No such thing as an innocent bystander: the conundrum of obesity, diabetes, and heart failure with preserved ejection fraction

Seferović, Petar; Polovina, Marija; Veljić, Ivana; Ašanin, Milika

doi:10.1093/eurjpc/zwad226

Cited by 2 publications

(4 citation statements)

References 22 publications

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“…4,5 Diabesity is a common denominator for a majority of patients with HFpEF and is linked to a higher symptom burden and worse outcomes compared to non-diabese patients and thus, of significant importance to cardiologists. 6,7 In addition, there is a substantial unmet medical need for novel therapies treating diabesity-related HF and preventing progression of asymptomatic cardio-metabolic syndromes to clinically overt HF. 8…”

Section: Introductionmentioning

confidence: 99%

Modulating Cardiac Energetics in Cardio-Metabolic Syndromes: A mechanistic, hyperpolarized MR Trial of Ninerafaxstat Treatment

Hundertmark,

Siu,

Matthews

et al. 2024

Preprint

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Background: Type 2 diabetes (T2D) and obesity are key contributors for heart failure (HF)-development, especially for HF with a preserved ejection fraction (HFpEF). On a molecular basis, excessive use of fatty acids (FA) induces lipotoxicity which in turn promotes inflammation, reduces mitochondrial pyruvate dehydrogenase (PDH) activity and impairs myocardial energetics and -function. Harnessing in-vivo, real time measurement of cellular metabolism via hyperpolarized pyruvate MR, we aimed to assess the effects of ninerafaxstat, a selective FA oxidation inhibitor, on cardiac energetics, metabolism & diastolic function in patients with cardio-metabolic syndromes. Methods: IMPROVE-DiCE was an open-label, mechanistic phase 2a trial. 21 participants received 200mg ninerafaxstat twice daily for four (n=5) or eight weeks (n=16). Myocardial energetics (phosphocreatine to adenosine triphosphate ratio, PCr/ATP), metabolism and function were assessed pre- & post-treatment using magnetic resonance imaging (MRI), 31P- and 1H-MR spectroscopy (MRS). We utilised hyperpolarized [1-13C]pyruvate MRS to assess in-vivo PDH-flux (n=9) and plasma metabolomics and proteomics to assess whole body metabolism. Results: Patients presented with impaired PCr/ATP, (median 1.6 [IQR 1.4, 2.1]), myocardial steatosis (2.2 % [IQR 1.5, 3.2]) and LV diastolic dysfunction (peak circumferential diastolic strain rate 0.86/s [IQR 0.82, 1.06]) at baseline. Ninerafaxstat treatment improved myocardial energetics by 32% (p<0.01), reduced myocardial triglyceride content by 34% (p=0.03) and showed a trend towards improved PDH-flux (mean 45% increase, p=0.08). Diastolic function was significantly improved post-treatment (peak diastolic strain rate by 10%, peak LV filling rate by 11%, both p<0.05). Conclusions: Metabolic modulation with ninerafaxstat significantly improved myocardial energetics, reduced myocardial steatosis and improved LV diastolic filling. Combining hyperpolarized MRS and metabolomics, is a powerful approach to examine the mechanism of action of novel metabolic modulators.

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Section: Introductionmentioning

confidence: 99%

Modulating Cardiac Energetics in Cardio-Metabolic Syndromes: A mechanistic, hyperpolarized MR Trial of Ninerafaxstat Treatment

Hundertmark,

Siu,

Matthews

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…This condition primarily affects individuals who are overweight or obese, raising intriguing questions about the intricate relationship between obesity and HFpEF 2 . Recent research indicates that obesity might not merely coexist with HFpEF but could actively contribute to its development and progression 3 …”

Section: Introductionmentioning

confidence: 99%

“… 2 Recent research indicates that obesity might not merely coexist with HFpEF but could actively contribute to its development and progression. 3 …”

Section: Introductionmentioning

confidence: 99%

“…2 Recent research indicates that obesity might not merely coexist with HFpEF but could actively contribute to its development and progression. 3 Individuals living with HFpEF and obesity face more adverse hemodynamic and clinical features. They experience a heavier symptom burden, reduced functional capacity, and a significantly impaired quality of life compared to HFpEF patients without obesity.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of semaglutide in patients with heart failure with preserved ejection fraction and obesity

Rehman,

Saidullah,

Asad

et al. 2024

Clinical Cardiology

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BackgroundSemaglutide, a once‐weekly glucagon‐like peptide‐1 receptor agonist, has shown promise in weight management and cardiovascular outcomes in other populations. This study aimed to evaluate the efficacy of semaglutide in heart failure with preserved ejection fraction (HFpEF) patients with obesity.MethodsA retrospective study analyzed 318 patients with HFpEF, of which 104 received semaglutide and 214 received placebo. Primary endpoints included evaluating changes in exercise capacity and weight management.ResultsSemaglutide treatment led to significant improvements in the primary endpoints. Patients in the semaglutide group demonstrated substantial enhancements in exercise capacity, as measured by the 6‐min walk distance, compared to the placebo group (mean difference 15.1 meters, 95% CI 5.8 to 24.4, p = 0.002). Additionally, semaglutide resulted in substantial weight loss compared to placebo (mean difference −2.9%, 95% CI −4.1–−1.7, p = 0.001). Several secondary endpoints, including reductions in C‐reactive protein levels and improvements in other clinical parameters, further supported the efficacy of semaglutide. Adverse events were generally well‐tolerated, with no unexpected safety concerns.ConclusionSemaglutide demonstrated significant clinical benefits in HFpEF patients with obesity, as evidenced by improved symptoms, physical function, and weight reduction.

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No such thing as an innocent bystander: the conundrum of obesity, diabetes, and heart failure with preserved ejection fraction

Cited by 2 publications

References 22 publications

Modulating Cardiac Energetics in Cardio-Metabolic Syndromes: A mechanistic, hyperpolarized MR Trial of Ninerafaxstat Treatment

Modulating Cardiac Energetics in Cardio-Metabolic Syndromes: A mechanistic, hyperpolarized MR Trial of Ninerafaxstat Treatment

Efficacy and safety of semaglutide in patients with heart failure with preserved ejection fraction and obesity

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