Sex & Gender in Acute Care Medicine

1. Sex & Gender in Acute Care Medicine Chapter 2: Cardiology

2. Chapter 2: Gender in Acute Care Cardiology Morgan Soffler Alyson J. McGregor BasmahSafdar

3. Acute Coronary Syndromes – Case Study • A 54 year old women presents with a sensation of burning in her chest x 1 week • The burning is associated with shortness of breath and fatigue • She attributed her symptoms to anxiety but came in at the urging of her son • Her symptoms are worse when walking upstairs and became acutely worse today

4. ACS – Case Study • Pt has a past medical history of diabetes • No family history of coronary artery disease, stroke, or sudden death • She smokes 10 cigarettes/day • Her only medication is 1000 mg Metformin 2x daily

5. ACS – Case Study • On exam, she is afebrile with a BP of 145/85 • Heart rate of 98 bpm • Normal respirations, O2 saturation of 96% on room air • She has clear lung fields and no JVD • Cardiac exam shows regular rate and rhythm without murmurs, gallops, or rubs • PMI is nondisplaced

6. ACS – Case Study • Abdominal exam is benign, extremities are without edema, 2+ pedal pulses • EKG with sinus rhythm and T-wave inversions in leads I and AVL • Initial troponin is negative • Chest X-ray is normal

7. Clinical Questions • How would you approach a cardiac work-up in this patient? • What are the gender-specific elements in diagnosis and management that you should consider?

8. Acute Coronary Syndromes • ACS should be the first diagnostic consideration for this patient • Coronary artery disease (CAD) is the leading cause of death for women and men in the U.S. • CAD onset occurs 10-15 years earlier in men than in women • More women die of CAD each year than men • Mortality rates in women have increased in the past decade

9. Gender-Specific Approach to ACS • According to 2012 ACA/AHA guidelines, the initial approach should include gender-specific risk stratification • 3 basic pillars for identifying CAD • History of presentation • Serial ECG • Biomarkers Should be determined before conducting an anatomical or functional stress test

10. ACS Presentation • Only about 1/3 of women with ischemic heart disease experience warning chest pain • Compared to men, women are more likely to complain of shortness of breath, fatigue, and weakness in the month prior to MI • Earlier reports suggest women are more likely to present with atypical symptoms

11. ACS Presentation • Recent study of 2,475 ED patients found that chest pain/discomfort was the most common complaint in men and women • Differences in how women describe chest discomfort and in the frequency of atypical symptoms • Women under-recognize symptoms and delay seeking care (by 2-3 hrs on average)

12. Role of Cardiac Risk Factors • There is gender-specific moderation of cardiac risk factors • Copenhagen City Heart Study found a twofold higher risk of MI in women with type-2 diabetes • Smoking increases the risk of CAD in women by 25% compared to men • Dyslipidemia, hypertension increase risk in men more so than in women

13. Role of Cardiac Risk Factors • Nontraditional risk factors (depression, autoimmune disorders) are more frequent in women • Depression has been associated with a fourfold increase in post-AMI mortality • Gender-specific risk attribution is important in assessing overall risk to symptomatic patients

14. Investigative Studies • Serial ECGs recommended in men and women • Frequency of ST segment abnormalities is similar in men and women with ACS • Women more often have T-wave inversions • New evidence that 99th percentile for troponin assays is lower in women • Changing the diagnostic threshold would increase precision of diagnosis

15. Risk Stratification Scores • Divide patients into low-, intermediate-, and high-risk groups to guide management • Framingham Score and ATP-III underestimate 10-year risk of CAD in women compared to Reynolds Risk score • Reynolds Risk score is derived from 24,000 women and is unique in its consideration of sex-related factors (CRP, metabolic syndrome)

16. Risk Stratification Scores • Age also affects accuracy of traditional scores • Young women have a low pretest probability of developing CAD • Yet a recent study reported a high burden of cardiac risk factors in young (<55) women compared to general population • Traditional scores underestimate risk in these populations

17. Risk Stratification Scores • These scores provide immediate assessment for risk of AMI and death in patients with acute chest pain • Of these scores, only the EDACS includes gender and has been validated in at least one study TIMI score, GRACE risk score, HEART score, Vancouver Chest Pain rule, QPTP ACS instrument, EDACS

18. Diagnostic Testing • 2013 ACC/AHA guidelines recommend no differences in testing for men and women • Sensitivity and specificity of diagnostic tests are influenced by • Lower prevalence of CAD in premenopausal women • Lower incidence of single vessel disease in women

