Sex Hormones and Change in N-Terminal Pro–B-Type Natriuretic Peptide Levels: The Multi-Ethnic Study of Atherosclerosis

Ying, Wendy; Zhao, Di; Ouyang, Pamela; Subramanya, Vinita; Vaidya, Dhananjay; Ndumele, Chiadi E; Sharma, Kavita; Shah, Sanjiv J.; Heckbert, Susan R.; Lima, João A.C.; deFilippi, Christopher R.; Budoff, Matthew J.; Post, Wendy S.; Michos, Erin D.

doi:10.1210/jc.2018-01437

Cited by 38 publications

(39 citation statements)

References 50 publications

(35 reference statements)

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“…There are also known sex differences in natriuretic peptide biology, with "cross talk" between these peptides and sex hormones, possibly leading to a decrease in natriuretic peptide levels after the menopause. 5,[23][24][25][26][27][28] This potential relative natriuretic peptide deficiency will lead to reduced cGMP-protein kinase G (PKG) signaling. [24][25][26][27][28][29][30][31] Any reduction in cGMP-PKG signaling due to a relative natriuretic peptide deficiency may be exacerbated in postmenopausal women by of loss of alternative, estrogen-dependent, stimulation of this pathway through endothelial nitric oxide synthase activation and nitric oxide generation.…”

Section: Discussionmentioning

confidence: 99%

Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction

et al. 2020

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Background: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction (HFpEF), the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women, compared with men. Methods: In a pre-specified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial which compared sacubitril-valsartan and valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. Results: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older, had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP levels than men. For the primary outcome, the rate ratio for sacubitrilvalsartan versus valsartan was 0.73 (95% CI 0.59-0.90) in women and 1.03 (0.84-1.25) in men; P interaction=0.017. The benefit from sacubitril-valsartan was due to reduction in heart failure hospitalization. The improvement in NYHA class and renal function with sacubitrilvalsartan was similar in women and men, whereas the improvement in KCCQ-CSS was less in women than in men. The difference in adverse events, between sacubitril-valsartan and valsartan, was similar in women and men. Conclusion: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. While the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding.

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Section: Discussionmentioning

confidence: 99%

Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction

et al. 2020

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“…93 They have an important role in contemporary HF management, with BNP and its amino-terminal-peptide fragment (NT-proBNP) being the most important molecules used to diagnose (or exclude) HF in patients presenting with acute dyspnoea (Class I, Level A evidence). 2,13,86,101 In the general population, circulating levels of cardiac NPs are approximately two-fold higher in women compared with men ( Figure 3B), 26,27,44,45 [20][21][22][23][24]103,104 which may partly explain the relative cardiac NP deficiency in men. The exact mechanism through which testosterone reduces cardiac NP levels remains poorly understood, although up-regulation of neprilysin activity by testosterone may be one possible explanation.…”

Section: Unlikelymentioning

confidence: 99%

“…• Testosterone suppresses NP levels [20][21][22][23][24] • Oestrogens may increase NP levels, 25 but more data needed…”

Section: Natriuretic Peptidesmentioning

confidence: 99%

“…2,18,27,88,101 In a meta-analysis community-dwelling individuals (grey) using pooled data from multiple studies. [24][25][26][27]30,33,[40][41][42] On average, N-terminal pro-B-type natriuretic peptide (NT-proBNP) is ∼45-fold higher in HF patients compared with healthy individuals, followed by troponins (∼6-fold), soluble interleukin-1 receptor-like 1 (sST2, ∼2.5-fold), and galectin-3 (∼1.5-fold). (B) Impact of sex on circulating biomarker levels in the general population and in HF patients.…”

Section: Heart Failure Prediction and Prognosismentioning

confidence: 99%

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Sex‐related differences in contemporary biomarkers for heart failure: a review

