are

Cardiac enzymes (eg, CK-MB [creatine kinase MB isoenzyme])

Cell contents (eg, troponin I, troponin T, myoglobin)

These biomarkers are released into the bloodstream after myocardial cell necrosis. The biomarkers appear at different times after injury, and levels decrease at different rates. Sensitivity and specificity for myocardial cell injury vary significantly among these biomarkers. Assays that measure cardiac troponins (cTn), which have been in use for many years, are sensitive and specific. Newer, highly sensitive assays of cardiac troponin (hs-cTn) that are also very precise are preferred. These assays can reliably measure cTn levels (T or I) as low as 0.003 to 0.006 ng/mL (3 to 6 pg/mL); some research assays go as low as 0.001 ng/mL (1 pg/mL).

The less sensitive cTn tests were unlikely to detect cardiac troponins except in patients who had an acute cardiac disorder. Thus, a "positive" cTn test (ie, above the limit of detection) was very specific. However, hs-cTn tests can detect small amounts of troponin in many healthy people. Thus, troponin levels detected with hs-cTn tests need to be referenced to the normal range, and are defined as "elevated" only when higher than 99% of the reference population. Furthermore, although an elevated troponin level indicates myocardial cell injury, it does not indicate the cause of the damage (although any troponin elevation increases the risk of adverse outcomes in many disorders). In addition to acute coronary syndromes, many other cardiac and non-cardiac disorders can elevate cardiac troponin levels (see table ); not all elevated levels detected with hs-cTn represent myocardial infarction, and not all myocardial necrosis results from an acute coronary syndrome event even when the etiology is ischemic. However, by detecting lower levels of troponin, hs-cTn assays enable earlier identification of MI than other assays, and have replaced other cardiac biomarker tests in many centers.

Patients suspected of having a myocardial infarction should have a hs-cTn assay done on presentation and 2 to 3 hours later. Troponin should be measured at 0 and 6 hours if a standard cTn assay is used.

All laboratory tests should be interpreted in the context of the pre-test disease probability (see also Understanding Medical Tests and Test Results Likelihood ratios (LRs) Test results may help make a diagnosis in symptomatic patients (diagnostic testing) or identify occult disease in asymptomatic patients (screening). If the tests were appropriately ordered on... read more ). This is especially relevant for the hs-cTn assay, given the very high sensitivity of this test, but applies to all assays of cTn.

An hs-cTn assay must be interpreted based on the patient's pre-test probability of disease, which is estimated clinically based on:

Risk factors for ACS

Coronary angiography

After initial evaluation and therapy, coronary angiography may be used in patients with evidence of ongoing ischemia (ECG findings or symptoms), hemodynamic instability, recurrent ventricular tachyarrhythmias, and other abnormalities that suggest recurrence of ischemic events. Some experts also recommend that angiography be done before hospital discharge in patients with STEMI who have inducible ischemia on stress imaging or an ejection fraction < 40%.

Diagnosis reference

1. Badertscher P, Boeddinghaus J, Nestelberger T, et al . Effect of Acute Coronary Syndrome Probability on Diagnostic and Prognostic Performance of High-Sensitivity Cardiac Troponin. Clin Chem 2018;64(3):515-525. doi:10.1373/clinchem.2017.279513

Treatment of Acute MI

Prehospital care: Oxygen, aspirin , nitrates, and triage to an appropriate medical center

Pharmacologic therapy: Antiplatelet agents, antianginal drugs, anticoagulants, and in some cases other medications

Reperfusion therapy: Fibrinolytics or angiography with percutaneous coronary intervention or coronary artery bypass surgery

Post-discharge rehabilitation and chronic medical management of coronary artery disease

Choice of pharmacologic therapy Medications for Acute Coronary Syndromes Treatment of acute coronary syndromes (ACS) is designed to relieve distress, interrupt thrombosis, reverse ischemia, limit infarct size, reduce cardiac workload, and prevent and treat complications... read more and choice of reperfusion strategy Overview of Revascularization for Acute Coronary Syndromes Revascularization is the restoration of blood supply to ischemic myocardium in an effort to limit ongoing damage, reduce ventricular irritability, and improve short-term and long-term outcomes... read more are discussed elsewhere.

Prehospital care

Triage to appropriate medical center

A reliable IV route must be established, oxygen given (typically 2 L by nasal cannula), and continuous single-lead ECG monitoring started. Prehospital interventions by emergency medical personnel (including ECG, chewed aspirin [160 to 325 mg], and pain management with nitrates) can reduce risk of mortality and complications. Early diagnostic data and response to treatment can help determine the need for and timing of revascularization Overview of Revascularization for Acute Coronary Syndromes Revascularization is the restoration of blood supply to ischemic myocardium in an effort to limit ongoing damage, reduce ventricular irritability, and improve short-term and long-term outcomes... read more .

Hospital admission

Risk-stratify patient and choose reperfusion strategy

Pharmacologic therapy with antiplatelets, anticoagulants and other medications based on reperfusion strategy

On arrival to the emergency department, the patient's diagnosis is confirmed. Pharmacologic therapy and timing of revascularization depend on the clinical picture and diagnosis.

For STEMI, reperfusion strategy can include fibrinolytic therapy or immediate PCI. For patients with NSTEMI, angiography may be done within 24 to 48 hours of admission if the patient is clinically stable. If the patient is unstable (eg, ongoing symptoms, hypotension, or sustained arrhythmias), then angiography must be done immediately (see figure ).

Approach to Myocardial Infarction

Pharmacologic treatment of acute myocardial infarction.

All patients should be given antiplatelet agents Antiplatelet Agents Treatment of acute coronary syndromes (ACS) is designed to relieve distress, interrupt thrombosis, reverse ischemia, limit infarct size, reduce cardiac workload, and prevent and treat complications... read more , anticoagulants Anticoagulant Agents Treatment of acute coronary syndromes (ACS) is designed to relieve distress, interrupt thrombosis, reverse ischemia, limit infarct size, reduce cardiac workload, and prevent and treat complications... read more , and if chest pain is present, antianginal drugs. The specific medications used depend on the reperfusion strategy and other factors; their selection and use is discussed in Medications for Acute Coronary Syndrome Medications for Acute Coronary Syndromes Treatment of acute coronary syndromes (ACS) is designed to relieve distress, interrupt thrombosis, reverse ischemia, limit infarct size, reduce cardiac workload, and prevent and treat complications... read more . Other medications, such as beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and statins, should also be given (see table ).

Patients with acute myocardial infarction should be given the following (unless contraindicated):

Antiplatelet agents Antiplatelet Agents Treatment of acute coronary syndromes (ACS) is designed to relieve distress, interrupt thrombosis, reverse ischemia, limit infarct size, reduce cardiac workload, and prevent and treat complications... read more : Aspirin , clopidogrel , or both ( prasugrel or ticagrelor are alternatives to clopidogrel )

Anticoagulants Anticoagulant Agents Treatment of acute coronary syndromes (ACS) is designed to relieve distress, interrupt thrombosis, reverse ischemia, limit infarct size, reduce cardiac workload, and prevent and treat complications... read more : A heparin (unfractionated or low molecular weight heparin ) or bivalirudin

Glycoprotein IIb/IIIa inhibitor when PCI is done

Antianginal therapy usually nitroglycerin

Beta-blocker

ACE inhibitor

All patients are given aspirin 160 to 325 mg (not enteric-coated), if not contraindicated, at presentation and 81 mg once a day indefinitely thereafter. Chewing the first dose before swallowing quickens absorption. Aspirin reduces short-term and long-term mortality risk.

In patients undergoing PCI, a loading dose of clopidogrel (300 to 600 mg orally once), prasugrel (60 mg orally once), or ticagrelor (180 mg orally once) improves outcomes, particularly when administered 24 hours in advance. For urgent PCI, prasugrel and ticagrelor are more rapid in onset and may be preferred.

Either a low molecular weight heparin (LMWH), unfractionated heparin , or bivalirudin is given routinely to patients unless contraindicated (eg, by active bleeding). Unfractionated heparin is more complicated to use because it requires frequent (every 6 hours) dosing adjustments to achieve target activated partial thromboplastin time (aPTT). The LMWHs have better bioavailability, are given by simple weight-based dose without monitoring aPTT and dose titration, and have lower risk of heparin -induced thrombocytopenia Heparin-induced thrombocytopenia Platelet destruction can develop because of immunologic causes (viral infection, drugs, connective tissue or lymphoproliferative disorders, blood transfusions) or nonimmunologic causes (sepsis... read more . Bivalirudin is recommended for patients with a known or suspected history of heparin -induced thrombocytopenia Anticoagulants are continued for:

Duration of PCI in patients undergoing this procedure

Duration of hospital stay (in patients on LMWH) or 48 hours (in patients on unfractionated heparin ) in all other cases

Consider a glycoprotein IIb/IIIa inhibitor during PCI for patients with high-risk lesions (high thrombus burden, no reflow). Abciximab , tirofiban , and eptifibatide appear to have equivalent efficacy, and the choice of drug should depend on other factors (eg, cost, availability, familiarity). Glycoprotein IIb/IIIa inhibitors are continued for 6 to 24 hours.

Reperfusion therapy in acute myocardial infarction

For patients with STEMI: Immediate percutaneous coronary intervention or fibrinolytics

For patients with NSTEMI: Immediate percutaneous coronary intervention for unstable patients or within 24 to 48 hours for stable patients

Patients with unstable NSTEMI (ie, those with ongoing symptoms, hypotension, or sustained arrhythmias) should be taken directly to the cardiac catheterization laboratory to identify coronary lesions requiring PCI or coronary artery bypass grafting (CABG).