19. Diagnostic Testing • Exercise treadmill test has diminished accuracy (61-70%) in women compared to men (70-80%) • Coronary CT angiogram (cCTA) provides excellent image quality • However, there’s a non-negligible lifetime risk of cancer associated with cCTA • Risk appears highest in younger women with combined cardiac and aortic scans

20. Clinical Pearls • CAD is the leading cause of death in the U.S. • In women: more atypical symptoms, absent warning chest pain, delayed diagnosis and treatment • The Reynolds Risk Score is a sex-specific risk stratification tool • Exercise stress testing has a high false positive rate in women - best used in women with intermediate pretest probability

21. Sex-Specific Pathophysiology • Women have less obstructive pathology • Chest pain symptoms do not correlate with severity of stenosis • Women have worse outcomes after AMI – despite having smaller infarcts and more preserved systolic function • Higher rates of other disorders suggestive of vascular dysfunction (migraines, Reynaud’s phenomenon)

22. Sex-Specific Pathophysiology • Coronary artery obstruction is the most common cause of ischemic chest pain • There are alternate mechanisms of chest pain that are more prevalent in women than men • Syndrome X, which includes coronary and microvessel dysfunction • Women have stiffer aortas and smaller coronary vessels than men

23. Non-Obstructive CAD • The WISE study found that up to 47% of women undergoing elective angiography had <50% obstruction of the coronary artery • Compared to 17% of men • Vasoreactive dysfunction coexists with non-obstructive CAD causing angina despite negative angiography • 20% of women with normal or non-obstructive angiography have myocardial ischemia based on perfusion imaging

24. Clinical Pearls • Obstructive CAD is the most common cause of ischemic chest pain in men and women • Other causes such as Syndrome X and microvascular disease are more common in women • Women who undergo coronary angiography are more likely than men to have non-obstructive CAD (<50% stenosis)

25. Treatment of ACS in Women • For patients with STEMI, immediate reperfusion is recommended in men and women • PCI has been found to be superior to fibrinolysis in women with STEMI • Yet timing of treatment is more important than treatment strategy

26. Treatment of ACS in Women • NSTEMI treatments do not demonstrate sex-specific advantages • However, recommended anticoagulant dose is lower in women • Due to higher risk of bleeding that may be related to lower body weight • PCI is associated with a 33% decreased risk of death, MI, or repeat ACS in biomarker positive women

27. Treatment of ACS in Women • Biomarker negative women had greater risk • This risk of adverse outcomes was not evident in men • Invasive therapy is recommended for all men • But only for intermediate-high-risk women • Medical management is recommended for low-risk women • No randomized controlled trials compare PCI and CABG in men and women

28. Prognosis of ACS in Women • Women with prior MI have higher morbidity and mortality rates than their male counterparts -- acutely and long term • This trend applies across the spectrum of coronary disease • Women with ACS have higher rates of cardiogenic shock, bleeding, and vascular complications

29. Prognosis of ACS in Women • In a study of women presenting with chest pain, those with non-obstructive CAD had a 16% five-year adverse event rate • Compared to 7.9% adverse event rate in women with normal coronary arteries • The extent of non-obstructive CAD is a significant estimator of mortality in women • In men, number of non-obstructive lesions does not appear to be an estimator of mortality

30. Clinical Pearls • Medical and interventional treatments for STEMI and NSTEMI are equally effective in men and women • Women with acute MI have higher mortality than their male counterparts • Women with non-obstructive CAD have higher rates of future CAD than women with normal coronary arteries on angiography

31. Case Conclusion and Rationale • Patient has atypical symptoms of ACS, significant risk factors (diabetes and smoking) • Initial negative troponin is reassuring, but ECG shows evidence of ischemia in lateral leads • She is treated with aspirin and a beta • Admitted to Chest Pain Unit for monitoring on telemetry, repeat troponin, and ECGs • Exercise treadmill testing is indeterminate

32. Case Conclusion and Rationale • Echocardiogram shows mild diastolic dysfunction with preserved systolic function • Patient discharged; worsening symptoms at follow up • Cardiac catheterization reveals non-obstructive CAD • Medical optimization, treatment with tricyclic antidepressants and exercise ultimately improve her symptoms

33. Takotsubo Cardiomyopathy (TC) • A reversible cardiomyopathy • Often precipitated by emotional stress • Now referred to as “Apical Ballooning Syndrome” or “Broken Heart Syndrome” • Majority of patients are women, typically post-menopausal and white

34. Takotsubo Cardiomyopathy (TC) • Patients typically present with signs and symptoms of ACS and recent severe emotional stress • ECG abnormalities are common • Anterior ST segment elevation has been reported in >90% of patients • Patients may develop deep symmetrical T-wave inversions within 25-48 hrs and may have prolonged QTc interval

