bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2024–10–06
six papers selected by
Kyle McCommis, Saint Louis University
  1. Afterload-induced Decreases in Fatty Acid Oxidation Develop Independently of Increased Glucose Utilization.
  2. Leveraging metabolism for better outcomes in heart failure.
  3. Efficacy and Safety of Finerenone Across the Ejection Fraction Spectrum in Heart Failure with Mildly Reduced and Preserved Ejection Fraction: a Prespecified Analysis of The FINEARTS-HF Trial.
  4. Usp20 deletion promotes eccentric cardiac remodeling in response to pressure overload and increases mortality.
  5. Fueling the Heart: What Are the Optimal Dietary Strategies in Heart Failure?
  6. Intracardiac energy inefficiency during decompensated and compensated heart failure.
  1. bioRxiv. 2024 Sep 18. pii: 2024.09.17.613531. [Epub ahead of print]
    Afterload-induced Decreases in Fatty Acid Oxidation Develop Independently of Increased Glucose Utilization.
    Hande C Piristine, Herman I May, Nan Jiang, Daniel Daou, Francisco Olivares-Silva, Abdallah Elnwasany, Pamela Szweda, Luke Szweda, Caroline Kinter, Michael Kinter, Gaurav Sharma, Xiaodong Wen, Craig R Malloy, Michael E Jessen, Thomas G Gillette, Joseph A Hill.
       Background: Metabolic substrate utilization in HFpEF (heart failure with preserved ejection fraction), the leading cause of heart failure worldwide, is pivotal to syndrome pathogenesis and yet remains ill defined. Under resting conditions, oxidation of free fatty acids (FFA) is the predominant energy source of the heart, supporting its unremitting contractile activity. In the context of disease-related stress, however, a shift toward greater reliance on glucose occurs. In the setting of obesity or diabetes, major contributors to HFpEF pathophysiology, the shift in metabolic substrate use toward glucose is impaired, sometimes attributed to the lower oxygen requirement of glucose oxidation versus fat metabolism. This notion, however, has never been tested conclusively. Furthermore, whereas oxygen demand increases in the setting of increased afterload, myocardial oxygen availability remains adequate for fatty acid oxidation (FAO). Therefore, a "preference" for glucose has been proposed.
    Methods and Results: Pyruvate dehydrogenase complex (PDC) is the rate-limiting enzyme linking glycolysis to the TCA cycle. As PDK4 (PDC kinase 4) is up-regulated in HFpEF, we over-expressed PDK4 in cardiomyocytes, ensuring that PDC is phosphorylated and thereby inhibited. This leads to diminished use of pyruvate as energy substrate, mimicking the decline in glucose oxidation in HFpEF. Importantly, distinct from HFpEF-associated obesity, this model positioned us to abrogate the load-induced shift to glucose utilization in the absence of systemic high fat conditions. As expected, PDK4 transgenic mice manifested normal cardiac performance at baseline. However, they manifested a rapid and severe decline in contractile performance when challenged with modest increases in afterload triggered either by L-NAME or surgical transverse aortic constriction (TAC). This decline in function was not accompanied by an exacerbation of the myocardial hypertrophic growth response. Surprisingly, metabolic flux analysis revealed that, after TAC, fractional FAO decreased, even when glucose/pyruvate utilization was clamped at very low levels. Additionally, proteins involved in the transport and oxidation of FFA were paradoxically downregulated after TAC regardless of genotype.
    Conclusions: These data demonstrate that cardiomyocytes in a setting in which glucose utilization is robustly diminished and prevented from increasing do not compensate for the deficit in glucose utilization by up-regulating FFA use.
    DOI:  https://doi.org/10.1101/2024.09.17.613531
  2. Cardiovasc Res. 2024 Oct 01. pii: cvae216. [Epub ahead of print]
    Leveraging metabolism for better outcomes in heart failure.
    Yann Huey Ng, Yen Chin Koay, Francine Z Marques, David M Kaye, John F O'Sullivan.
      Whilst metabolic inflexibility and substrate constraint have been observed in heart failure for many years, their exact causal role remains controversial. In parallel, many of our fundamental assumptions about cardiac fuel use are now being challenged like never before. For example, the emergence of sodium glucose cotransporter 2 inhibitor (SGLT2i) therapy as one of the four "pillars" of heart failure therapy is causing a revisit of metabolism as a key mechanism and therapeutic target in heart failure. Improvements in the field of cardiac metabolomics will lead to a far more granular understanding of the mechanisms underpinning normal and abnormal human cardiac fuel use, an appreciation of drug action, and novel therapeutic strategies. Technological advances and expanding biorepositories offer exciting opportunities to elucidate the novel aspects of these metabolic mechanisms. Methodologic advances include comprehensive and accurate substrate quantitation such as metabolomics and stable-isotope fluxomics, improved access to arterio-venous blood samples across the heart to determine fuel consumption and energy conversion, high quality cardiac tissue biopsies, biochemical analytics, and informatics. Pairing these technologies with recent discoveries in epigenetic regulation, mitochondrial dynamics, and organ-microbiome metabolic crosstalk will garner critical mechanistic insights in heart failure. In this state-of-the-art review, we focus on new metabolic insights, with an eye on emerging metabolic strategies for heart failure. Our synthesis of the field will be valuable for a diverse audience with an interest in cardiac metabolism.