For patients with uncomplicated NSTEMI, reperfusion is not as urgent because a completely occluded infarct-related artery at presentation is uncommon. Such patients typically undergo angiography within the first 24 to 48 hours of hospitalization to identify coronary lesions requiring PCI or CABG.

Fibrinolytics are not indicated for any patients with NSTEMI. Risk outweighs potential benefit.

Choice of reperfusion strategy is further discussed in Revascularization for Acute Coronary Syndromes Overview of Revascularization for Acute Coronary Syndromes Revascularization is the restoration of blood supply to ischemic myocardium in an effort to limit ongoing damage, reduce ventricular irritability, and improve short-term and long-term outcomes... read more .

Rehabilitation and post-discharge treatment

Functional evaluation

Changes in lifestyle: Regular exercise, diet modification, weight loss, smoking cessation

Medications: Continuation of antiplatelet agents, beta-blockers, ACE inhibitors, and statins

Patients who did not have coronary angiography during admission, have no high-risk features (eg, heart failure, recurrent angina, ventricular tachycardia or ventricular fibrillation after 24 hours, mechanical complications such as new murmurs, shock), and have an ejection fraction > 40% whether or not they received fibrinolytics usually should have stress testing of some sort before or shortly after discharge (see table ).

Functional Evaluation After Myocardial Infarction

The acute illness and treatment of myocardial infarction should be used to strongly motivate the patient to modify risk factors. Evaluating the patient’s physical and emotional status and discussing them with the patient, advising about lifestyle (eg, smoking, diet, work and play habits, exercise), and aggressively managing risk factors may improve prognosis.

On discharge, all patients should be on appropriate antiplatelet agents, statins, antianginals, and other medications based on comorbidities.

Treatment references

1. Meine TJ, Roe MT, Chen AY, et al : Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. Am Heart J 149(6):1043–1049, 2005. doi 10.1016/j.ahj.2005.02.010

2. Kubica J, Adamski P, Ostrowska M, et al : Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J 37(3):245–252, 2016. doi: 10.1093/eurheartj/ehv547

3. Wang WT, Hellkamp A, Doll JA, et al . Lipid Testing and Statin Dosing After Acute Myocardial Infarction. J Am Heart Assoc. 2018;7(3):e006460. Published 2018 Jan 25. doi:10.1161/JAHA.117.006460

4. Lawton JS, Tamis-Holland JE, Bangalore S, et al : 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the ACC/AHA Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 79(2):e21–e129, 2022. doi: 10.1016/j.jacc.2021.09.006

Prognosis for Acute MI

Risk should be estimated via formal clinical risk scores (eg, Thrombosis in Myocardial Infarction [TIMI]—see tables and ) or a combination of the following high-risk features:

Recurrent angina/ischemia at rest or during low-level activity

Heart failure

Worsening mitral regurgitation

High-risk stress test result (test stopped in ≤ 5 minutes due to symptoms, marked ECG abnormalities, hypotension, or complex ventricular arrhythmias)

Hemodynamic instability

Sustained ventricular tachycardia

Diabetes mellitus

PCI within past 6 months

Prior coronary artery bypass grafting (CABG)

LV ejection fraction < 0.40

Mortality rates tend to be higher in females and in patients with diabetes.

Most fatalities among patients who survive initial hospitalization occur in the first 3 to 4 months. Persistent ventricular arrhythmia, heart failure, poor ventricular function, and recurrent ischemia indicate high risk. Many authorities recommend stress ECG before hospital discharge or within 6 weeks of MI. Good exercise performance without ECG abnormalities is associated with a favorable prognosis; further evaluation is usually not required. Poor exercise performance is associated with a poor prognosis.

Cardiac performance after recovery depends largely on how much functioning myocardium survives the acute attack. Acute damage adds to scars from previous infarcts. When left ventricular dysfunction is significant, long term survival is lower.

Prognosis references

1. De Luca G, van 't Hof AW, de Boer MJ, et al . Impaired myocardial perfusion is a major explanation of the poor outcome observed in patients undergoing primary angioplasty for ST-segment-elevation myocardial infarction and signs of heart failure. Circulation 2004;109(8):958-961. doi:10.1161/01.CIR.0000120504.31457.28

2. Roe MT, Messenger JC, Weintraub WS, et al . Treatments, trends, and outcomes of acute myocardial infarction and percutaneous coronary intervention. J Am Coll Cardiol. 2010;56(4):254-263. doi:10.1016/j.jacc.2010.05.008

Acute myocardial infarction (MI) is myocardial necrosis resulting from acute obstruction of a coronary artery.

Symptoms of acute myocardial infarction include chest pain or discomfort with or without dyspnea, nausea, and/or diaphoresis.

Women and patients with diabetes are more likely to present with atypical symptoms, and 20% of acute MI are silent.

Diagnosis is by ECG and cardiac biomarkers.

Immediate treatment includes oxygen, antianginals, antiplatelets, and anticoagulants.

For patients with ST-segment elevation MI, do immediate angiography with percutaneous coronary intervention (PCI); if immediate PCI is not available, give fibrinolytics.

For patients with non–ST-segment elevation MI who are stable, do angiography within 24 to 48 hours; for those who are unstable, do immediate angiography with PCI.

Following recovery, initiate or continue antiplatelets, beta-blockers, angiotensin-converting enzyme inhibitors, and statins.

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Myocardial Infarction and Older Women

LaKeisha Williams, PharmD, MSPH Clinical Assistant Professor

Ellen McKnight PharmD Candidate 2017

Christopher Gillard, PharmD, BCPS Clinical Assistant Professor Xavier University of Louisiana College of Pharmacy New Orleans, Louisiana

US Pharm. 2016;41(9)44-47. ​ ABSTRACT: Myocardial infarction (MI), a major cause of cardiovascular disease morbidity and mortality, affects approximately 2.7 million women in the United States. Due to an increased prevalence rate of MI among older women and women of minority populations, differences between men and women regarding the management of MI should be considered. Women tend to experience atypical symptoms of MI and are often misdiagnosed or diagnosed too late, due to physiologic differences in a woman’s heart that may pose a challenge to clinicians. Identifying sex differences in the etiology, epidemiology, and pathophysiology of MI can assist healthcare providers in developing individualized action plans for women with MI. Overall, the management of MI encompasses a multidisciplinary team approach that necessitates effort from the patient, provider, family, and healthcare system.

M yocardial infarction (MI), also known as a heart attack, is a major cause of morbidity and mortality. Although overall mortality rates are trending down, coronary heart disease (CHD) currently affects approximately 6.6 million women in the United States. Of this population, 2.7 million have a history of MI. 1 Prevalence rates of MI have been reported to be higher among older women and women of minority populations. 2 Mehta et al state that black women have a higher prevalence of acute MI compared with other women, including higher rates of sudden cardiac death. Asian Indian women have higher mortality rates, which may be associated with higher rates of cardiovascular disease (CVD) risk factors. 3 Differences in the management and treatment of MI in men and women may be associated with the rates of morbidity and mortality related to cardiovascular events. Therefore, when managing the cardiovascular health of women, it is important to take into account the significant differences between men and women regarding the epidemiology, risk factors, diagnosis, treatment, and prognosis of CHD. 4,5

Epidemiology of MI in Women

CHD, including MI, continues to be the leading cause of death among women in the U.S. 2 Although the prevalence of CHD increases with age for women and men, the incidence of MI in women increases dramatically following menopause, with rates 3 times those of women the same age who remain premenopausal. 6-8 Data from 44 years of follow-up in the original Framingham Study cohort shows that the incidence of MI at ages 65 to 94 years compared with ages 35 to 64 years more than doubles in men and triples in women, respectively. 7 Depending on clinical outcome and prognosis, women > 65 years have a higher risk of death within one year after a first MI compared with younger women. 2

Cardiovascular Risk Factors in Women

There are various risk calculators and estimators available to assess cardiovascular risk. Risk calculators such as the Reynolds or Framingham Risk Scores can assist providers in predicting a woman’s risk of developing CVD,  MI, or stroke in the future. The Framingham risk calculator, which utilizes information from the Framingham Heart Study, is designed for adults > 20 years who do not have a history of heart disease or diabetes. 9 A person’s age, gender, cholesterol, smoking status, and blood pressure (BP) reading are required in order to assess risk. The Reynolds Risk Score is slightly different from the Framingham tool in that in addition to obtaining a person’s age, BP, cholesterol, and smoking status, it uses a person’s high-sensitivity C-reactive protein (hsCRP) levels to measure inflammation. 10 The tool also assesses a person’s genetic risk by asking the question, “Did your mother or father have a heart attack before age 60?” 10 The use of additional biomarkers such as hsCRP may be more useful in women, especially if specific risk factors are unclear. 10

There are several cardiovascular risk factors that women have in common with men: age, family history, comorbid conditions, cigarette smoking, and other lifestyle factors. 6 However, researchers have noted several differences in risk factors between women and men. Several studies have found that the impact of smoking is larger in women than in men. 11-13 In the Tromsø study, the incidence of an MI was 18.3% in women > 68 years (n=453; hazard ratio [HR]=2.5 [1.9-3.2] who actively smoked 10-19 cigarettes per day compared with 21.2% in men > 60.7 years (n=769; HR=1.9 [1.5-2.4]). 12 Negative cardiovascular effects associated with MI have also been found in passive smokers, or in non-smokers who involuntarily inhale cigarette smoke. The INTERHEART study showed that passive smoking accounted for 10.8% of MIs in women who had never smoked cigarettes; Iversen et al reported that there was a 52.1% incidence of MI among women > 68 years versus an incidence of 36.2% among men > 60.7 years who lived with a smoker > 30 years. 12,14 However, most of the increased risk of CVD events is drastically reduced within two to three years of smoking cessation. 15

Hip fracture surgery in elderly women has been linked with an increased risk of MI, known as perioperative MI (PMI). PMI often remains unrecognized, and mortality is higher in elderly women. PMI symptoms are often masked by analgesia, sedation, and transient and subtle ECG changes. Gupta et al, in a cohort study of 1,212 elderly patients, found that PMI is associated with a 15-fold increased risk of in-hospital death and a 4.3-fold increased risk of 30-day mortality in the elderly. Measurement of the cardiac biomarker troponin can promote the early detection of a silent PMI in postoperative elderly women and can decrease PMI-associated short- and long-term mortality in this population. 16  

Postmenopausal status has been associated with an increased risk of CHD; however, there have been conflicting views on whether surgical or natural menopause affects cardiovascular risk. 6,17,18 The Women’s Health Initiative trial found that predominantly healthy women who took estrogen plus progestin oral contraceptives experienced a 29% increase in CHD events compared to placebo; CHD events were defined as an acute MI requiring overnight hospitalization, silent MI diagnosed with an electrocardiogram (ECG), or CHD death. 19 It is important to note that hormone replacement therapy is not recommended for CHD prevention. 6

A history of pregnancy complications, such as gestational hypertension and diabetes, preeclampsia, and spontaneous pregnancy loss, has been associated with an increased future risk of CVD. 6,20,21 Additional risk factors for CHD are shown in Table 1 .

