bims-hafaim 2024-11-24 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2024–11–24
six papers selected by
Kyle McCommis, Saint Louis University

SGLT2 inhibition improves coronary flow velocity reserve and contractility: role of glucagon signaling.
Anaplerotic filling in heart failure: a review of mechanism and potential therapeutics.
Effects of Tirzepatide on the Clinical Trajectory of Patients with Heart Failure, a Preserved Ejection Fraction, and Obesity.
A Cross-Sectional Study of Capillary Blood Ketone Concentrations in Heart Failure Based on Sodium-Glucose Co-Transporter-2 Inhibitor Use and Heart Failure Type.
Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial.
Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity.

Cardiovasc Diabetol. 2024 Nov 15. 23(1): 408

SGLT2 inhibition improves coronary flow velocity reserve and contractility: role of glucagon signaling.

Sven O Göpel, Damilola Adingupu, Jue Wang, Elizaveta Semenova, Margareta Behrendt, Rasmus Jansson-Löfmark, Christine Ahlström, Ann-Cathrine Jönsson-Rylander, V Sashi Gopaul, Russell Esterline, Li-Ming Gan, Rui-Ping Xiao.

   BACKGROUND: SGLT2 inhibitors, a T2DM medication to lower blood glucose, markedly improve cardiovascular outcomes but the underlying mechanism(s) are not fully understood. SGLT2i's produce a unique metabolic pattern by lowering blood glucose without increasing insulin while increasing ketone body and glucagon levels and reducing body weight. We tested if glucagon signaling contributes to SGLT2i induced improvement in CV function.
METHODS: Cardiac contractility and coronary flow velocity reserve (CFVR) were monitored in ob/ob mice and rhesus monkeys with metabolic syndrome using echocardiography. Metabolic status was characterized by measuring blood ketone levels, glucose tolerance during glucose challenge and Arg and ADMA levels were measured. Baysian models were developed to analyse the data.
RESULTS: Dapagliflozin improved CFVR and contractility, co-application of a glucagon receptor inhibitor (GcgRi) blunted the effect on CFVR but not contractility. Dapagliflozin increased the Arg/ADMA ratio and ketone levels and co-treatment with GcgRi blunted only the Dapagliflozin induced increase in Arg/ADMA ratio but not ketone levels.
CONCLUSIONS: Since GcgRi co-treatment only reduced the Arg/ADMA increase we hypothesize that dapagliflozin via a glucagon-signaling dependent pathway improves vascular function through the NO-signaling pathway leading to improved vascular function. Increase in ketone levels might be a contributing factor in SGLT2i induced contractility increase and does not require glucagon signaling.

Keywords:  Argenine/ADMA ratio; Cardiac contractility; Coronary flow velocity reserve; Echocardiography; Glucagon; Heart failure; Metabolic syndrome; SGLT2 inhibitor

DOI:  https://doi.org/10.1186/s12933-024-02491-w
Cardiovasc Res. 2024 Nov 21. pii: cvae248. [Epub ahead of print]

Anaplerotic filling in heart failure: a review of mechanism and potential therapeutics.

Karm A Alhasan, Melissa A King, Badal S B Pattar, Ian A Lewis, Gary D Lopaschuk, Steven C Greenway.

  Heart failure (HF) is a complex syndrome and a leading cause of mortality worldwide. While current medical treatment is based on known pathophysiology and is effective for many patients, the underlying cellular mechanisms are poorly understood. Energy deficiency is a characteristic of HF, marked by complex alterations in metabolism. Within the tricarboxylic acid cycle, anaplerosis emerges as an essential metabolic process responsible for replenishing lost intermediates, thereby playing a crucial role in sustaining energy metabolism and consequently cardiac function. Alterations in cardiac anaplerosis are commonly observed in HF, demonstrating potential for therapeutic intervention. This review discusses recent advances in understanding the anaplerotic adaptations that occur in HF. We also explore therapeutics that can directly modulate anaplerosis or are likely to confer cardioprotective effects through anaplerosis, which could potentially be implemented to rescue the failing heart.

Keywords:  anaplerosis; cardiac metabolism; cardiovascular disease; heart failure; mitochondria

DOI:  https://doi.org/10.1093/cvr/cvae248
Circulation. 2024 Nov 18.

Effects of Tirzepatide on the Clinical Trajectory of Patients with Heart Failure, a Preserved Ejection Fraction, and Obesity.

