bims-hafaim 2022-11-13 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022–11–13
six papers selected by
Kyle McCommis, Saint Louis University

Effects of Dapagliflozin in Asian Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF.
Ketone Body Exposure of Cardiomyocytes Impairs Insulin Sensitivity and Contractile Function through Vacuolar-Type H+-ATPase Disassembly-Rescue by Specific Amino Acid Supplementation.
Dapagliflozin in patients with heart failure with mildly reduced and preserved ejection fraction treated with a mineralocorticoid receptor antagonist or sacubitril/valsartan.
Sex Differences in Characteristics, Outcomes and Treatment Response with Dapagliflozin across the Range of Ejection Fraction in Patients with Heart Failure: Insights from DAPA-HF and DELIVER.
SGLT2 Inhibitors Improve Cardiac Failure by Reducing Whole-Body Oxygen Demand: A Hypothesis.
Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial.

JACC Asia. 2022 Apr;2(2): 139-153

Effects of Dapagliflozin in Asian Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF.

Kieran F Docherty, Inder S Anand, Chern-En Chiang, Vijay K Chopra, Akshay S Desai, Masafumi Kitakaze, Subodh Verma, Pham N Vinh, Silvio E Inzucchi, Lars Køber, Mikhail N Kosiborod, Felipe A Martinez, Olof Bengtsson, Piotr Ponikowski, Marc S Sabatine, Mikaela Sjöstrand, Scott D Solomon, Anna Maria Langkilde, Pardeep S Jhund, John J V McMurray.

   Background: Patients with heart failure with reduced ejection fraction (HFrEF) in Asia exhibit many differences from those in other parts of the world.
Objectives: This study sought to investigate the efficacy and safety of dapagliflozin, compared with placebo, in HFrEF patients in Asia, compared with those elsewhere, enrolled in the DAPA-HF (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure) trial.
Methods: Patients in New York Heart Association functional class II to IV with a left ventricular ejection fraction ≤40% and elevated N-terminal pro-B-type natriuretic peptide were eligible for the DAPA-HF trial. The primary outcome in the DAPA-HF trial was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death.
Results: Of the 4,744 patients in the DAPA-HF trial, 1,096 (23.1%) were enrolled in Asia; 721 (15.2% overall, 65.8% of patients in Asia) were enrolled in East Asia (237 in China, 343 in Japan, and 141 in Taiwan), 138 (2.9% overall, 12.6% in Asia) in South-East Asia (Vietnam), and 237 (5.0% overall, 21.6% in Asia) in South Asia (India). Patients from Asia had similar rates of worsening HF events and mortality compared with patients elsewhere. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint to the same extent in patients from Asia (HR: 0.65; 95% CI: 0.49 to 0.87) as elsewhere (HR: 0.77; 95% CI: 0.66 to 0.89) (P for interaction = 0.32). Consistent benefits were observed for the other prespecified outcomes and among the regions of Asia. Study drug discontinuation and prespecified adverse events did not differ between regions.
Conclusions: Dapagliflozin, compared with placebo, reduced the risk of worsening HF events and cardiovascular death to the same extent in Asian patients as elsewhere. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).

Keywords:  ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; Asia; BMI, body mass index; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire total symptom score; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro–B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; SGLT2 inhibitor; SGLT2, sodium-glucose cotransporter 2; eGFR, estimated glomerular filtration rate; ejection fraction; heart failure

DOI:  https://doi.org/10.1016/j.jacasi.2022.02.004
Int J Mol Sci. 2022 Oct 26. pii: 12909. [Epub ahead of print]23(21):

Ketone Body Exposure of Cardiomyocytes Impairs Insulin Sensitivity and Contractile Function through Vacuolar-Type H+-ATPase Disassembly-Rescue by Specific Amino Acid Supplementation.

Shujin Wang, Dietbert Neumann, B Daan Westenbrink, Francesco Schianchi, Li-Yen Wong, Aomin Sun, Agnieszka Strzelecka, Jan F C Glatz, Joost J F P Luiken, Miranda Nabben.

  The heart is metabolically flexible. Under physiological conditions, it mainly uses lipids and glucose as energy substrates. In uncontrolled diabetes, the heart switches towards predominant lipid utilization, which over time is detrimental to cardiac function. Additionally, diabetes is accompanied by high plasma ketone levels and increased utilization of energy provision. The administration of exogenous ketones is currently being investigated for the treatment of cardiovascular disease. Yet, it remains unclear whether increased cardiac ketone utilization is beneficial or detrimental to cardiac functioning. The mechanism of lipid-induced cardiac dysfunction includes disassembly of the endosomal proton pump (named vacuolar-type H+-ATPase; v-ATPase) as the main early onset event, followed by endosomal de-acidification/dysfunction. The de-acidified endosomes can no longer serve as a storage compartment for lipid transporter CD36, which then translocates to the sarcolemma to induce lipid accumulation, insulin resistance, and contractile dysfunction. Lipid-induced v-ATPase disassembly is counteracted by the supply of specific amino acids. Here, we tested the effect of ketone bodies on v-ATPase assembly status and regulation of lipid uptake in rodent/human cardiomyocytes. 3-β-hydroxybutyrate (3HB) exposure induced v-ATPase disassembly and the entire cascade of events leading to contractile dysfunction and insulin resistance, similar to conditions of lipid oversupply. Acetoacetate addition did not induce v-ATPase dysfunction. The negative effects of 3HB could be prevented by addition of specific amino acids. Hence, in sedentary/prediabetic subjects ketone bodies should be used with caution because of possible aggravation of cardiac insulin resistance and further loss of cardiac function. When these latter maladaptive conditions would occur, specific amino acids could potentially be a treatment option.