Clinical Presentation of MI in Women

Prompt recognition of symptoms is the first step in managing women patients with CHD. 22 Patients may present with chest pain, MI, heart failure, or sudden cardiac death. At the time of presentation, women are generally older than men. Women may not recognize initial symptoms of heart disease and, therefore, may not seek immediate medical attention. 5,23-26 Studies report that providers may not even evaluate symptoms of myocardial ischemia as early in women as they do in men owing to misdiagnosis, atypical symptoms, comorbidities, or underestimation of risk factors. 26-28 Differences in acute MI pathophysiology have also been noted between women and men. Men have higher rates of plaque rupture in the setting of acute MI, while plaque erosion is more common in women compared to men. 3

Although chest pain is one of the most common symptoms of an MI, the symptoms of women may be subtler than those of men and can sometimes be confusing. Women can experience an MI without chest pressure, and may instead experience shortness of breath, pressure or pain in the lower chest or upper abdomen, sweating, dizziness, lightheadedness or fainting, upper back pressure, nausea, or extreme fatigue. 2,29 It is often more common for women to attribute the symptoms of MI to less life-threatening conditions, such as acid reflux, influenza, and normal aging. 29 Also, women presenting with a first symptomatic MI, according to a report by Wilson and Douglas, are “more likely to have a history of diabetes, hypertension, hyperlipidemia, heart failure, and an unstable angina pattern than their male counterpart.” 7

Morphologic Differences in the Female Heart

Morphologic differences in the female heart may contribute to disparities in the diagnosis, treatment and prognosis of MI and other cardiovascular events among women. Westerman and Wenger report a longer QT interval and a faster resting heart rate in women, which may be attributed to the smaller size of the female heart and differences in hormones and autonomic tone. According to the authors, the hormones estrogen and progesterone are both present in cardiac myocytes, which may be associated with the QT interval length and cardiovascular event risk. Furthermore, differences in the heart’s anatomic structures among women may cause increased surgical risks and an increase in the prevalence of heart-valve disorders. Surgical procedures such as angioplasty and stenting may not be as effective in women compared to men due to variations of arterial plaque build-up. Women are more likely to experience diastolic dysfunction of the heart, which may pose additional treatment challenges. 30

Treatment Considerations for Women

There are several therapeutic agents available for the management of CHD. Treatment goals for acute coronary syndromes are aimed at relieving symptoms, preventing future secondary myocardial events, and preventing sudden cardiac death. 31,32 Acute management therapies, including nitroglycerin and supplemental oxygen, are aimed at symptom control and restoring oxygen supply and demand in MI. 31,32 Immediate antiplatelet therapy with aspirin has been shown to reduce mortality after an acute coronary event. 33 Additionally, aspirin as secondary prevention has been proven to reduce recurrent ischemia in both men and women similarly in clinical trials. 33,34

Regarding adverse effects, female patients usually have higher rates of bleeding from antiplatelets and thrombolytic drugs. The standards of care identify female sex as a risk factor for bleeding complications after an ST-elevated MI (STEMI). 32 However, weight- and kidney-function monitoring may be beneficial in lowering the bleeding risk among women. 3

Beta-receptor antagonists (beta-blockers) have been shown to reduce the rate of death from MI by reducing myocardial oxygen demand during periods of physical and mental stress and assisting in prevention of recurrent ischemia and life-threatening ventricular arrhythmias. 35 However, a study in 2005 by Blomkalns et al demonstrated that among female patients, beta-blockers were actually less likely to be administered compared to males presenting with MI. 36 Statins were also less likely to be administered for treatment of MI in women. 5,37 ACE inhibitors have been shown to be beneficial after an acute MI in several studies; however, their efficacy in women has not been specifically studied. 3,5 In a study conducted by Pregler et al, women were more likely to be inappropriately assigned to low-risk categories than men and were less likely to receive appropriate recommendations for lifestyle change and preventive pharmacotherapy. 37

Reperfusion therapy such as percutaneous coronary intervention (PCI) aims to restore blood flow to coronary arteries after an MI. 32 Although this cardiovascular intervention has been proven to reduce mortality and have better outcomes regardless of gender, evidence indicates that reperfusion therapy is more commonly performed in male patients. 38 Disparities in gender also exist in the management of patients with non-ST-segment elevation (NSTE) and ST-segment elevation acute coronary syndromes (ACS). Additional studies have reported discrimination in the provision of medical care for women, noting that they were less likely to be admitted to the coronary care unit, less likely to undergo invasive procedures, and less likely than men to be treated for cardiovascular events; older women, in particular, are less likely to receive further treatment. 39-41

Role of the Pharmacist

Pharmacists should play a key role in increasing patient awareness and knowledge about CHD, while assisting healthcare providers in identifying sex-specific barriers and factors among patients with MI and those at risk for CHD. Pharmacists can also utilize their medication expertise to provide evidence-based treatment recommendations, improve medication adherence, and assist in the development of tools that will be beneficial in improving CVD morbidity and mortality.

It is important that healthcare providers take into account physiologic, clinical, psychosocial, and health management differences among women compared to men when diagnosing MI, and in treating and monitoring patients with a history of MI. The use of risk calculators such as the Reynolds Risk Score, specifically developed for women, and the Framingham Risk Score may assist providers in assessing women for early signs of heart disease. Women also should be aware of the signs and symptoms of MI, and have an understanding of the disease, the appropriate management of medications, and ways of self-monitoring and incorporating healthy lifestyle behaviors. Furthermore, efforts from a multidisciplinary team that might include a cardiology specialist, pharmacist, nutritionist, and exercise physiologist as well as psychiatric and family support are vital in improving the quality of life and the cardiovascular health of older women. 42

