Outcomes With sGC Therapy in Patients With HFpEF: A Meta-Analysis of Prior Trials

Thakker, Ravi; Elbadawi, Ayman; Albaeni, Aiham; Perez, Christopher; Hasan, Syed Mustajab; Murrieta, Jose Iturrizaga; Almustafa, Ahmed; Duarte, Alexander G.; Berbarie, Rafic F.; Chatila, Khaled; Khalife, Wissam

doi:10.1016/j.cpcardiol.2021.100924

Cited by 7 publications

(8 citation statements)

References 18 publications

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“…Patients with HFrEF tended to respond by slightly decreasing NTproBNP levels, whereas, HFpEF phenotype has a tendency to respond either by neutral or increasing levels. This was contrary to a previous analysis of Zheng et al in which the authors reported that there was a decrease in NTproBNP levels with riociguat, but not with vericiguat 30 . Of note, VICTORIA trial had not been published at the time of that analysis 22 .…”

Section: Discussioncontrasting

confidence: 99%

The efficacy and safety of soluble guanylate cyclase modulation in patients with heart failure: a comprehensive meta-analysis of randomized controlled trials

Arayici,

Gunes,

Ellidokuz

et al. 2024

Sci Rep

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Soluble guanylate cyclase (sGC) modulation has been scrutinized in several disease states including heart failure (HF). Recently, it was shown that an sGC modulator improved HF-related hospitalization significantly, though, there was no benefit related to mortality. Herein, a comprehensive meta-analysis of randomized controlled trials (RCTs) for sGC modulation in HF patients was provided in agreement with the PRISMA statement. A total of 10 RCTs yielding 12 papers were included. There were 7526 patients with heart failure of each phenotype, 4253 in the sGC modulator group and 3273 in the placebo group. Use of sGC modulators in HF patients yielded no significant difference in the risk of all-cause mortality compared to placebo (RR = 0.97, 95% CI 0.88–1.08, p = 0.62). The use of sGC modulators was associated with a trend toward a considerable but non-significant increase in the incidence of SAEs (RR = 1.10, 95% CI 0.99–1.22, p = 0.07), as well as an increased incidence of hypotension and anemia. There was an overall neutral effect of sGC modulation on NT-proBNP levels, 6MWD and mortality, at a cost of slight increase in hypotension and anemia. Of note, the improvement in EQ-5D-based quality of life was significant. Hence, the benefit seems to be driven by distinctive domains of quality of life.

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Section: Discussioncontrasting

confidence: 99%

The efficacy and safety of soluble guanylate cyclase modulation in patients with heart failure: a comprehensive meta-analysis of randomized controlled trials

Arayici,

Gunes,

Ellidokuz

et al. 2024

Sci Rep

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“…So far, four outcomes studies in HFpEF patients treated with vericiguat have been conducted (CAPACITY HFpEF, VITALIY HFpEF, SOCRATES-PRESERVED and DILATE-1 trials). A meta-analysis has been performed by Thakker et al ( Thakker et al, 2021 ). Overall, the treatment with vericiguat did not improve the 6-min walk distance nor the Kansas City Cardiomyopathy Questionnaire physical limitation score.…”

Section: Therapeutic Options In Hfpef Between Facts and Beliefmentioning

confidence: 99%

Current Understanding of Molecular Pathophysiology of Heart Failure With Preserved Ejection Fraction

et al. 2022

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Heart Failure (HF) is the most common cause of hospitalization in the Western societies. HF is a heterogeneous and complex syndrome that may result from any dysfunction of systolic or diastolic capacity. Abnormal diastolic left ventricular function with impaired relaxation and increased diastolic stiffness is characteristic of heart failure with preserved ejection fraction (HFpEF). HFpEF accounts for more than 50% of all cases of HF. The prevalence increases with age: from around 1% for those aged <55 years to >10% in those aged 70 years or over. Nearly 50% of HF patients have HFrEF and the other 50% have HFpEF/HFmrEF, mainly based on studies in hospitalized patients. The ESC Long-Term Registry, in the outpatient setting, reports that 60% have HFrEF, 24% have HFmrEF, and 16% have HFpEF. To some extent, more than 50% of HF patients are female. HFpEF is closely associated with co-morbidities, age, and gender. Epidemiological evidence suggests that HFpEF is highly represented in older obese women and proposed as ‘obese female HFpEF phenotype’. While HFrEF phenotype is more a male phenotype. In addition, metabolic abnormalities and hemodynamic perturbations in obese HFpEF patients appear to have a greater impact in women then in men (Sorimachi et al., European J of Heart Fail, 2022, 22). To date, numerous clinical trials of HFpEF treatments have produced disappointing results. This outcome suggests that a “one size fits all” approach to HFpEF may be inappropriate and supports the use of tailored, personalized therapeutic strategies with specific treatments for distinct HFpEF phenotypes. The most important mediators of diastolic stiffness are the cardiomyocytes, endothelial cells, and extracellular matrix (ECM). The complex physiological signal transduction networks that respond to the dual challenges of inflammatory and oxidative stress are major factors that promote the development of HFpEF pathologies. These signalling networks contribute to the development of the diseases. Inhibition and/or attenuation of these signalling networks also delays the onset of disease. In this review, we discuss the molecular mechanisms associated with the physiological responses to inflammation and oxidative stress and emphasize the nature of the contribution of most important cells to the development of HFpEF via increased inflammation and oxidative stress.