Keywords:  contractile function; diabetic heart; endosomal CD36; ketone bodies; lipid-induced insulin resistance; vacuolar-type H+-ATPase

DOI:  https://doi.org/10.3390/ijms232112909
Eur J Heart Fail. 2022 Nov 07.

Dapagliflozin in patients with heart failure with mildly reduced and preserved ejection fraction treated with a mineralocorticoid receptor antagonist or sacubitril/valsartan.

Mingming Yang, Jawad H Butt, Toru Kondo, Karola S Jering, Kieran F Docherty, Pardeep S Jhund, Rudolf A de Boer, Brian L Claggett, Akshay S Desai, Adrian F Hernandez, Silvio E Inzucchi, Mikhail N Kosiborod, Carolyn S P Lam, Anna Maria Langkilde, Felipe A Martinez, Magnus Petersson, Sanjiv J Shah, Muthiah Vaduganathan, Ulrica Wilderäng, Scott D Solomon, John J V McMurray.

   AIMS: The effects of adding a sodium-glucose cotransporter 2 (SGLT2) inhibitor to a mineralocorticoid receptor antagonist (MRA) or an angiotensin receptor-neprilysin inhibitor (ARNI) in patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are uncertain, even though the use of all three drugs is recommended in recent guidelines.
METHODS AND RESULTS: The efficacy and safety of dapagliflozin added to background MRA or ARNI therapy was examined in patients with HFmrEF/HFpEF enrolled in the DELIVER trial. The primary outcome was the composite of worsening HF or cardiovascular death. Of 6263 patients, 2667 (42.6%) were treated with an MRA and 301 (4.8%) with an ARNI at baseline. Patients taking either were younger, more often men and had lower systolic blood pressure and ejection fraction; they were also more likely to have prior HF hospitalization. The benefit of dapagliflozin was similar whether patients were receiving these therapies. The hazard ratio for the effect of dapagliflozin compared to placebo on the primary outcome was 0.86 (95% confidence interval [CI] 0.74-1.01) for MRA non-users versus 0.76 (95% CI 0.64-0.91) for MRA users (pinteraction = 0.30). The corresponding values for ARNI non-users and users were 0.82 (95% CI 0.73-0.92) and 0.74 (95% CI 0.45-1.22), respectively (pinteraction = 0.75). None of the adverse events examined was more common with dapagliflozin compared to placebo overall or in the MRA and ARNI subgroups.
CONCLUSIONS: The efficacy and safety of dapagliflozin were similar, regardless of background treatment with an MRA or ARNI. SGLT2 inhibitors may be added to other treatments recommended in recent guidelines for HFmrEF/HFpEF.

Keywords:  Aldosterone; Ejection fraction; Heart failure; Mineralocorticoid receptor antagonist; Neprilysin; Sacubitril/valsartan; Sodium-glucose cotransporter 2

DOI:  https://doi.org/10.1002/ejhf.2722
Circulation. 2022 Nov 07.

Sex Differences in Characteristics, Outcomes and Treatment Response with Dapagliflozin across the Range of Ejection Fraction in Patients with Heart Failure: Insights from DAPA-HF and DELIVER.