1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation . 2015;131(4):e29-e322. 2. Writing Group Members, Mozaffarian D, Benjamin EJ, et al. Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation . 2016;133(4):e38-e60. 3. Mehta LS, Beckie TM, DeVon HA, et al. Acute myocardial infarction in women: a scientific statement from the American Heart Association. Circulation . 2016;133(9):916-947. 4. Lee PY, Alexander KP, Hammill BG, et al. Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA . 2001;286(6):708-713. 5. Douglas P. Management of coronary heart disease in women. UpToDate.com. Updated April 28, 2015. www.uptodate.com/contents/management-of-coronary-heart-disease-in-women. Accessed May 31, 2016. 6. Douglas P, Poppas A. Overview of cardiovascular risk factors in women. UpToDate.com. Updated January 22, 2016. www.uptodate.com/contents/overview-of-cardiovascular-risk-factors-in-women. Accessed June 2016. 7. Wilson P, Douglas P. Epidemiology of coronary heart disease. Uptodate.com. Updated January 23, 2015. www.uptodate.com/contents/epidemiology-of-coronary-heart-disease. Accessed May 2016. 8. Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and coronary heart disease. the Framingham Study. Ann Intern Med . 1978;89(2):157-161. 9. D’Agostino RB Sr., Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation . 2008;117(6):743-753. 10. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA . 2007;297(6):611-619. 11. Huxley RR, Woodward M. Cigarette smoking as a risk factor for coronary heart disease in women compared with men: a systematic review and meta-analysis of prospective cohort studies. Lancet . 2011;378(9799):1297-1305. 12. Iversen B, Jacobsen BK, Lochen ML. Active and passive smoking and the risk of myocardial infarction in 24,968 men and women during 11 years of follow-up: The Tromsø study. Eur J Epidemiol . 2013;28(8):659-667. 13. Njolstad I, Arnesen E, Lund-Larsen PG. Smoking, serum lipids, blood pressure, and sex differences in myocardial infarction. A 12-year follow-up of the Finnmark study. Circulation . 1996;93(3):450-456. 14. Teo KK, Ounpuu S, Hawken S, et al. Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study. Lancet . 2006;368(9536):647-658. 15. Rosenberg L, Palmer JR, Shapiro S. Decline in the risk of myocardial infarction among women who stop smoking. N Engl J Med . 1990;322(4):213-217. 16. Gupta BP, Huddleston JM, Kirkland LL, et al. Clinical presentation and outcome of perioperative myocardial infarction in the very elderly following hip fracture surgery. J Hosp Med . 2012;7(9):713-716. 17. Mondul AM, Rodriguez C, Jacobs EJ, Calle EE. Age at natural menopause and cause-specific mortality. Am J Epidemiol . 2005;162(11):1089-1097. 18. Hu G, Jousilahti P, Qiao Q, et al. The gender-specific impact of diabetes and myocardial infarction at baseline and during follow-up on mortality from all causes and coronary heart disease. J Am Coll Cardiol . 2005;45(9):1413-1418. 19. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA . 2002;288(3):321-333. 20. Ahmed R, Dunford J, Mehran R, et al. Pre-eclampsia and future cardiovascular risk among women: a review. J Am Coll Cardiol . 2014;63(18):1815-1822. 21. Kharazmi E, Dossus L, Rohrmann S, Kaaks R. Pregnancy loss and risk of cardiovascular disease: a prospective population-based cohort study (EPIC-Heidelberg). Heart . 2011;97(1):49-54. 22. Reeder G, Kennedy H, Rosenson R. Overview of the acute management of ST elevation myocardial infarction. UpToDate.com. Updated January 14, 2016. www.uptodate.com/contents/overview-of-the-acute-management-of-st-elevation-myocardial-infarction. Accessed May 31, 2016. 23. Stangl V, Witzel V, Baumann G, Stangl K. Current diagnostic concepts to detect coronary artery disease in women. Eur Heart J . 2008;29(6):707-717. 24. Orencia A, Bailey K, Yawn BP, Kottke TE. Effect of gender on long-term outcome of angina pectoris and myocardial infarction/sudden unexpected death. JAMA . 1993;269(18):2392-2397. 25. Kannel WB, Vokonas PS. Demographics of the prevalence, incidence, and management of coronary heart disease in the elderly and in women. Ann Epidemiol . 1992;2(1-2):5-14. 26. Douglas P. Clinical features and diagnosis of coronary heart disease in women. UpToDate.com. Updated August 19 2014. www.uptodate.com/contents/clinical-features-and-diagnosis-of-coronary-heart-disease-in-women. Accessed May 31, 2016. 27. Mosca L, Linfante AH, Benjamin EJ, et al. National study of physician awareness and adherence to cardiovascular disease prevention guidelines. Circulation . 2005;111(4):499-510. 28. Foa C, Artioli G. Gender differences in myocardial infarction: health professionals’ point of view. Acta Biomed . 2016;87 Suppl 2:7-18. 29. American Heart Association. Heart attack symptoms among women. Updated July 2015. www.heart.org/HEARTORG/Conditions/HeartAttack/WarningSignsofaHeartAttack/Heart-Attack-Symptoms-in-Women_UCM_436448_Article.jsp#.V3O6eKKPaeE. Accessed May 31, 2016. 30. Westerman S, Wenger NK. Women and heart disease, the underrecognized burden: sex differences, biases, and unmet clinical and research challenges. Clin Sci (Lond) . 2016;130(8):551-563. 31. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation . 2014;130(25):e344-e426. 32. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation . 2013;127(4):e362-e425. 33. Baigent C, Collins R, Appleby P, et al. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. the ISIS-2 (second international study of infarct survival) collaborative group. BMJ . 1998;316(7141):1337-1343. 34. Hennekens CH, Hollar D, Baigent C. Sex-related differences in response to aspirin in cardiovascular disease: an untested hypothesis. Nat Clin Pract Cardiovasc Med . 2006;3(1):4-5. 35. Nohria A, Vaccarino V, Krumholz HM. Gender differences in mortality after myocardial infarction: why women fare worse than men. Cardiol Clin . 1998;16(1):45-57. 36. Blomkalns AL, Chen AY, Hochman JS, et al. Gender disparities in the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: large-scale observations from the CRUSADE (can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the American College of Cardiology/American Heart Association guidelines) national quality improvement initiative. J Am Coll Cardiol . 2005;45(6):832-837. 37. Pregler J, Freund KM, Kleinman M, et al. The heart truth professional education campaign on women and heart disease: needs assessment and evaluation results. J Womens Health (Larchmt) . 2009;18(10):1541-1547. 38. Vaccarino V, Rathore SS, Wenger NK, et al. Sex and racial differences in the management of acute myocardial infarction, 1994 through 2002. N Engl J Med . 2005;353(7):671-682. 39. Pilgrim T, Heg D, Tal K, et al. Age- and gender-related disparities in primary percutaneous coronary interventions for acute ST-segment elevation myocardial infarction. PLoS One . 2015;10(9):e0137047. 40. Ayanian JZ, Epstein AM. Differences in the use of procedures between women and men hospitalized for coronary heart disease. N Engl J Med . 1991;325(4):221-225. 41. Medina HM, Cannon CP, Zhao X, et al. Quality of acute myocardial infarction care and outcomes in 33,997 patients aged 80 years or older: findings from Get With the Guidelines-Coronary Artery Disease (GWTG-CAD). Am Heart J . 2011;162(2):283-290.e2. 42. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation . 2016;133(4):e38-e360.

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Medication-Focused Overview of the 2022 AHA/ACC/HFSA Heart Failure Management

Managing modifiable risk factors in chronic coronary disease, related content, direct oral anticoagulants for the prevention of stroke in nonvalvular atrial fibrillation, adt side effects caused by electrophysiological changes in the heart, caffeine may protect against atrial fibrillation, swedish population study supports link between crc, use of antibiotics.

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Atypical Symptoms of Myocardial Infarction Associated with Coronary Risk Factors

Despite a remarkable decline in deaths due to cardiovascular disease over several decades, coronary heart disease remains a leading cause of morbidity and mortality in the United States.

Introduction

Despite a remarkable decline in deaths due to cardiovascular disease over several decades, coronary heart disease (CHD) remains a leading cause of morbidity and mortality in the United States. 1 More than 370,000 Americans die of CHD each year, and about 47% have at least one of the 3 key risk factors for CHD: high blood pressure, hyperlipidemia, and smoking. 2 Myocardial infarction (MI) remains the most common complication of CHD. An estimated 735,000 Americans experience an MI each year. 2

Among all age groups, CHD mortality rates fell as much as 52% in men and 49% in women between 1980 and 2002. 3 However, these trends have not been seen across all demographic groups. Specifically, there was a dramatic slowing in the average annual rate of decline of CHD mortality among younger females between 35-54 years of age. 3 Data from the National Health and Nutrition Examination Surveys show that the prevalence of MI has increased in women aged 35 to 54 years and declined in similarly aged men. 4 Women, continue to show much slower reductions in CHD mortality, bordering on stagnation. 3 In the last decade, the observed decline reflects mainly CHD mortality reductions among older adults. 3

The following sequence of events commonly occurs with an MI 5 :

• Sudden disruption of an atheromatous plaque by intraplaque hemorrhage or mechanical force leads to the exposure of subendothelial collagen and necrotic plaque contents to the bloodstream.
• When platelets adhere, they release thromboxane A2, adenosine diphosphate, and serotonin, which cause additional platelet aggregation and vasospasm.
• Coagulation adds to a growing thrombus.
• The thrombus may completely occlude the coronary artery lumen in a matter of minutes.

The relative contribution of various processes leading to ischemia differs markedly between genders: women with ischemic heart disease have obstructive and extensive epicardial artery disease less frequently than men 5 ; this implies that in women, other mechanisms—such as abnormal coronary vasomotion, nonatherosclerotic coronary artery dissection, impaired coronary microcirculation, thrombophilia, or as yet unknown processes contribute to ischemic syndromes more frequently than in men. 6-9

Common symptoms of MI include 10 :

• Chest pain that does not go away with rest or that worsens with a deep breath
• Shortness of breath
• Pain or discomfort that radiates to arms or to the jaw
• Nausea and vomiting

Diaphoresis

Common symptoms of MI are apparent to health care providers. But, too often, patients who are experiencing the typical signs of MI may or may not recognize these episodes as an emergency and may not seek help immediately. 11 Patients who experience atypical symptoms, have an even greater risk of neglecting to seek emergency care. 8 Recent evidence suggests that in patients with CHD, 70% to 80% of episodes of ischemia are actually asymptomatic. 9 Three factors most likely account for the large proportion of asymptomatic episodes include dysfunction of afferent nerves, transient reduced perfusion, and differing pain thresholds among patients. 10

Study: Excessive Alcohol Consumption Causes Gut Microbiome Imbalance

Although alcohol is not absorbed by the intestines, research has demonstrated that excessive drinking causes the liver to produce too much acetate which may lead to intestinal bacterial overgrowth.

Knock Out Aches and Pains From Cold

The symptoms associated with colds, most commonly congestion, coughing, sneezing, and sore throats, are the body's response when a virus exerts its effects on the immune system. Cold symptoms peak at about 1 to 2 days and last 7 to 10 days but can last up to 3 weeks.

COPD: Should a Clinician Treat or Refer?

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines the condition as follows: “COPD is a common, preventable, and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.”

Diabetic Ketoacidosis Is Preventable With Proper Treatment

Cancer, diabetes, and heart disease account for a large portion of the $3.3 trillion annual US health care expenditures. In fact, 90% of these expenditures are due to chronic conditions. About 23 million people in the United States have diabetes, 7 million have undiagnosed diabetes, and 83 million have prediabetes.

What Are the Latest Influenza Vaccine Recommendations?

Clinicians should recommend routine yearly influenza vaccinations for everyone 6 months or older who has no contraindications for the 2019-2020 influenza season starting at the end of October, according to the Advisory Committee on Immunization Practices.

What Is the Best Way to Treat Pharyngitis?

There are many different causes of throat discomfort, but patients commonly associate a sore throat with an infection and may think that they need antibiotics. This unfortunately leads to unnecessary antibiotic prescribing when clinicians do not apply evidence-based practice.

