Menopause-Related Estrogen Decrease and the Pathogenesis of HFpEF

Sabbatini, A.; Kararigas, Georgios

doi:10.1016/j.jacc.2019.12.049

Cited by 108 publications

(88 citation statements)

References 94 publications

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“…However, as recent experimental evidence has emphasized, they exert a relevant cardioprotective role governing important intracellular processes, such as the intracellular ion flux [ 18 ] and the hypertrophic response of cardiomyocytes [ 19 ], as well as the collagen synthesis of the extracellular matrix in response to stressors [ 20 ]. It is currently assumed that the decline of estrogen at menopause is a major contributor to the pathogenesis of heart failure, particularly the phenotype with preserved ejection fraction, a clinical entity very common in older women with hypertension, central obesity and glycemic derangement [ 21 ]. In the current real-world study, we found a trend towards an increased risk of heart failure and CV events in women treated with aromatase inhibitors, a pure anti-estrogen agent, as compared to those treated with tamoxifen, an agonist/antagonist estrogen drug with possibly cardioprotective activity [ 22 , 23 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

Adjuvant Hormonotherapy and Cardiovascular Risk in Post-Menopausal Women with Breast Cancer: A Large Population-Based Cohort Study

Franchi

Tritto

Tarantini

et al. 2021

Cancers

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Background: Whether aromatase inhibitors (AIs) increase the risk of cardiovascular (CV) events, compared to tamoxifen, in women with breast cancer is still debated. We evaluated the association between AI and CV outcomes in a large population-based cohort of breast cancer women. Methods: By using healthcare utilization databases of Lombardy (Italy), we identified women ≥50 years, with new diagnosis of breast cancer between 2009 and 2015, who started adjuvant therapy with either AI or tamoxifen. We estimated the association between exposure to AI and CV outcomes (including myocardial infarction, ischemic stroke, heart failure or any CV event) by a Cox proportional hazard model with inverse probability of treatment and censoring weighting. Results: The study cohort included 26,009 women starting treatment with AI and 7937 with tamoxifen. Over a median follow-up of 5.8 years, a positive association was found between AI and heart failure (Hazard Ratio = 1.20, 95% CI: 1.02 to 1.42) and any CV event (1.14, 1.00 to 1.29). The CV risk increased in women with previous CV risk factors, including hypertension, diabetes and dyslipidemia. Conclusions: Adjuvant therapy with AI in breast cancer women aged more than 50 years is associated with increased risk of heart failure and combined CV events.

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Section: Discussionmentioning

confidence: 99%

Adjuvant Hormonotherapy and Cardiovascular Risk in Post-Menopausal Women with Breast Cancer: A Large Population-Based Cohort Study

Franchi

Tritto

Tarantini

et al. 2021

Cancers

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“…A higher proportion of women among HFpEF patients might result from their higher life expectancy [72]. However, estrogen deficiency has been postulated as one of the contributors underlying HFpEF development in post-menopausal women [74][75][76]. Among HF-pEF patients, women have smaller LV dimensions with poorer diastolic reserve and higher LV filling pressures at rest and exercise [77].…”

Section: Practical Considerations On Clinical Profilesmentioning

confidence: 99%

On the search for the right definition of heart failure with preserved ejection fraction