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“… 14 , 44 , 45 , 46 , 47 NO therapeutics failed to provide benefit when compared with the standard of care but were shown to be safe and well tolerated in patients with HFpEF. 15 , 16 , 44 , 48 …”

Section: Discussionmentioning

confidence: 99%

Combination Sodium Nitrite and Hydralazine Therapy Attenuates Heart Failure With Preserved Ejection Fraction Severity in a “2‐Hit” Murine Model

LaPenna

Doiron

et al. 2023

JAHA

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Background Recent studies have suggested that cardiac nitrosative stress mediated by pathological overproduction of nitric oxide (NO) via inducible NO synthase (iNOS) contributes to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Other studies have suggested that endothelial NO synthase (eNOS) dysfunction and attenuated NO bioavailability contribute to HFpEF morbidity and mortality. We sought to further investigate dysregulated NO signaling and to examine the effects of a NO‐based dual therapy (sodium nitrite+hydralazine) following the onset of HFpEF using a “2‐hit” murine model. Methods and Results Nine‐week‐old male C57BL/6 N mice (n=15 per group) were treated concurrently with high‐fat diet and N(ω)‐nitro‐L‐arginine methyl ester (L‐NAME) (0.5 g/L per day) via drinking water for 10 weeks. At week 5, mice were randomized into either vehicle (normal saline) or combination treatment with sodium nitrite (75 mg/L in the drinking water) and hydralazine (2.0 mg/kg IP, BID). Cardiac structure and function were monitored with echocardiography and invasive hemodynamic measurements. Cardiac mitochondrial respiration, aortic vascular function, and exercise performance were also evaluated. Circulating and myocardial nitrite were measured to determine the bioavailability of NO. Circulating markers of oxidative or nitrosative stress as well as systemic inflammation were also determined. Severe HFpEF was evident by significantly elevated E/E', LVEDP, and Tau in mice treated with L‐NAME and HFD, which was associated with impaired NO bioavailability, mitochondrial respiration, aortic vascular function, and exercise capacity. Treatment with sodium nitrite and hydralazine restored NO bioavailability, reduced oxidative and nitrosative stress, preserved endothelial function and mitochondrial respiration, limited the fibrotic response, and improved exercise capacity, ultimately attenuating the severity of “two‐hit” HFpEF. Conclusions Our data demonstrate that nitrite, a well‐established biomarker of NO bioavailability and a physiological source of NO, is significantly reduced in the heart and circulation in the “2‐hit” mouse HFpEF model. Furthermore, sodium nitrite+hydralazine combined therapy significantly attenuated the severity of HFpEF in the “2‐hit” cardiometabolic HFpEF. These data suggest that supplementing NO‐based therapeutics with a potent antioxidant and vasodilator agent may result in synergistic benefits for the treatment of HFpEF.

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Outcomes With sGC Therapy in Patients With HFpEF: A Meta-Analysis of Prior Trials

Cited by 7 publications

References 18 publications

The efficacy and safety of soluble guanylate cyclase modulation in patients with heart failure: a comprehensive meta-analysis of randomized controlled trials

The efficacy and safety of soluble guanylate cyclase modulation in patients with heart failure: a comprehensive meta-analysis of randomized controlled trials

Current Understanding of Molecular Pathophysiology of Heart Failure With Preserved Ejection Fraction

Combination Sodium Nitrite and Hydralazine Therapy Attenuates Heart Failure With Preserved Ejection Fraction Severity in a “2‐Hit” Murine Model

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