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EMPACT-MI: Empagliflozin Post MI Does Not Lower Risk of First HF Hospitalization, Death

Apr 06, 2024

ACC News Story

The SGLT2 inhibitor empagliflozin did not lower the risk of a first hospitalization for heart failure (HF) or death from any cause among patients with an increased risk for HF following acute myocardial infarction (MI), according to the results of the EMPACT-MI study, presented during a Late-Breaking Clinical Trial session at ACC.24 and published simultaneously in the New England Journal of Medicine .

The event-driven, double-blind trial, conducted from December 2020 to March 2023 at 451 sites in 22 countries, randomly assigned 6,522 patients (median age 63 years, 24.9% women, 83.6% White, 1.4% Black, 12.8% Asian) who had been hospitalized for acute MI and were at risk for HF with newly reduced left ventricular ejection fraction (LVEF) or congestion or both to either 10 mg daily of empagliflozin or a placebo in addition to standard care within 14 days of admission. At baseline, 78.4% of patients had an LVEF ≤45%, and 57.0% had signs or symptoms of congestion that resulted in treatment during the index hospitalization.

Results showed that first hospitalization for HF or death from any cause, the composite primary endpoint, occurred in 267 patients (8.2%) in the empagliflozin group and 298 patients (9.1%) in the placebo group during the median follow-up of 17.9 months. The two groups had incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio [HR], 0.90; 95% CI, 0.76-1.06; p=0.21).

For the separate components of the primary endpoint, first hospitalization for HF alone occurred in 118 patients (3.6%) in the empagliflozin group and 153 patients (4.7%) in the placebo group (HR, 0.77; 95% CI, 0.60-0.98) and death from any cause occurred in 169 (5.2%) in the empagliflozin group and 178 (5.5%) in the placebo group (HR, 0.96; 95% CI, 0.78-1.19). Results were similar across all sensitivity analyses for the primary endpoint.

In terms of key secondary endpoints, total number of hospitalizations for HF or death from any cause occurred in 317 cases in the empagliflozin group and 385 in the placebo group (rate ratio [RR], 0.87; 95% CI, 0.68-1.10). Total number of nonelective cardiovascular hospitalizations or death from any cause were 666 and 730, respectively (RR, 0.92; 95% CI, 0.78-1.07). Total number of nonelective hospitalizations for any cause or death from any cause were 998 and 1,138 (RR, 0.87; 95% CI, 0.77-1.0), and total number of hospitalizations for MI or death from any cause were 276 and 274 (RR, 1.06; 95% CI, 0.83-1.35).

The authors noted that an exploratory analysis showed that cardiovascular death occurred in 132 patients (4.0%) in the empagliflozin group and 131 (4.0%) in the placebo group (HR, 1.03; 95% CI, 0.81-1.31). The time to death from cardiovascular causes and time to a first HF hospitalization or cardiovascular death were similar in both groups. Adverse events were similar in the two groups and consistent with the known safety profile of empagliflozin.

Among study limitations the authors noted the lack of central adjudication of endpoint events, which were assessed by site investigators using prespecified definitions, and lack of analysis of outpatient HF events, as well as unsuccessful efforts to improve representation within the trial.

"We found that empagliflozin did not reduce mortality after a heart attack but did reduce the risk of [HF] after heart attack," said Javed Butler, MD, FACC , the study's lead author. "To have a 25% to 30% reduction in [HF] hospitalizations is pretty clinically meaningful, but if you put it together with all-cause mortality, it was not a positive study for our primary endpoint."

In an accompanying editorial comment , Jean Rouleau, MD, FACC , wrote that, "The good news is that the prognosis of patients with left ventricular dysfunction, congestion, or both after an acute [MI] have improved markedly. The challenge is that the identification of additional therapies is increasingly difficult, especially because a large percentage … promptly undergo reperfusion." Moreover, the results of this trial do not support the routine use of SGLT2 inhibitors in this population, but in patients with indications for the drug, such as type 2 diabetes or chronic kidney disease, a recent MI may provide an opportunity to start this treatment and decrease the risk of HF.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: ACC Annual Scientific Session, ACC24, Myocardial Infarction, Heart Failure, Novel Agents, Sodium-Glucose Transporter 2 Inhibitors

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All Eyes on Women: Tiffany Chang, Female Leader and Beauty Queen at the Forefront

In a breathtaking fusion that marries glamour and intellect, Tiffany Chang, the crowned Miss Asia USA 2024, is stepping onto the stage with a mission: to inspire women to break barriers in the male-dominated fields of science, technology, engineering, and mathematics or STEM.

Los Angeles, CA, California, United States - April 12, 2024 —

Chang dismantles barriers for women in the field of STEM.

In a breathtaking fusion that marries glamour and intellect, Tiffany Chang, the crowned Miss Asia USA 2024, is stepping onto the stage with a mission: to inspire women to break barriers in the male-dominated fields of science, technology, engineering, and mathematics or STEM. 

Armed with a vision to elevate women in STEM fields, Chang, a Taiwanese Stanford student studying Engineering Management and Human-Centered Design, is already making waves with her refreshing approach on the traditional beauty pageant platform. Her journey began with realizing that her reign and the Miss Asia USA platform could be a powerful catalyst for promoting diversity and inclusivity in STEM.

Based on her engineering background, she recognized the lack of representation of women, especially of Asian descent, in these fields. Determined to change the narrative, Chang seizes the opportunity to use her platform to advocate for gender equality and encourage young girls to pursue their passions.

During the talent show segment of the Miss Taiwanese American 2022 beauty pageant, Chang unveiled her magnum opus: the world's first beauty pageant robot. This ingenious invention showcases the beauty queen’s technical prowess and signifies how she bridges the gap between the pageant world and STEM.

By integrating technology and creativity, Chang sends a powerful message that beauty and intelligence are not mutually exclusive – they can coexist harmoniously, inspiring others to embrace their multifaceted identities. It is both a demonstration of technological marvels and a celebration of femininity in science and innovation.

Chang on Shattering Industry Expectations

Chang’s initiative is timely as women remain significantly underrepresented in STEM fields. Recent statistics report women comprise only a fraction of the workforce in engineering, computer science, and other STEM-related industries. The lack of female representation not only perpetuates gender stereotypes but also hinders innovation and progress.

Chang aims to change the narrative through her work as Miss Asia USA 2024 and send a powerful message: girls can have fun with science and still embody their beauty. By shattering stereotypes and showcasing the limitless possibilities when intelligence and elegance unite, she hopes to inspire the next generation of young women to pursue their dreams boldly, whether on the runway or in other professions.

Advocacy in Action

Chang’s excitement soared as she visited Taiwan in March and got the chance to see Taiwan Semiconductor Manufacturing Company (TSMC), the country's largest semiconductor manufacturer, and Kneron, an AI startup in Taiwan that pioneered a 3D artificial intelligence (AI) solution and edge AI chip. Her visit catalyzed a deeper understanding and advancement in semiconductor technology. 

For Chang, her visit catalyzed a deeper understanding and advancement in semiconductor technology, strengthened her passion for championing Taiwan's technological excellence, and fueled her mission to empower more female Asians to pursue STEM careers.

In a statement resonating with aspiring young women everywhere, Chang shares, "We, as women, should not be afraid to step outside the box. We can be in any field like STEM, and as long as we have the passion for it, we can reach our goals." Her words echo a sentiment of empowerment and resilience, inspiring countless others to defy societal norms and pursue their dreams fearlessly.

As Chang reigns as Miss Asia USA 2024, she not only embodies beauty and grace but sets an example for aspiring women looking to make their mark in STEM industries. With boundless motivation, she dismantles barriers and champions inclusivity and diversity through her advocacy and innovative initiatives.

The work is not easy, but Chang looks forward with her steadfast determination and visionary spirit in shaping a world where women in STEM shine brightly and unapologetically.

Contact Info: Name: Tiffany Chang Email: Send Email Organization: Virgelia Productions Website: https://www.tiffanyachang.com/

Source: Baden Bower

Release ID: 89126989

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Michigan Minds Podcast: Navigating Circumstantial Barriers through U-M’s Center for the Education of Women+

• Morgan Sherburne

In this episode of Michigan Minds, Tiffany Marra , PhD, discusses creating systemic change to diversify enrollment and how the CEW+ supports the U-M community, and shares stories to explore during Women’s History Month. Marra is the director of the University of Michigan Center for the Education of Women+ (CEW+), ensuring that the center is addressing the needs of women and underserved individuals at U-M and in the community through career and education counseling, funding, workshops, events and a diverse, welcoming community.

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Woman pushed down flight of church steps in Queens and critically injured

By Alice Gainer

Updated on: April 9, 2024 / 10:08 AM EDT / CBS New York

NEW YORK -- The NYPD is looking for a man who pushed a parishioner down a flight of church steps and then robbed her on Sunday morning.

Security video from Saint Demetrios Church in Jamaica, Queens shows a man following a 68-year-old woman at 84-35 152nd St. He surprises her and comes around as she reaches the top of the steps before he violently pushes her.

The woman fell all the way to the ground.

The person is then seen taking her purse, which police say had $300, credit cards, a cellphone and car keys.

She was taken to a local hospital in critical condition.

The church's priest said the congregation is in shock.

"She's a very humble, nice woman, has her faith, family. Hoping and praying she'll recover fully from this," Father Konstantinos Kalogridis said. "I visited her last night in the hospital. She was conscious, alert. I gave her a blessing, gave her Holy Communion. She did her cross. She was able to say, Thank you, I understand.'"

Police said the suspect also took the woman's 2006 Nissan Altima and fled.

Alice Gainer joined CBS2 as a reporter and anchor in January 2013. She covers breaking, feature and general assignment stories.

