The problem with heart failure

By Sophie Piesse

Humans have probably suffered from cardiovascular disease since the beginning of time. Several Egyptian mummies were discovered with evidence of atherosclerosis, a disease in which we see a build-up of fatty deposits in the arteries, called plaque [1]. Atherosclerosis can prevent blood flow to the heart muscle itself, preventing oxygenation of cardiomyocytes and leading to an acute myocardial infarction (a heart attack) [2]. The discovery that humans suffered from cardiovascular disease more than 3,000 years ago showed that the factors contributing to disease progression are nothing new. However, the modern westernised diet of foods high in sugar and saturated fat has led to a global escalation in the prevalence of cardiovascular disease [3]. This has meant that over the last century, scientists have worked to understand the physiology of the heart, and the way that cardiovascular disease manifests in these patients. Astonishingly, the end stage of most cardiovascular diseases ⁠— heart failure ⁠— affects 2% of the world’s population [4]. Heart failure is the inability of the heart to pump enough blood around the body at the required rate. This leads to a wide variety of symptoms like fatigue, shortness of breath, swelling and heart palpitations [5]. While the incidence of heart failure is decreasing, the burden of the disease remains high owing to our ageing population [6].

Image by Robina Weermeiher on Unsplash

Half of those afflicted with heart failure are women [7]. We see a variety of sex-related differences in heart failure, such as how the disease develops, the clinical presentation, and potential outcomes [8]. For example, women are more likely to develop heart failure later in life than men, when they are post-menopausal [8]. Women also tend to develop a specific type of heart failure; heart failure with preserved ejection fraction (HFpEF) [8]. Ejection fraction is the fraction of blood pushed out of the left ventricle into the systemic circulation with each contraction. In men with heart failure, we see a higher rate of heart failure with reduced ejection fraction [9].

Differences occurring in heart failure between men and women (or anyone with ovaries) are thought to be the result of differences in sex hormone levels. Estrogen is a sex hormone, the majority of which is produced in the ovary. Those without ovaries produce much less estrogen. Estrogen receptors are present in the tissue of the heart and estrogen has been shown to act in a protective way to prevent cell death and cellular enlargement in the heart [4],[10],[11]. This aids in preventing adverse myocardial remodelling. Myocardial remodelling is the change in shape and size of the heart following a heart attack [12]. In adverse myocardial remodelling, we see mass cell death and deposition of collagen fibres as a result of ischemia at the site of infarction [4]. Collagen distorts the structure of the heart, while enlargement of cardiomyocytes causes the left ventricle to enlarge [13]. Both of these changes contribute to a decrease in functionality of the left ventricle.

Following menopause and the cessation of estrogen production, women have an increased risk of developing heart failure. Animal studies have shown that the heart failure of a post-menopausal model shows more similarities to heart failure in a male [11]. Therefore when estrogen production is lost, the heart may become more vulnerable to developing more severe heart failure. Hormone replacement therapy in postmenopausal women has been shown to be protective against heart failure in some cases [14]. It is currently unknown when estrogen acts during myocardial remodelling and how this activity changes after menopause.

Unfortunately, we have an overall lack of understanding of heart failure in older women. Women have been chronically under-studied in clinical trials on heart disease compared to men of the same age [15]. A randomised controlled trial in 2002 assessed that previous clinical trials in the US had failed to gain an accurate representation of the population suffering from heart failure [16]. The majority of those included in clinical trials were young, white, cisgender men who displayed a reduced ejection fraction [16]. This has created a void of clinical data on myocardial infarction, myocardial remodelling, and heart failure in women that still exists today [4], [16]. Importantly, it has created a therapeutic gap between women and men, as the first line of therapy for heart failure is a drug, the angiotensin-converting enzyme (ACE) inhibitor [9]. ACE inhibitors work by blocking the renin-angiotensin-aldosterone system, leading to vasodilation, reducing systemic vascular resistance and increasing blood flow [17]. ACE inhibitors are highly effective at treating heart failure with reduced ejection fraction, reducing mortality by 31% after one year [9].

In heart failure with preserved ejection fraction, there is no clinically approved therapy, placing women at risk [18]. ACE inhibitors do not change the mortality rate in those with HFpEF [9]. On top of that, women may experience a delay in diagnosis and treatment as a result of the misconception that heart failure is less common in women [7]. It only gets worse from there. Women with heart failure are less likely to receive approved treatments, more likely to be incorrectly dosed, and more likely to experience adverse drug effects [4], [19]. Women have a higher rate of hospital readmission and overall worse quality of life following initial heart failure diagnosis [19].