35. Takotsubo Cardiomyopathy (TC) • Cardiac enzyme elevation is variable but often abnormal • On cardiac catheterization, patients with TC show no evidence of obstructive CAD • Prospective studies show systolic dysfunction • With ejection fractions ranging from 9-29% • TC has a distinctive apical ballooning with associated basal hypercontractility at end systole

36. Takotsubo Cardiomyopathy (TC) • No strict diagnostic criteria for TC • Several mechanisms are proposed, including transient multi-vessel epicardial spasm and microvascular ischemia • Unknown why women are predisposed to TC • Thought to be related to gender differences in myocardial sensitivity to catecholamines • TC should be managed in the same way as ACS

37. Clinical Course of TC • TC has a favorable prognosis; in-hospital mortality is low (~1 to 3%) • Complications, though uncommon, can include hemodynamic instability, arrhythmias, heart failure, and cardiogenic shock • Most common causes of mortality are cardiogenic shock and systemic embolization

38. Clinical Pearls • Takotsubo’s Cardiomyopathy has a clinical presentation similar to ACS • Often precipitated by stress • Initial management is similar to acute management of STEMI • Prognosis is almost uniformly favorable

39. Spontaneous Coronary Artery Dissection (SCAD) • A rare cause of acute MI • Approx. 82% of cases occur in women • Thought to be caused by a tear in or bleeding from the vasavasorum in the endocardium • In the largest cohort study (n=87), chest pain was the presenting complaint in 91% of patients • 49% presented with STEMI / 44% with NSTEMI

40. Spontaneous Coronary Artery Dissection (SCAD) • Many patients in this cohort reported exertion prior to event • Another large contingent was postpartum • SCAD is treated like ACS • Patients should receive emergent angiography followed by PCI or CABG • In-hospital mortality is low, yet 10-year recurrence rate is about 30%

41. Heart Failure (HF) • HF can result from a number of structural and functional cardiac disorders • ED visits for HF have increased by 20% in the past decade • Most common ED discharge diagnosis, particularly in elderly women

42. Definition and Types of HF • Echocardiography is routinely used to measure ejection fraction (EF) and to classify HF patients into two groups: • Those with reduced systolic function (HFREF; heart failure with reduced EF) • Those with preserved systolic function (HFPEF; heart failure with preserved EF)

43. Definition and Types of HF • Most studies show that more men than women have HFREF • The most common cause of HFREF in the US is coronary artery disease • Previous MI is seen less frequently in patients with HFPEF, which is more common in women • HFPEF is associated with marked increase in all-cause mortality

44. Lack of Evidence in Women • Although equal numbers of men and women live with HF, women are underrepresented in clinical studies • What we currently know about HF is largely based on data collected from men • This makes it difficult to determine differences in clinical characteristics in men and women with HF

45. Sex Differences in HF: Physiology • Women are twice as likely to develop HFPEF • Many factors contribute to this discrepancy • Left ventricular chamber size and mass are 15-40% smaller in women • Men experience loss of myocardium at 1g per year; left ventricular mass is preserved in women • Left ventricular diastolic dysfunction correlates with arterial stiffness in women, but not in men

46. Cardiovascular Questions 1. Which of the following are sex specific diagnostic approaches to Acute Coronary Syndrome (ACS)? (A) History of Present Illness (B) Serial ECG (C) Cardiac Biomarkers (D) A&C (E) All of the above Answer: (E) All of the above In accordance with the 2012 American College of Cardiology and the American Heart Association guidelines, the initial approach for risk stratification relies upon HPI, serial ECG and biomarkers prior to conducting anatomical or functional stress tests. Reference: 1. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. Jun 11 2013;127(23):e663-828.