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5 Arrested in Connection with Torture Death of Michigan Woman Held Captive in Pennsylvania

Authorities are also investigating the death of a second woman that is related to this case, the district attorney said

Luzerne County District Attorney's Office

A Michigan woman who traveled to Pennsylvania to visit someone she thought was a "friend" allegedly ended up being held captive, tortured and killed by that person and four others who are now facing murder charges, the Luzerne County district attorney announced. 

On April 9, Luzerne County District Attorney Sam Sanguedolce said at a press conference that the badly decomposed body of Nicole Cuevas-Ingram, 38, of Saginaw, Mich., had been found buried in the basement of a home in Wilkes-Barre on Feb. 27.

Her body was wrapped in a tarp and tied with electrical cords and rope and her head was covered in two plastic shopping bags, according to court documents obtained by the Times Leader.

Her remains were surrounded by moth balls in the basement of the home, where she was buried in April 2023 after being viciously killed, Sanguedolce said at the press conference, which was streamed by PAhomepage.com and viewed by PEOPLE.

Cuevas-Ingram came to Wilkes-Barre in 2023 “with one of the people that murdered her that resided at 142 Carlisle Street believing they were friends,” the district attorney alleged.

“Obviously that went awry fairly quickly," he said. "I think she came really just for a visit and tried to get home but was unsuccessful in that endeavor unfortunately by nature of the fact that she couldn’t escape her kidnappers that resulted in her death.”

On April 9, the five suspects — Desiree Linnette, 43, and her daughter, Sarai Doyle, 24, of Edwardsville; Jason Race, 43, and Faith Beamer, 39, of Wilkes-Barre; and William Wolfe, 54, were arrested.

Luzerne County District Attorney's Office (2)

They are charged with homicide, conspiracy to commit murder, kidnapping, conspiracy to commit kidnapping, aggravated assault and abuse of a corpse. 

Luzerne County District Attorney's Office (3)

While Cuevas-Ingram was held captive, the district attorney alleged she “was handcuffed to a basement post, and over the course of several weeks, she was severely beaten.

“The beatings resulted in bruising, a broken ankle, nearly all of her ribs were broken, her nasal cavity was destroyed, her head was shaved, she was stabbed and slashed in several places including her arm, torso and all over her back, and her hyoid bone in her neck was broken, that is generally indicative to investigators of strangulation,” Sanguedolce said.

“The evidence revealed she was kicked and stomped and strangled,” he said.

According to court documents obtained by the Times Leader, a witness saw Cuevas-Ingram drooling and with a shaved head in the kitchen.

When Cuevas-Ingram soiled herself while she was handcuffed, Linnette and Race allegedly became so angry that Race stomped on Cuevas-Ingram’s head until she died, the court documents state.

Investigators claim to have found the black boots Race allegedly wore when he stomped on Cuevas-Ingram’s head, according to the court documents.

Her death was ruled a homicide by asphyxiation, he said. 

During the press conference, Sanguedolce also said authorities are investigating the death of a second woman, Deborah Fox, 69, who could be related to this case.

Fox was the former owner of the home, where Cuevas-Ingram was allegedly held against her will, tortured and killed, Sanguedolce said.

Her decomposed body was found in a wooded area in Wilkes-Barre on March 26.

Police are continuing to investigate both cases.

The suspects are being held without bail at various correctional institutions in the area, the district attorney said. It is unclear whether they have retained attorneys who can speak on their behalf.

Anyone with information regarding past residents of the property or anyone with information about the remains is asked to contact members of the Wilkes-Barre Police Detective Division, either Lt. Matthew Stash at 570-208-0911 or Detective James Conmy at 570-208-6775.

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Myocardial Infarction Signs and Symptoms: Females vs. Males

Kyle j schulte.

1 Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Allopathic Medicine, Fort Lauderdale, USA

Harvey N Mayrovitz

2 Medical Education, Nova Southeastern University Dr. Kiran C. Patel College of Allopathic Medicine, Fort Lauderdale, USA

Cardiovascular disease is the number one killer of females in the United States today, and myocardial infarction (MI) plays a role in many of these deaths. Females also present with more “atypical” symptoms than males and appear to have differences in pathophysiology underlying their MIs. Despite both differences in symptomology and pathophysiology being present in females versus males, a possible link between the two has not been studied extensively. In this systematic review, we analyzed studies examining differences in symptoms and pathophysiology of MI in females and males and evaluated possible links between the two. A search was performed for sex differences in MI in the databases PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature) Complete, Biomedical Reference Collection: Comprehensive, Jisc Library Hub Discover, and Web of Science. Seventy-four articles were ultimately included in this systematic review. Typical symptoms for both ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) such as chest, arm, or jaw pain were more common in both sexes, but females presented on average with more atypical symptoms such as nausea, vomiting, and shortness of breath. Females with MI also presented with more prodromal symptoms such as fatigue in days leading up to MI, had longer delays in presentation to the hospital after symptom onset, and were older with more comorbidities than males. Males on the other hand were more likely to have a silent or unrecognized MI, which concurs with their overall higher rate of MI. As they age, females have a decrease in antioxidative metabolites and worsened cardiac autonomic function than male. In addition, at all ages, females have less atherosclerotic burden than mles, have higher rates of MI not related to plaque rupture or erosion, and have increased microvasculature resistance when they have an MI. It has been proposed that this physiological difference is etiologic for the male-female difference in symptoms, but this has not been studied directly and is a promising area of future research. It is also possible that differences in pain tolerance between males and females may play a role in differing symptom recognition, but this has only been studied one time where females with higher pain thresholds were more likely to have unrecognized MI. Again, this is a promising area for future study for the early detection of MI. Finally, differences in symptoms for patients with different atherosclerotic burden and for patients with MI due to a cause other than plaque rupture or erosion has not been studied and are both promising avenues to improve detection and patient care in the future.

Introduction and background

As of this writing, cardiovascular disease is the number one killer of females in the United States, having been responsible for 301,280 deaths in 2019 [ 1 - 3 ]. Considering just myocardial infarction (MI), males have a higher incidence than females, with males accounting for approximately 70% of MIs and having an MI 7-10 years earlier than females [ 2 , 4 ]. Despite this, females experience a greater one-year mortality rate after an MI with an odds ratio (OR) of 1.6 [ 5 ]. Some of this mortality difference may be attributable to differences in age and comorbidity burden at first MI, where females present later and with more risk factors such as type 2 diabetes mellitus [ 1 , 5 - 7 ]. Despite the impact of MI on females, it is less well defined than for males, with the symptoms of females described as “atypical” versus the “typical” male symptoms [ 8 , 9 ].

A part of the greater mortality burden in females may be due to the lack of recognition of these atypical symptoms by physicians and patients alike, as females with MI are less likely to receive timely and evidence-based interventions upon MI symptom onset [ 5 , 7 , 10 ]. Females who are having an MI also tend to present to the hospital later after symptom onset than males, which may indicate a possible lack of knowledge in the general population of the dangers of MI in females or a lack of knowledge of the differences in symptomology that females present with [ 11 - 13 ]. These differences appear to be present across race and culture, though Black and Hispanic females in the United States are more likely to present with atypical MI symptoms than White females [ 14 ].

While some differences in treatment and in outcomes experienced by females with an MI may be due to a lack of awareness or other systemic social factors, a difference in pathophysiology leading to differences in symptoms may also be at play. Females do appear to have differing cardiac physiology and MI pathophysiology from males, which may further exacerbate the mortality difference between sexes [ 5 , 15 - 17 ]. Despite some differences in symptomology and pathophysiology having been previously considered [ 5 , 18 , 19 ], few links between the two have been established. The goal of the present investigation is to elucidate the sex differences in MI symptomology and explore the pathophysiological differences that may underlie them. 

This systematic review was created in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines (Figure ​ (Figure1). 1 ). Articles were included if they satisfied the following criteria: they were written in English, the study included adults with a sample size of at least 30, the study focused on MI symptomology or pathophysiology, and had a consideration of sex differences in cardiac physiology. Articles were excluded if they did not characterize symptoms at the onset of MI and had a primary outcome other than myocardial infarction, ischemic heart disease, or sex differences in cardiac physiology. PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature) Complete, Biomedical Reference Collection: Comprehensive Edition, Jisc Library Hub Discover, and Web of Science were searched for articles satisfying the inclusion and exclusion criteria. A total of 6851 titles were retrieved, which after removing duplicates resulted in 4474 unique articles. Articles were reviewed for inclusion by one reviewer working independently. On full-text review, articles were excluded or included based on primary outcome describing symptomology or pathophysiology of MI with a focus on sex differences. In the final review, 74 articles were included. For examination of bias within included articles, both reviewers examined the full text of the articles selected.

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Prevalence of typical and atypical symptoms in males vs. females

Females often present with more “atypical” symptoms than males [ 20 - 22 ]. Typical symptoms of both sexes are chest, arm, or jaw pain of a dull, heavy, tight, or crushing quality whereas atypical symptoms are other common but less frequent presentations such as nausea, vomiting, diaphoresis, shortness of breath, dizziness, and pain in locations other than those described earlier [ 8 , 23 ]. Upon arrival at hospital, both sexes report chest pain and feelings of chest tightness or pressure as their most common MI symptom [ 9 , 22 , 24 ]; however, males report chest pain 13-15% more frequently than females as their chief complaint [ 25 , 26 ]. One study suggests that some of the reporting differences may be due to the patient interview process associated with the clinician interview strategy [ 27 ]. 