Image by Towfiqu Barbhuiya on Unsplash

The lack of diversity in clinical trials has not only impacted cis-gender women; information on how heart failure impacts people of colour and the transgender community is also severely lacking. It is heart-wrenching to see the clear disadvantage that women and minority groups have been placed in as a result of prejudice within the scientific community. Considering cardiovascular disease impacts a large majority of people across the world and will likely continue to do so, studying only one group of people is poor practice. Sadly, we are still seeing the same issues within clinical trials being reported today [20]. Until we have a better idea of how heart failure impacts the wider population, those with the disease will continue to suffer.

References

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[2] P. Dutta et al., “Myocardial infarction accelerates atherosclerosis,” vol. 487, no. 7407, pp. 325–329, 2012, doi: 10.1038/nature11260.

[3] E. Oikonomou et al., “Western Dietary Pattern Is Associated With Severe Coronary Artery Disease,” vol. 69, no. 4, pp. 339–346, Apr. 2018, doi: 10.1177/0003319717721603.

[4] A. Postigo and M. Martínez-Sellés, “Sex Influence on Heart Failure Prognosis,” vol. 7, p. 616273, 2020, doi: 10.3389/fcvm.2020.616273.

[5] J. J. Atherton et al., “National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Guidelines for the Prevention, Detection, and Management of Heart Failure in Australia 2018,” vol. 27, no. 10, pp. 1123–1208, Oct. 2018, doi: 10.1016/j.hlc.2018.06.1042.

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[8] G. Savarese and D. D’Amario, Sex Differences in Heart Failure. Cham: Springer International Publishing, 2018, pp. 529–544.

[9] G. Sayer, and G. Bhat, PhD, “The Renin-Angiotensin-Aldosterone System and Heart Failure,” vol. 32, no. 1, pp. 21–32, 2014, doi: 10.1016/j.ccl.2013.09.002.

[10] M. Piro, R. Della Bona, A. Abbate, L. M. Biasucci, and F. Crea, “Sex-related differences in myocardial remodeling,” 2010, doi: 10.1016/j.jacc.2009.09.065.

[11] H. Lu, G. C. Meléndez, S. P. Levick, and J. S. Janicki, “Prevention of adverse cardiac remodeling to volume overload in female rats is the result of an estrogen-altered mast cell phenotype,” vol. 302, no. 3, pp. 811–817, Feb. 2012, doi: 10.1152/ajpheart.00980.2011.

[12] S. Dunlay and V. Roger, “Gender Differences in the Pathophysiology, Clinical Presentation, and Outcomes of Ischemic Heart Failure,” vol. 9, no. 4, pp. 267–276, Dec. 2012, doi: 10.1007/s11897-012-0107-7.

[13] A. Bhatt, A. Ambrosy, and E. Velazquez, “Adverse Remodeling and Reverse Remodeling After Myocardial Infarction,” vol. 19, no. 8, pp. 1–10, Aug. 2017, doi: 10.1007/s11886-017-0876-4.

[14] F. Naftolin, J. Friedenthal, R. Nachtigall, and L. Nachtigall, “Cardiovascular health and the menopausal woman: the role of estrogen and when to begin and end hormone treatment,” vol. 8, 2019, doi: 10.12688/f1000research.15548.1.

[15] B. Bozkurt and S. Khalaf, “Heart Failure in Women,” vol. 13, no. 4, pp. 216–223, Oct. 2017, doi: 10.14797/mdcj-13-4-216.

[16] A. Heiat, C. P. Gross, and H. M. Krumholz, “Representation of the Elderly, Women, and Minorities in Heart Failure Clinical Trials,” vol. 162, no. 15, pp. 1682–1688, Aug. 2002, doi: 10.1001/archinte.162.15.1682.

[17] P. A. Poole-Wilson, “ACE inhibitors and ARBs in chronic heart failure: the established, the expected, and the pragmatic,” vol. 87, no. 2. Elsevier Inc, United States, pp. 373–389, 2003, doi: 10.1016/S0025-7125(02)00174-8.

[18] J. J. McMurray et al., “Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction Insights From PARAGON-HF,” vol. 141, no. 5, pp. 338–351, Feb. 2020, doi: 10.1161/CIRCULATIONAHA.119.044491.

[19] R. López-Vilella et al., “The Female Sex Confers Different Prognosis in Heart Failure: Same Mortality but More Readmissions,” vol. 8, p. 618398, 2021, doi: 10.3389/fcvm.2021.618398.

[20] X. Jin, C. Chanamouli, B. Allocco, E. Gong, C. S. P. Lam, and L. L. Yan, “Women’s Participation in Cardiovascular Clinical Trials From 2010 to 2017,” vol. 141, no. 7, pp. 540–548, Feb. 2020, doi: 10.1161/CIRCULATIONAHA.119.043594.