SUMMIT Trial Study Group

BACKGROUND: Patients with heart failure, a preserved ejection fraction (HFpEF), and obesity have significant disability and suffer frequent exacerbations of heart failure. We hypothesized that tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, would improve a comprehensive suite of clinical endpoints, including measures of health status, functional capacity, quality of life, exercise tolerance, patient well-being, and medication burden in these patients.
METHODS: 731 patients in class II-IV heart failure, ejection fraction ≥50%, and body mass index ≥30 kg/m2 were randomized(double-blind) to tirzepatide(titrated up to 15mg subcutaneously weekly)(n=364) or placebo(n=367), added to background therapy for a median of 104 weeks (Q1=66, Q3=126 weeks).
PRIMARY ENDPOINTS: tirzepatide reduced the combined risk of cardiovascular death or worsening heart failure and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score(KCCQ-CSS). The current expanded analysis included sensitivity analyses of the primary endpoints, 6-minute walk distance(6MWD), EQ-5D-5L health state index, Patient Global Impression of Severity Overall Health(PGIS), NYHA class, use of heart failure medications, and a hierarchical composite based on all-cause death, worsening heart failure, and 52-week changes in KCCQ-CSS and 6MWD.
RESULTS: Patients were aged 65.2±10.7, 53.8%(n=393) were female; BMI 38.2±6.7kg/m2, KCCQ-CSS 53.5±18.5, 6MWD 302.8±81.7meters, and 53%(n=388) had a worsening heart failure event in the prior 12 months. Compared with placebo, tirzepatide produced a consistent beneficial effect across all composites of death and worsening heart failure events, analyzed as time-to-first-event (hazard ratios 0.41-0.67). At 52 weeks, tirzepatide increased KCCQ-CSS 6.9 points (95%CI, 3.3, 10.6, P<0.001), 6MWD 18.3 meters (95%CI, 9.9, 26.7, P<0.001) and EQ-5D-5L 0.06 (95%CI, 0.03, 0.09, P<0.001). The tirzepatide group shifted to a more favorable PGIS (proportional odds ratio 1.99 (95%CI, 1.44, 2.76) and NYHA class (proportional odds ratio 2.26 (95%CI, 1.54, 3.31), both P<0.001 and required less heart failure medications (P=0.015). The broad spectrum of effects was reflected in benefits on the hierarchical composite (win ratio 1.63, 95%CI, 1.17, 2.28;P=0.004).
CONCLUSIONS: Tirzepatide produced a comprehensive, meaningful improvement in heart failure across multiple complementary domains; enhanced health status, quality of life, functional capacity, exercise tolerance and well-being; and reduced symptoms and medication burden in patients with HFpEF and obesity.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.124.072679
Heart Lung Circ. 2024 Nov 18. pii: S1443-9506(24)01770-0. [Epub ahead of print]

A Cross-Sectional Study of Capillary Blood Ketone Concentrations in Heart Failure Based on Sodium-Glucose Co-Transporter-2 Inhibitor Use and Heart Failure Type.

Jia Yong Tan, Luke Andrew Ephraums, Joshua Mark Inglis, Huyen Thi Thanh Nguyen, Mahesh Michael Umapathysivam, Natalie Jane Simpson, Josephine Helen Harris, Christine Mary Burdeniuk, Carmine Gerardo De Pasquale, Tilenka Rosemary Jenni Thynne.

   BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are standard-of-care treatment in heart failure (HF). The risk of ketosis in patients with HF is unclear, especially during hospitalisation.
AIM: We aimed to evaluate the normal ketone concentration range in HF patients.
METHOD: We performed a cross-sectional study of inpatients with acutely decompensated HF and outpatients with stable HF. Ketone concentrations were measured and analysed based on SGLT2i use. Baseline demographic data (age, gender, body mass index [BMI]), time since last meal, HF type, type 2 diabetes status, insulin use, and blood parameters (creatinine, glycosylated haemoglobin A1c [HbA1c] and N-terminal pro-B-type natriuretic peptide) were collected from patients or medical records. The primary outcome was capillary blood ketone concentration in patients with acute decompensated HF and stable chronic HF stratified by SGLT2i use. Multivariate regression was also performed using ketones as the outcome variable, with age, gender, BMI, glucose levels, HbA1c, time since last meal and presence of insulin therapy as predictor variables.
RESULTS: A total of 20 individuals with decompensated HF (n=5 SGLT2i treated) and 47 with stable chronic HF (n=22 SGLT2i treated) were recruited. Median ketone concentrations were similar in all groups irrespective of SGLT2i use and the presence of acute decompensation (0.1 mmol/L, biggest interquartile range 0.2 mmol/L, p=0.49). Apart from time from last meal, multivariate regression analysis showed no association of ketone concentration with SGLT2i use, age, gender, BMI, type 2 diabetes status, insulin use and blood glucose level.
CONCLUSIONS: Ketone concentrations were low in individuals with HF regardless of SGLT2i use or the presence of acute decompensation.