When accounting for interview styles, males and females were equally likely to report chest pain on open-ended questioning, but males reported chest pain more frequently on narrowed questioning followed by a checklist [ 27 ]. Some symptoms are reported far more frequently by females and some physical findings are more prevalent. Symptoms reported more often by females include nausea, vomiting, dizziness, and fear of death. More frequent physical findings for females are those consistent with congestive heart failure such as lung crackles or rales [ 26 ], and the presence of dyspnea [ 9 , 24 , 25 ], although one study indicates no sex-related difference [ 28 ]. 

The location of the pain reported by females is more often the jaw or neck with other pain locations being the upper back, left arm, left shoulder, left hand, and abdomen, in no particular order of frequency [ 9 , 22 , 24 - 26 , 28 ]. With increased age, females report less chest pain and more shortness of breath although no such association was seen with males [ 25 ]. Males appear to present with more chest pain but also present with more burning or pricking pain sensation and with more diaphoresis than females [ 9 , 22 ]. In addition to having a wider variety of possible symptoms, females also present with more symptoms during a given MI than males [ 20 , 21 , 24 ]. For example, among patients aged 18 to 55 years, females presented with 10% more symptoms than males per MI [ 21 ], and among a patient population with average age over 75, females presented with 17% more symptoms than males per MI [ 20 ]. Finally, when analyzing for possible common symptom phenotypes (e.g. chest pain with dyspnea or chest pain with nausea and vomiting), it was reported that for females 18-55 years and over 75, there is a more heterogeneous population of symptom presentations when compared to males. Females had significantly more phenotypes and these phenotypes were more broadly distributed across the population [ 20 , 21 ].

Prodromal symptoms in the sexes and racial similarities

In addition to altered symptomology in the acute phase of MI, females are also more likely to have prodromal symptoms in the days and weeks leading up to an MI, with some occurring more than a year prior. The most reported of these, in the order of prevalence, are feeling tired or with unusual fatigue, sleep disturbance, anxiety, shortness of breath, and arm, back, or chest pain [ 15 , 29 , 30 ]. These prodromal symptoms have not been shown to be associated with hypertension, hyperlipidemia, or age over 50 [ 31 ], although these symptoms are also associated with some cardiovascular risk factors, including family history of cardiovascular disease, obesity, DM, prior hysterectomy, smoking, secondhand smoke exposure, and lack of regular exercise.

With respect to prodromal symptoms, over 50% of females had a disturbance in sleep from normal within four weeks of their MI versus 32% of males who experienced such sleep disturbances [ 29 , 32 ]. It has also been reported that sleep disturbance prior to MI may be increasing since it has been reported that more females and males experienced sleep disturbances within four weeks of MI in 2008 than in 2000 [ 32 ]. Considering the sleep issue, it should be noted that most sleep-related findings come from one laboratory [ 14 , 15 , 29 - 31 , 33 ]. This group has indicated that sleep disturbances may also be an important factor for those with other cardiovascular risk factors for those patients that have sleep disturbance accompanied by changes in thinking/remembering and increased anxiety, fatigue, and pain prior to their MI [ 29 ].

An investigation into the prevalence and extent of prodromal symptoms by age has suggested three clusters. Cluster 1 includes older patients in whom the prevalence of prodromal symptoms is limited. Cluster 2 includes a diverse group who present with feelings of unusual fatigue and sleep disturbance in over 70% of members. Cluster 3 includes the youngest patients and has more minorities than the other groups. Patients in this cluster presented with unusual fatigue, sleep disturbance, anxiety, shortness of breath, arms that felt weak or heavy, and hand and arm tingling in over 70% of members [ 15 ]. Prodromal symptoms appear to vary slightly in intensity and number by race among females [ 14 ]. In all females, at least five prodromal symptoms per MI were present with Black females more likely to experience more prodromal symptoms (7.48 per MI) and more severe prodromal symptoms than Hispanic females (6.98 per MI), who in turn were more likely to experience more prodromal symptoms and more severe prodromal symptoms than White females (5.84 per MI) [ 14 ]. It has been reported that certain prodromal symptoms are predictive of future MI for males and females, with jaw or tooth discomfort (OR 2.15), unusual fatigue (OR 2.11), arm discomfort (OR 2.00), and ache in arms (OR 1.93) being significantly predictive of an MI within 90 days [ 33 ].

Risk factors, age, and comorbidities as they relate to symptoms and presentation

Males and females have different comorbidities and risk factors when presenting with MI. On average, females having an MI are older and more likely to have a history of congestive heart failure, DM, hypertension, lower BMI, and lower smoking rates than males [ 6 , 10 , 22 , 26 , 28 , 34 ]. On the other hand, males are more likely to present with a history of MI and peptic ulcer disease [ 26 ]. There is conflicting evidence on whether hyperlipidemia in MI differs between the sexes, as some studies show more hyperlipidemia in females [ 10 , 22 ], some show greater rates in males [ 34 ], and others show no difference between the sexes [ 9 ]. It is also unclear whether a history of diagnosed angina as a risk factor differs between the sexes since one study found a greater rate of angina in females [ 28 ] and another found a greater rate of angina in males [ 26 ]. It is unclear whether some risk factors influence symptom presentation and patient interpretation of their symptoms as MI. Atypical symptoms are more common in older males and females [ 35 , 36 ]. However, in females with DM, one study showed no difference in atypical symptomology [ 35 ] while DM was predictive of upcoming atypical MI in a Chinese cohort. This cohort also showed female sex, previous acute MI, and hyperlipidemia as predictive factors for upcoming MI with atypical symptoms [ 36 ].

Risk factors may also be different based on patients' age. Compared to the general population, females under the age of 55 are reported to be more likely to present with an MI if they have a history of obesity, stroke, transient ischemic attack, chronic kidney disease, chronic lung disease, DM, or hypertension [ 37 , 38 ]. In these females, DM and hypertension account for a sixfold and threefold increase in the risk of MI, respectively [ 37 ]. In males under age 55, previous history of cardiac arrhythmia, hyperlipidemia, ST-segment elevation MI (STEMI), and coronary artery stenosis greater than 50% was found more often than in females [ 38 ].

Smoking ≥ 20 cigarettes/day was associated with an increased rate of MI in both sexes, but females smoking ≥ 20 cigarettes/day had a higher risk of MI (hazard ratio (HR) = 3.46) than males smoking ≥ 20 cigarettes/day (HR = 2.23) [ 4 ]. For persons with hypertension, the rate of MI was increased in both sexes but females had a higher HR (2.52) than males (1.71). An increased risk was also associated with DM although there were differences between type 1 and type 2 DM. Females with type 1 DM had a significantly higher risk of MI (HR = 8.18) than males with type 1 DM (HR = 2.81), and females with type 2 DM had a higher risk (HR = 1.96) than males with type 2 DM (HR = 1.33). The absolute difference in risks between the sexes did not change with age, though the relative risks compared to the general population decreased with age for both females and males [ 4 ]. One study had differing results in young patients, where females and males under 55 who had MIs had no difference in the prevalence of DM but females who had MIs and were over 55 had higher rates of DM than males [ 6 ]. 

Delays in presentation

Females tend to present to the hospital later than males after MI symptom onset [ 13 , 39 , 40 ]. Females wait to call emergency medical service (EMS) three minutes longer than males, and as measured by the EMS call, arrive at the hospital 10 minutes later than males [ 41 ]. These delays may be in part due to females being more likely to report vomiting as a chief symptom when calling EMS thereby being less likely to receive a high-priority ambulance response [ 23 ].

Ambulance-related delays are particularly present for African American females, who present to the hospital on average one hour later than the general population of males and females and 1.5 hours later than White females. For these African American females, a greater chest pain intensity was associated with an even greater delay whereas there was no delay for increased pain in White females [ 39 ]. /females who have a STEMI have a longer symptom-to-hospital arrival time than males although this time interval is not different between males and females when there is a non-STEMI (NSTEMI) [ 42 ].

There is some lack of clarity in this hospital delay in females compared to males, which may be related to typical versus atypical presentations of MI. In a Chinese cohort, females of all ages presented later than males of all ages, but when controlling for symptom type, no difference in hospital delay was seen between females and males [ 40 ]. On the other hand, a Swedish cohort showed no delay in symptom-to-hospital arrival time between males and females in the general population but for patients older than 65, the delay for 30.5% of females was more than four hours whereas only 25% of males were delayed by a similar amount [ 43 ]. Other common risk factors for symptom-to-hospital arrival time delay include being a non-White patient, low socioeconomic status, low education level, increasing age, and medical history of hypertension, DM, and renal insufficiency [ 13 , 40 ]. Disparities in the time delays may be related to the presence of typical versus atypical symptoms. Symptoms that match those expected for an MI reduced delay times in both sexes [ 12 ], while the presence of atypical symptoms increased delay times in both sexes with a larger delay in females than males [ 11 ].

Unrecognized and silent MI

With any discussion of symptoms of MI, it is important to discuss MIs that are asymptomatic (silent MI) and those that go unnoticed by patients and physicians (unrecognized MI). It is difficult to quantify the difference between silent MI and unrecognized MI, as all silent MIs are unrecognized by definition, while patients may vaguely recall chest pain years ago as a possible unrecognized MI, so the terms are often used interchangeably.

As with MI as a whole, males are more likely to have had a previous silent MI [ 44 ], with one study showing a rate of unrecognized MI in males ages 18-80 of 2.67 per 1000 person-years and a rate in females of 1.69 per 1000 person-years [ 45 ]. The rate of silent MI also changes with race, with Asians being most likely to have a silent MI, followed by Whites, then Hispanics, and finally African Americans [ 44 ]. Unrecognized MI accounts for approximately 30% of MIs in females and 16% of MIs in males [ 45 ], and somewhere between 20% and 40% of all MIs in the general population [ 46 ]. Unrecognized MI is also associated with hypertension (OR 1.82), being a former or active smoker (OR 1.82), and elevated blood glucose (OR 1.41). The entire spectrum of blood glucose dysfunction appears to be related to silent and unrecognized MI and may affect males and females differently. Impaired glucose tolerance is more common among females (OR 4.1) with unrecognized MI but not associated with unrecognized MI in males [ 47 ].