47. Cardiovascular Questions 2. Which of the following statements are true regarding presentation of Acute Coronary Syndrome (ACS) in men and women? (A) Chest pain is the most common presenting complaint in both men and women. (B) Women are more likely then men to not experience any chest pain. (C) Men are less likely to report associated symptoms of fatigue, nausea, jaw/shoulder pain then women. (D) B&C (E) All of the above Answer: (E) All of the above HPI: Chest pain is the most common presenting complaint in both men and women. The difference in gender is found in their description of chest discomfort (instead of pain) and the increased reporting of associated symptoms of fatigue, nausea, jaw/shoulder pain by women. Women are also more likely then men to not experience any chest pain (42% women vs. 21% men). In general, women under-recognize their symptoms and delay seeking care by 2-3 hours. References: 1. JAMA Intern Med. 2014 Feb 1;174(2):241-9. doi: 10.1001/jamainternmed.2013.12199. Sex-specific chest pain characteristics in the early diagnosis of acute myocardial infarction. RubiniGimenez M1, Reiter M2, Twerenbold R3, Reichlin T4, Wildi K5, Haaf P2, Wicki K2, Zellweger C5, Hoeller R5, Moehring B5, Sou SM5, Mueller M2, Denhaerynck K2, Meller B2, Stallone F2, Henseler S2, Bassetti S6, Geigy N7, Osswald S2, Mueller C2.  2. Khan NA, Daskalopoulou SS, Karp I, et al. Sex differences in acute coronary syndrome symptom presentation in young patients. JAMA internal medicine. Nov 11 2013;173(20):1863-1871.  3. Canto AJ, Kiefe CI, Goldberg RJ, et al. Differences in symptom presentation and hospital mortality according to type of acute myocardial infarction. American heart journal. Apr 2012;163(4):572-579.  4. Ting HH, Chen AY, Roe MT, et al. Delay from symptom onset to hospital presentation for patients with non-ST-segment elevation myocardial infarction. Archives of internal medicine. Nov 8 2010;170(20):1834-1841.

48. Cardiovascular Questions 3. Which of the following risk factors have a greater influence of myocardial infarction (MI) in women as compared to men? (A) Diabetes (B) Hypertension (C) Depression (D) Smoking (E) A, C & D Answer: (E) Diabetes, depression, and smoking predispose women to a greater risk of MI than men. References: 1. AlmdalT, Scharling H, Jensen JS, Vestergaard H. The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Archives of Internal Medicine 2004;164(13):1422–26. 2. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. British Medical Journal (clinical research ed.) 2006;332(7533):73–78. 3. 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. 4. Gender, Depression, and One-Year Prognosis After Myocardial Infarction. Frasure-Smith, Nancy PhD; Lesperance, Francois MD; Juneau, Martin MD; Talajic, Mario MD; Bourassa, Martial G. MD.

49. Cardiovascular Questions 4. Which of the following statements are accurate with regard to biomarker use in men and women with ACS? (A) The 99th percentile for troponin assays is higher for men as compared to women (B) The 99th percentile for troponin assays is the same for men and women. (C) The 99th percentile for troponin assays is higher for women as compared to men (D) The 99th percentile for troponin assays is lower for men as compared to women (E) C & D Answer: (A) Biomarkers: New data indicate that the 99th percentile for troponin assays are consistently lower for women as compared to men. High-sensitivity troponin assays change the diagnostic threshold and increase the precision of diagnosis in women. Additional prognostic value has been attributed to beta-natriuretic protein and C-reactive protein in women, however larger trials are needed before these biomarkers become standard of care in ACS. References: 1. High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study. Shah AS, Griffiths M, Lee KK, McAllister DA, Hunter AL, Ferry AV, Cruikshank A, Reid A, Stoddart M, Strachan F, Walker S, Collinson PO, Apple FS, Gray AJ, Fox KA, Newby DE, Mills NL. 2. BMJ. 2015 Jan 21;350:g7873. doi: 10.1136/bmj.g7873. Erratum in: BMJ. 2015;350:h626.

50. Cardiovascular Questions 5. Coronary artery obstruction >50% is the most common cause of ischemic chest pain regardless of gender. However, clinicians now understand the existence of alternate mechanisms of cardiac chest pain, which are more prevalent in women than in men and can be categorized as which of the following? (A) Coronary artery spasm (B) Slow Flow Phenomenon (C) Microvascular Spasm (D) Cardiac Syndrome X (E) All of the above Answer: (E) All of the above Two major categories of non-obstructive coronary artery disease include a)Large vessel vasoreactive dysfunction commonly seen as coronary artery spasm and b) Small vessel (microvessel) dysfunction. Small vessel dysfunction represents a heterogeneous group of disorders including slow flow phenomenon, microvascular angina, microvascular spasm and cardiac syndrome X. Two theoretical explanations of sex specific differences in coronary pathophysiology that lead to greater vessel dysfunction are 1) women have a higher proportion of vascular conditions in general, including hypertensive disorders of pregnancy, peri-partum dissection, migraine, vasculitis, and Raynauds 2) women also have smaller coronary vessels and more diffuse disease patterns which may contribute. Vasoreactive dysfunction often co-exists with non-obstructive coronary artery disease causing angina despite ‘negative’ angiography. At least 20% of women with normal or nonobstructive angiography have evidence of myocardial ischemia by perfusion imaging. *see next slide for references