Suthahar

Meems

et al. 2020

European J of Heart Fail

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The use of circulating biomarkers for heart failure (HF) is engrained in contemporary cardiovascular practice and provides objective information about various pathophysiological pathways associated with HF syndrome. However, biomarker profiles differ considerably among women and men. For instance, in the general population, markers of cardiac stretch (natriuretic peptides) and fibrosis (galectin‐3) are higher in women, whereas markers of cardiac injury (cardiac troponins) and inflammation (sST2) are higher in men. Such differences may reflect sex‐specific pathogenic processes associated with HF risk, but may also arise as a result of differences in sex hormone profiles and fat distribution. From a clinical perspective, sex‐related differences in biomarker levels may affect the objectivity of biomarkers in HF management because what is considered to be ‘normal’ in one sex may not be so in the other. The objectives of this review are, therefore: (i) to examine the sex‐specific dynamics of clinically relevant HF biomarkers in the general population, as well as in HF patients; (ii) to discuss the overlap between sex‐related and obesity‐related effects, and (iii) to identify knowledge gaps to stimulate research on sex‐related differences in HF.

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“…Sex differences in prevalence and outcomes of diastolic dysfunction and HF have been reported ( O’Meara et al, 2007 ; Meyer et al, 2013 ; Gori et al, 2014 ) and might be partially explained by withdrawal of estrogens at the time of menopause ( Merz and Cheng, 2016 ) given that functional estrogen receptors reside in the myocardium ( Mahmoodzadeh et al, 2006 ). Indeed, myocardium remodeling can result from pathways involving sex hormones and the natriuretic peptide system, which modulates diastolic dysfunction and HF ( Hong et al, 1992 ; Maffei et al, 2001 ; Lam et al, 2011 ; Goncalves et al, 2017 ; Subramanya et al, 2018 ; Ying et al, 2018 ). However, comorbidities ( Abramov et al, 2011 ; Paulus and Tschöpe, 2013 ) and age ( Loffredo et al, 2014 ) also affect cardiac function and could explain the differences observed in several patient studies.…”

Section: Introductionmentioning

confidence: 99%

Passive Stiffness of Left Ventricular Myocardial Tissue Is Reduced by Ovariectomy in a Post-menopause Mouse Model

et al. 2018

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Background: Heart failure (HF) – a very prevalent disease with high morbidity and mortality – usually presents with diastolic dysfunction. Although post-menopause women are at increased risk of HF and diastolic dysfunction, poor attention has been paid to clinically and experimentally investigate this group of patients. Specifically, whether myocardial stiffness is affected by menopause is unknown.Aim: To investigate whether loss of female sexual hormones modifies the Young’s modulus (E) of left ventricular (LV) myocardial tissue in a mouse model of menopause induced by ovariectomy (OVX).Methods: After 6 months of bilateral OVX, eight mice were sacrificed, fresh LV myocardial strips were prepared (∼8 × 1 × 1 mm), and their passive stress–stretch relationship was measured. E was computed by exponential fitting of the stress–stretch relationship. Subsequently, to assess the relative role of cellular and extracellular matrix components in determining OVX-induced changes in E, the tissues strips were decellularized and subjected to the same stretching protocol to measure E. A control group of eight sham-OVX mice was simultaneously studied.Results: E (kPa; m ± SE) in OVX mice was ∼twofold lower than in controls (11.7 ± 1.8 and 22.1 ± 4.4, respectively; p < 0.05). No significant difference between groups was found in E of the decellularized tissue (31.4 ± 12.05 and 40.9 ± 11.5, respectively; p = 0.58).Conclusion: Loss of female sexual hormones in an OVX model induces a reduction in the passive stiffness of myocardial tissue, suggesting that active relaxation should play a counterbalancing role in diastolic dysfunction in post-menopausal women with HF.

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Sex Hormones and Change in N-Terminal Pro–B-Type Natriuretic Peptide Levels: The Multi-Ethnic Study of Atherosclerosis

Cited by 38 publications

References 50 publications

Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction

Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction

Sex‐related differences in contemporary biomarkers for heart failure: a review

Passive Stiffness of Left Ventricular Myocardial Tissue Is Reduced by Ovariectomy in a Post-menopause Mouse Model

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