et al. 2020

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The definition of heart failure with preserved ejection fraction (HFpEF) has evolved from a clinically based "diagnosis of exclusion" to definitions focused on objective evidence of diastolic dysfunction and/ /or elevated left ventricular filling pressures. Despite advances in our understanding of HFpEF pathophysiology and the development of more sophisticated imaging modalities, the diagnosis of HFpEF remains challenging, especially in the chronic setting, given that symptoms are provoked by exertion and diagnostic evaluation is largely conducted at rest. Invasive hemodynamic study, and in particularinvasive exercise testing, is considered the reference method for HFpEF diagnosis. However, its use is limited as opposed to the high number of patients with suspected HFpEF. Thus, diagnostic criteria for HFpEF should be principally based on non-invasive measurements. As no single non-invasive variable can adequately corroborate or refute the diagnosis, different combinations of clinical, echocardiographic, and/or biochemical parameters have been introduced. Recent years have brought an abundance of HF-pEF definitions. Here, we present and compare four of them: 1) the 2016 European Society of Cardiology criteria for HFpEF; 2) the 2016 echocardiographic algorithm for diagnosing diastolic dysfunction; 3) the 2018 evidence-based H 2 FPEF score; and 4) the most recent, 2019 Heart Failure Association HFA-PEFF algorithm. These definitions vary in their approach to diagnosis, as well as sensitivity and specificity. Further studies to validate and compare the diagnostic accuracy of HFpEF definitions are warranted. Nevertheless, it seems that the best HFpEF definition would originate from a randomized clinical trial showing a favorable effect of an intervention on prognosis in HFpEF.

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“…Systemic inflammation plays a major role in the development of HFpEF (Franssen et al., 2016; Paulus & Tschope, 2013). Notably, men and women differ in the activation of adaptive and innate immunity, with females exhibiting an attenuated inflammatory response, with decreased inflammatory cytokine production (Kararigas et al., 2014; Sabbatini & Kararigas, 2020). In addition, cytokine receptors and parts of the inflammasome are regulated in a sex‐specific manner (Sabbatini & Kararigas, 2020).…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the incidence and mode of death in rats with heart failure with preserved ejection fraction

Elkholey

Morris

Niewiadomska

et al. 2021

Experimental Physiology

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New Findings What is the central question of this study?Prior studies failed to address the role of sex in modifying the pathophysiology and response to therapy in heart failure with preserved ejection fraction (HFpEF), potentially introducing bias into translational findings. We aimed to explore sex differences in outcomes and sought to identify the underlying mechanisms in a well‐established rat model of HFpEF. What is the main finding and its importance?Male rats with HFpEF exhibited worse survival compared with females and were at a higher risk for sudden death, attributable in part to QT prolongation, autonomic dysregulation and enhanced inflammation. These data might provide the basis for the development of sex‐specific interventions in HFpEF targeting these abnormalities. Abstract Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure, and sudden death is the leading cause of mortality. We aimed to explore sex differences in outcomes in rats with HFpEF and sought to identify the underlying mechanisms. Dahl salt‐sensitive rats of either sex were randomized into high‐salt diet (HS diet; 8% NaCl, n = 46, 50% female) or low‐salt diet (LS diet; 0.3% NaCl; n = 24, 50% female) at 7 weeks of age. After 6 and 10 weeks of LS or HS diets, the ECG, heart rate variability, cytokines and echocardiographic parameters were measured. The animals were monitored daily for development of HFpEF and survival. Over 6 weeks of HS diet, rats developed significant hypertension and signs of HFpEF. Compared with female HS diet‐fed rats, males exhibited more left ventricular dilatation, a longer QT interval, and worse autonomic tone, as assessed by heart rate variability and elevated inflammatory cytokines. Ten of 23 (46%) male rats died during follow‐up, compared with two of 23 (9%) female rats (P = 0.01). There were four sudden deaths in males (with ventricular tachycardia documented in one rat), whereas the females died of heart failure. In conclusion, male rats with HFpEF exhibit worse survival compared with females and are at a higher risk for sudden death, attributable in part to QT prolongation, autonomic dysregulation and enhanced inflammation. These data might provide the basis for the development of sex‐specific interventions in HFpEF targeting these abnormalities.

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Menopause-Related Estrogen Decrease and the Pathogenesis of HFpEF

Cited by 108 publications

References 94 publications

Adjuvant Hormonotherapy and Cardiovascular Risk in Post-Menopausal Women with Breast Cancer: A Large Population-Based Cohort Study

Adjuvant Hormonotherapy and Cardiovascular Risk in Post-Menopausal Women with Breast Cancer: A Large Population-Based Cohort Study

On the search for the right definition of heart failure with preserved ejection fraction

Sex differences in the incidence and mode of death in rats with heart failure with preserved ejection fraction

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