Xiaowen Wang, Muthiah Vaduganathan, Brian L Claggett, Sheila M Hegde, Maria Pabon, Ian J Kulac, Orly Vardeny, Eileen O'Meara, Shelley Zieroth, Tzvetana Katova, Martina M McGrath, Anne-Catherine Pouleur, Pardeep S Jhund, Akshay S Desai, Silvio E Inzucchi, Mikhail N Kosiborod, Rudolf A de Boer, Lars Køber, Marc S Sabatine, Felipe A Martinez, Piotr Ponikowski, Sanjiv J Shah, Adrian F Hernandez, Anna Maria Langkilde, John J V McMurray, Scott D Solomon, Carolyn S P Lam.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a key pharmacotherapy in heart failure (HF) with both reduced and preserved ejection fraction. The benefit of other HF therapies may be modified by sex, but whether sex modifies the treatment effect and safety profile of SGLT2 inhibitors remains unclear. Our analyses aim to assess the impact of sex on the efficacy and safety of dapagliflozin.
METHODS: In a pre-specified patient-level pooled analysis of DAPA-HF and DELIVER, clinical outcomes were compared by sex (including the composite of cardiovascular [CV] death or worsening HF events; CV death; all-cause death, total events (first and recurrent HF hospitalization and CV death), and Kansas City Cardiomyopathy Questionnaire [KCCQ] scores) across the spectrum of left ventricular ejection fraction (EF).
RESULTS: Of a total of 11,007 randomized patients, 3856 (35%) were women. Women with HF were older, had higher body mass index, but were less likely to have a history of diabetes and myocardial infarction/stroke; and more likely to have hypertension and atrial fibrillation, compared to men. At baseline, women had higher EF but worse KCCQ scores than men. After adjusting for baseline differences, women were less likely than men to experience CV death (adjusted hazard ratio [aHR] 0.69, 95% CI 0.60-0.79), all-cause death (aHR 0.69, 95% 0.62-0.78), HF hospitalizations (aHR 0.82, 95% CI 0.72-0.94), and total events (adjusted rate ratio 0.77, 95% CI 0.71-0.84). Dapagliflozin reduced the primary endpoint in both men and women similarly (p-interaction=0.77) with no sex-related differences in secondary outcomes (all p-interactions > 0.35) or safety events. The benefit of dapagliflozin was observed across the entire EF spectrum and was not modified by sex (p-interaction > 0.40). There were no sex-related differences in serious adverse events, adverse events, or drug discontinuation due to adverse events.
CONCLUSIONS: In DAPA-HF and DELIVER, the response to dapagliflozin was similar between men and women. Sex did not modify the treatment effect of dapagliflozin across the range of ejection fraction.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.122.062832
Clin Drug Investig. 2022 Nov 07.

SGLT2 Inhibitors Improve Cardiac Failure by Reducing Whole-Body Oxygen Demand: A Hypothesis.

Takeshi Onoue, Masaharu Kataoka.

Beyond the effects of lowering glycated hemoglobin, recent evidence for sodium-glucose cotransporter 2 (SGLT2) inhibitors has revolutionarily impacted the management of patients with heart failure. However, the mechanism of SGLT2 inhibitors that can explain the following features has not been clarified. First, SGLT2 inhibitors significantly reduced the risk of heart failure in the early stage. Second, SGLT2 inhibitors are effective in treating heart failure without increasing cardiac output. Third, the effects of SGLT2 inhibitors are incremental and complementary to those of conventional therapies for heart failure. Fourth, SGLT2 inhibitors can improve prognosis in patients with heart failure independent of the ejection fraction. Fifth, SGLT2 inhibitors show consistent effects on heart failure, irrespective of etiology. Based on the perspective of Guyton's physiology and clinical experiences that SGLT2 inhibitors reduced oxygen consumption of the whole body, we provided a demand-reducing theory that SGLT2 inhibitors alleviate the imbalance between oxygen demand and supply not by increasing cardiac output but by reducing oxygen consumption of the whole body, which can explain several unique characteristics of SGLT2 inhibitors.

DOI: https://doi.org/10.1007/s40261-022-01220-z
Circulation. 2022 Nov 06.

Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial.

Kim A Connelly, C David Mazer, Pankaj Puar, Hwee Teoh, Chao-Hung Wang, Tamique Mason, Farhad Akhavein, Ching-Wen Chang, Min-Hui Liu, Ning-I Yang, Wei-Siang Chen, Yu-Hsiang Juan, Erika Opingari, Yaseen Salyani, William Barbour, Aryan Pasricha, Shamon Ahmed, Andrew Kosmopoulos, Raj Verma, Michael Moroney, Ehab Bakbak, Aishwarya Krishnaraj, Deepak L Bhatt, Javed Butler, Mikhail N Kosiborod, Carolyn S P Lam, David A Hess, Otavio Rizzi Coelho-Filho, Myriam Lafreniere-Roula, Kevin E Thorpe, Adrian Quan, Lawrence A Leiter, Andrew T Yan, Subodh Verma.

Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. While it has been theorized that SGLT2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine if SGLT2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. Methods: Between April 2021 and January 2022, 169 individuals, 40-80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomized to empagliflozin (10 mg/day; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area (BSA) as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to baseline BSA and LV ejection fraction. Results: Among the 169 participants (141 men [83%], mean age 59.3 ± 10.5 years), baseline LVMi was 63.2 ± 17.9 g/m2 and 63.8 ± 14.0 g/m2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group vs. placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1,1.5 g/m2) (P=0.74). Median baseline (IQR) NT-proBNP was 51 pg/mL (20, 105 pg/mL) and 55 pg/mL (21, 132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin vs. placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mmHg (-5.2, 2.6 mmHg) (P=0.52), 0.69 mmHg (-1.9, 3.3 mmHg) (P=0.60) and -6.1 pg/mL (-37.0, 24.8 pg/mL) (P=0.70) for systolic blood pressure, diastolic blood pressure and NT-proBNP, respectively. No clinically meaningful between group differences in LV volumes (diastolic and systolic indexed to baseline BSA) or ejection fraction were observed. No difference in adverse events was noted between the groups. Conclusions: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, SGLT2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04461041clinicaltrials.gov Identifier: NCT04461041.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.122.062769