    Keywords:  SGLT2i; cardiac metabolism; epigenetics; heart failure; microbiome; therapy
    DOI:  https://doi.org/10.1093/cvr/cvae216
  3. Circulation. 2024 Sep 29.
    Efficacy and Safety of Finerenone Across the Ejection Fraction Spectrum in Heart Failure with Mildly Reduced and Preserved Ejection Fraction: a Prespecified Analysis of The FINEARTS-HF Trial.
    Kieran F Docherty, Alasdair D Henderson, Pardeep S Jhund, Brian L Claggett, Akshay S Desai, Katharina Mueller, Prabhakar Viswanathan, Andrea Scalise, Carolyn S P Lam, Michele Senni, Sanjiv J Shah, Adriaan A Voors, Faiez Zannad, Bertram Pitt, Muthiah Vaduganathan, Scott D Solomon, John Jv McMurray.
       BACKGROUND: The effect of treatments for heart failure may vary among patients according to left ventricular ejection fraction (LVEF). In the FINEARTS-HF, the nonsteroidal MRA finerenone reduced the risk of cardiovascular death and total worsening heart failure events in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). We examined the effect of finerenone according to LVEF in FINEARTS-HF.
    METHODS: FINEARTS-HF was a randomized, placebo-controlled trial examining the efficacy and safety of finerenone in patients with heart failure and LVEF &#x226540%. The treatment effect of finerenone was examined in prespecified analyses according to LVEF categories (<50%, ≥50 to <60%, and ≥60%) and with LVEF as a continuous variable. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death.
    RESULTS: Baseline LVEF data were available for 5993 of the 6001 participants in FINEARTS-HF. Mean and median LVEF were 53 ± 8% and 53% (IQR 46% -58%), respectively. LVEF was <50% in 2172 (36), between 50 to <60% in 2674 (45%), and ≥60% in 1147 (19%). Patients with a higher LVEF were older, more commonly female, were less likely to have a history of coronary artery disease, and more frequently had a history of hypertension and chronic kidney disease compared to those with a lower LVEF. Finerenone reduced the risk of cardiovascular death and total heart failure events consistently across LVEF categories: LVEF <50% rate ratio (RR) = 0.84 (95% CI 0.68, 1.03), LVEF ≥50 to <60% RR = 0.80 (0.66, 0.97) and LVEF ≥60% RR = 0.94 (0.70, 1.25); p interaction = 0.70. There was no modification of the benefit of finerenone across the range of LVEF when analyzed as a continuous variable (p interaction = 0.28). There was a similar consistent effect of finerenone on reducing the total number of worsening heart failure events (continuous p interaction = 0.26).
    CONCLUSIONS: In patients with HFmrEF/HFpEF, finerenone reduced the risk of cardiovascular death and worsening heart failure events, irrespective of LVEF.
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.072011
  4. Am J Physiol Heart Circ Physiol. 2024 Oct 04.
    Usp20 deletion promotes eccentric cardiac remodeling in response to pressure overload and increases mortality.
    Pierre-Yves Jean-Charles, Bipradas Roy, Samuel Mon-Wei Yu, Gianluigi Pironti, Karim Nagi, Lan Mao, Suneet Kaur, Dennis M Abraham, Stuart Maudsley, Howard A Rockman, Sudha K Shenoy.
      Left ventricular hypertrophy (LVH) caused by chronic pressure overload with subsequent pathological remodeling is a major cardiovascular risk factor for heart failure and mortality. The role of deubiquitinases in LVH has not been well-characterized. To define if the deubiquitinase ubiquitin-specific peptidase 20 (USP20) regulates LVH, we subjected USP20 knockout (KO) and cognate wild type (WT) mice to chronic pressure overload by transverse aortic constriction (TAC) and measured changes in cardiac function by serial echocardiography followed by histological and biochemical evaluations. USP20-KO mice showed severe deterioration of systolic function within 4-weeks of TAC compared to WT cohorts. Both USP20-TAC and WT-TAC cohorts presented cardiac hypertrophy following pressure overload. However, USP20-KO-TAC mice showed an increase in cardiomyocyte length and developed maladaptive eccentric hypertrophy, a phenotype generally observed with volume-overload states and decompensated heart failure. In contrast, WT-TAC mice displayed increase in cardiomyocyte width, producing concentric remodeling that is characteristic of pressure overload. In addition, cardiomyocyte apoptosis, interstitial fibrosis and mouse mortality were augmented in USP20-KO-TAC compared to WT-TAC mice. Quantitative mass spectrometry of LV tissue revealed that the expression of sarcomeric myosin heavy chain 7 (MYH7), a fetal gene normally upregulated during cardiac remodeling was significantly reduced in USP20-KO after TAC. Mechanistically, we identified increased degradative lysine-48 polyubiquitination of MYH7 in USP20-KO hearts indicating that USP20-mediated deubiquitination likely prevents protein degradation of MYH7 during pressure overload. Our findings suggest that USP20-dependent signaling pathways regulate the layering pattern of sarcomeres to suppress maladaptive remodeling during chronic pressure overload and prevent cardiac failure.