On the other hand, impaired fasting glucose and pre-diabetes have been shown to increase the risk of unrecognized MI in males but not females [ 48 ]. Patients with type 2 DM are more likely to have had silent or unrecognized MI regardless of sex, with an increased risk in females with microalbuminuria [ 49 , 50 ]. The prognosis of unrecognized MI is most likely similar to recognized MI but difficult detection makes mortality estimation difficult. MRI is significantly more accurate at detecting silent MI than ECG or echocardiography and its use in the future may help better quantify and detect silent MI in the general population [ 46 ].

Pathophysiology

There are physiological and pathophysiological differences in females and males that may impact differences in MI aspects between the sexes, but direct connections are not fully elucidated. For example, as females age, there is increased acetylation of mitochondrial DNA indicating decreased mitochondrial function compared to males. Young females have increased antioxidative metabolite presence when compared to males, but this difference is lost with age. There is also increased inflammatory macrophage presence and a corresponding increase in pro-inflammatory molecules such as NF-kB and IL-18 in female hearts where no increase is seen in males [ 17 ]. Females also show decreased heart rate variability with age as compared to males, suggesting a greater age-related reduction in autonomic function in females versus males [ 51 ]. It has also been reported that the presence of angiotensin I converting enzyme phenotype DD appears to double the risk of MI in males but not in females [ 52 ]. Though females present with a differing androgen hormonal profile than males, no association between differing endothelial or cardiac androgen receptor subtypes and MI or other cardiovascular diseases has been shown [ 53 ].

The role of atherosclerotic burden

At younger ages, females have an overall lower atherosclerotic burden as measured by intima media thickness than males, though this difference attenuates with age and is nonsignificant after age 65 [ 54 ]. When measured directly, males also have an increased number of atherosclerotic plaques on average compared to females at all ages [ 54 - 56 ]. One study showed no increase in plaque burden in females with age [ 55 ], though others found an increase but less than the increase seen in males [ 54 , 56 ]. When females have a >75% stenosis as measured by the diameter of plaque compared to the diameter of the coronary artery, there is a five-to-seven-fold increase in risk for infarction, while males show a doubling in risk [ 55 , 56 ]. When females have a low obstructive plaque burden but still have an MI, there is evidence that most of these MIs are due to plaque rupture or erosion, though this study did not examine MIs of males with the same conditions [ 57 ].

Coronary perfusion differences between males and females also impact MI feature differences. About 5-10% of MIs are considered to occur with nonobstructive coronary artery disease (myocardial infarction with no obstructive coronary artery disease (MINOCA)) [ 58 ]. MINOCA patients are younger, have more NSTEMI events, have lower cardiac troponin levels, and have greater ejection fractions than obstructive MI patients. Females with MINOCA are on average eight years older and have smaller MIs than males. Females also have significantly less multivessel disease than males (30% of females vs. 90% of males), which is consistent with the decreased prevalence of atherosclerotic plaques in females versus males [ 58 ]. When in an enhanced systemic inflammatory state (measured by increased vertebral bone marrow activity as a surrogate for leukocyte production) females have decreased myocardial perfusion and decreased left ventricular systolic function whereas no such decrease is seen in males [ 59 ].

Myocardial microvasculature considerations

For both males and females, increased myocardial microvasculature resistance is a sensitive predictor of future MI, the severity of a current MI, and adverse cardiac events following MI [ 60 - 63 ]. The two major ways to assess myocardial microvasculature resistance are by using coronary flow reserve (CFR) and an index of microvascular resistance (IMR). CFR is determined by resting mean transit time divided by hyperemic mean transit time of saline across an investigated vessel. IMR is determined by mean distal coronary pressure multiplied by hyperemic mean transit time of saline. Worse scores of either CFR or IMR predict worse outcomes of MI, and worse scores of both of these parameters in the same patient are most predictive of worse outcomes [ 64 ]. In MI patients, when examining arteries not responsible for an infarct compared to stable angina patients, MI patients have worse CFR throughout the heart, not just in the arteries involved with the infarcts [ 65 ]. Insulin resistance is also predictive of impaired CFR and overall impaired coronary microcirculatory function, again highlighting its important role in the hearts of females and males [ 66 ].

A sex-related difference attributable to microvascular differences is unclear. While it is true that small vessel disease is associated with unrecognized MI and a larger proportion of females than males with MI have unrecognized MI, no difference between females and males in microvasculature disease has been repeatedly shown throughout the literature, with few studies examining sex difference [ 67 ]. It has been shown that increasing age and time since menopause both are correlated with an overall decrease in systemic capillary refill time. Females who had used oral contraceptives in the past or used hormone replacement therapy after menopause had better microcirculatory function than those who did not, highlighting a possible protective role of both estrogen and progesterone in microcirculatory function and therefore cardiac events [ 68 ].

Pain tolerance as a possible differential factor

It has been proposed that sex differences in pain sensitivity may play into symptom differences in MI [ 18 ]. There are differences in pain sensitivity between the sexes and in states of inflammation females have a further reduced sensitivity [ 69 ]. However, pain tolerance as an explanation for differences in presentation between females and males has only been directly studied to our knowledge one time, where the presence of unrecognized MI was correlated with a higher pain threshold in females but not in males [ 18 ].

Type 1 versus type 2 MI

The vast majority of MIs are considered type 1 or type 2. Type 1 are infarcts related to a primary coronary event such as plaque erosion or rupture and type 2 are infarcts related to ischemia or other oxygen supply versus demand mismatches [ 70 , 71 ]. Depending on the study, 15-25% of MIs are type 2, though inconsistent awareness and diagnosis make the true number difficult to ascertain [ 71 - 73 ]. Patients with type 2 are more likely to be older and be females [ 71 - 73 ]. Independent of age, type 2 MIs are more likely to have other comorbidities including (in order of frequency) chronic kidney disease, atrial fibrillation, heart failure, anemia, depression, chronic obstructive pulmonary disease, valvular heart disease, liver disease, alcohol use disorder, and substance abuse disorder [ 71 - 73 ]. Type 1 patients are more likely to have risk factors for plaque formation including (in order of frequency) dyslipidemia, being a smoker, prior percutaneous coronary intervention, prior MI, and prior coronary artery bypass graft [ 71 ]. While type 2 patients are more likely to be older females, about 12% of younger females do not fit into one of the classical MI categories as their MIs oftentimes do not have evidence for myocardial supply versus demand mismatch. These categories may need to be amended to include obstructive and nonobstructive coronary artery disease without evidence for supply-demand mismatch to include these patients [ 74 ].

The objective of this review was to examine the symptomatic and pathophysiological differences between MI in males and females and possible links between the two. Though there are clear differences in both symptoms and pathophysiology of MI in males and females, links between the two are tenuous or omitted altogether from many articles. Symptomatically, females present most often with chest pain when having an MI, but so often present with “atypical” symptoms that the term atypical itself may need to be amended, as females present more often with an atypical symptom than they do without one. Prodromal symptoms also seem to be more common in females, which may be related in part to their increased likelihood of nonobstructive MI. This follows since prodromal symptoms should not occur weeks and months prior to an acute thrombus formation. Risk factor differences between the sexes also exist, with smoking, hypertension, and DM all impacting females more negatively than males. Clear pathophysiological differences also exist between the sexes, with females expressing a lower overall atherosclerotic burden on average than males when they have an MI. This difference in plaque burden, however, has not been evaluated for differences in symptoms in these patients, so its role in symptom differences is unclear at this time. Differences between females and males in the prevalence of type 1 versus type 2 MI also exist, though no studies included in this review examined symptom differences between the two MI variants.

There are a handful of explanations explored in this review for a pathophysiological difference leading to the symptomatic differences between males and females. It has been proposed that the difference in microvasculature resistance between males and females is etiologic for their presentation with atypical symptoms [ 75 ]. Increased microvascular resistance has been linked to unrecognized MI in females, and females are more likely to experience greater rates of resistance in their coronary microvasculature following menopause. It may be that these microvascular changes with age and menopause predispose females to more atypical symptoms that then go unrecognized. While no clear-cut causal relationship has been shown, it is a promising area of study for the future that may yield new avenues for MI recognition and treatment in females. It has also been proposed that sex differences in pain tolerance or sensation may predispose females to the wider variety of symptoms that are seen. Only one study has been completed in the area, however, where a link was drawn between unrecognized MI in females and a higher pain threshold. This is an area of research that should be expanded upon, as identifying females with higher pain thresholds may be a key player in the early recognition of symptoms for these patients.

Study limitations

Much of the limitation in this study comes down to a lack of evidence and a lack of studies examining the roles of different pathophysiological states and symptoms. While both symptom differences between males and females and the pathophysiology of MI in males and females have been studied extensively, very few conclusions other than speculation can be drawn about the aspects of physiology and pathophysiology that are causal in these symptom differences between the sexes.

Conclusions

There are differences between both symptoms and pathophysiology in MIs in females and males. However, few studies have examined a link between the two. Evaluation of symptom changes for patients with differing microvascular resistance and pain tolerance is especially promising in this realm. Differences in symptoms for patients with differing atherosclerotic burden and for patients with type 1 versus type 2 MI have not been studied to our knowledge and both may yield a further explanation of these symptom differences between females and males. Further studies with a focus on pathophysiological or physiological causes of symptom differences in MI between females and males are warranted.

The authors have declared that no competing interests exist.