    Keywords:  apoptosis; cardiac hypertrophy; deubiquitinase; eccentric hypertrophy; heart failure
    DOI:  https://doi.org/10.1152/ajpheart.00329.2024
  5. Nutrients. 2024 Sep 18. pii: 3157. [Epub ahead of print]16(18):
    Fueling the Heart: What Are the Optimal Dietary Strategies in Heart Failure?
    Anahita Ataran, Alexander Pompian, Hamidreza Hajirezaei, Rehman Lodhi, Ali Javaheri.
       OBJECTIVES: Heart failure (HF) is a global health concern with rising incidence and poor prognosis. While the essential role of nutritional and dietary strategies in HF patients is acknowledged in the existing scientific guidelines and clinical practice, there are no comprehensive nutritional recommendations for optimal dietary management of HF.
    METHODS: In this review, we discuss results from recent studies on the obesity paradox and the effects of calorie restriction and weight loss, intermittent fasting, the Western diet, the Mediterranean diet, the ketogenic diet, and the DASH diet on HF progression.
    RESULTS: Many of these strategies remain under clinical and basic investigation for their safety and efficacy, and there is considerable heterogeneity in the observed response, presumably because of heterogeneity in the pathogenesis of different types of HF. In addition, while specific aspects of cardiac metabolism, such as changes in ketone body utilization, might underlie the effects of certain dietary strategies on the heart, there is a critical divide between supplement strategies (i.e., with ketones) and dietary strategies that impact ketogenesis.
    CONCLUSION: This review aims to highlight this gap by exploring emerging evidence supporting the importance of personalized dietary strategies in preventing progression and improving outcomes in the context of HF.
    Keywords:  Mediterranean-style diet; calorie restriction; diet; heart failure; ketogenic diet; weight loss
    DOI:  https://doi.org/10.3390/nu16183157
  6. ESC Heart Fail. 2024 Sep 27.
    Intracardiac energy inefficiency during decompensated and compensated heart failure.
    Tetsuma Kawaji, Kazuhisa Kaneda, Hidenori Yaku, Bingyuan Bao, Shun Hojo, Yuji Tezuka, Shintaro Matsuda, Hiroki Shiomi, Masashi Kato, Takafumi Yokomatsu, Shinji Miki, Koh Ono.
       AIMS: The mechanisms underlying the acute decompensation of heart failure (HF) remain unclear. The present study examined intracardiac dynamics during decompensated HF using echo-vector flow mapping.
    METHODS AND RESULTS: Fifty patients admitted for decompensated HF were prospectively enrolled, and intracardiac energy loss (EL) was assessed by echo-vector flow mapping at admission (decompensated HF) and discharge (compensated HF). Outcome measures were average EL in the left ventricle (LV) in decompensated and compensated HF and were compared with those in 40 stable non-HF patients with cardiovascular diseases. The mean age of HF patients was 80.8 ± 12.4 years. The prevalence of both females and atrial fibrillation was 48.0%. The prevalence of HF with a reduced ejection fraction (<40%) (HFrEF) was 34.0%. The prevalence of decompensated HF classified into clinical scenario 1 was 33.3%. Blood pressure and NT-proBNP were significantly higher in decompensated HF than in compensated HF, while the ejection fraction (EF) was significantly lower. Average EL was significantly higher in compensated HF patients than in non-HF patients (40 mW/m·L vs. 26 mW/m·L, P = 0.047). A multivariable analysis identified age, systolic blood pressure, LVEF, and the absence of chronic obstructive pulmonary disease as independent risk factors for high LV-EL regardless of the presence of HF. Furthermore, average EL in HF patients was significantly higher under acute decompensated conditions than under compensated conditions (55 mE/m·L vs. 40 mE/m·L, [+18 mE/m·L, P = 0.03]). Higher EL under decompensated HF conditions was significant in non-HFrEF (+19 mW/m·L, P = 0.009) and clinical scenario 1 (+23 mW/m·L, P = 0.008). The multivariable analysis identified eGFR as an independent risk factor for a decrease in average LV-EL under decompensated conditions.
    CONCLUSIONS: Energy inefficiency in LV was apparent even in stable HF patients and significant under acute decompensated conditions, particularly in HF with preserved EF and clinical scenario 1.
    Keywords:  Heart failure; Intracardiac inefficiency; Vector flow mapping
    DOI:  https://doi.org/10.1002/ehf2.15034
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