Keywords:  Heart failure; Ketones; Sodium-glucose co-transporter 2 inhibitors

DOI:  https://doi.org/10.1016/j.hlc.2024.07.013
Nat Med. 2024 Nov 17.

Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial.

Barry A Borlaug, Michael R Zile, Christopher M Kramer, Seth J Baum, Karla Hurt, Sheldon E Litwin, Masahiro Murakami, Yang Ou, Navneet Upadhyay, Milton Packer.

Patients with obesity-related heart failure with preserved ejection fraction (HFpEF) display circulatory volume expansion and pressure overload contributing to cardiovascular-kidney end-organ damage. In the SUMMIT trial, patients with HFpEF and obesity were randomized to the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide (n = 364, 200 women) or placebo (n = 367, 193 women). As reported separately, tirzepatide decreased cardiovascular death or worsening heart failure. Here, in this mechanistic secondary analysis of the SUMMIT trial, tirzepatide treatment at 52 weeks, as compared with placebo, reduced systolic blood pressure (estimated treatment difference (ETD) -5 mmHg, 95% confidence interval (CI) -7 to -3; P < 0.001), decreased estimated blood volume (ETD -0.58 l, 95% CI -0.63 to -0.52; P < 0.001) and reduced C-reactive protein levels (ETD -37.2%, 95% CI -45.7 to -27.3; P < 0.001). These changes were coupled with an increase in estimated glomerular filtration rate (ETD 2.90 ml min-1 1.73 m-2 yr-1, 95% CI 0.94 to 4.86; P = 0.004), a decrease in urine albumin-creatinine ratio (ETD 24 weeks, -25.0%, 95% CI -36 to -13%; P < 0.001; 52 weeks, -15%, 95% CI -28 to 0.1; P = 0.051), a reduction in N-terminal prohormone B-type natriuretic peptide levels (ETD 52 weeks -10.5%, 95% CI -20.7 to 1.0%; P = 0.07) and a reduction in troponin T levels (ETD 52 weeks -10.4%, 95% CI -16.7 to -3.6; P = 0.003). In post hoc exploratory analyses, decreased estimated blood volume with tirzepatide treatment was significantly correlated with decreased blood pressure, reduced microalbuminuria, improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and increased 6-min walk distance. Moreover, decreased C-reactive protein levels were correlated with reduced troponin T levels and improved 6-min walk distance. In conclusion, tirzepatide reduced circulatory volume-pressure overload and systemic inflammation and mitigated cardiovascular-kidney end-organ injury in patients with HFpEF and obesity, providing new insights into the mechanisms of benefit from tirzepatide. ClinicalTrials.gov registration: NCT04847557 .

DOI: https://doi.org/10.1038/s41591-024-03374-z
N Engl J Med. 2024 Nov 16.

Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity.

SUMMIT Trial Study Group

BACKGROUND: Obesity increases the risk of heart failure with preserved ejection fraction. Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, causes considerable weight loss, but data are lacking with respect to its effects on cardiovascular outcomes.
METHODS: In this international, double-blind, randomized, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, 731 patients with heart failure, an ejection fraction of at least 50%, and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 30 to receive tirzepatide (up to 15 mg subcutaneously once per week) or placebo for at least 52 weeks. The two primary end points were a composite of adjudicated death from cardiovascular causes or a worsening heart-failure event (assessed in a time-to-first-event analysis) and the change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better quality of life).
RESULTS: A total of 364 patients were assigned to the tirzepatide group and 367 to the placebo group; the median duration of follow-up was 104 weeks. Adjudicated death from cardiovascular causes or a worsening heart-failure event occurred in 36 patients (9.9%) in the tirzepatide group and in 56 patients (15.3%) in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.41 to 0.95; P = 0.026). Worsening heart-failure events occurred in 29 patients (8.0%) in the tirzepatide group and in 52 patients (14.2%) in the placebo group (hazard ratio, 0.54; 95% CI, 0.34 to 0.85), and adjudicated death from cardiovascular causes occurred in 8 patients (2.2%) and 5 patients (1.4%), respectively (hazard ratio, 1.58; 95% CI, 0.52 to 4.83). At 52 weeks, the mean (±SD) change in the KCCQ-CSS was 19.5±1.2 in the tirzepatide group as compared with 12.7±1.3 in the placebo group (between-group difference, 6.9; 95% CI, 3.3 to 10.6; P<0.001). Adverse events (mainly gastrointestinal) leading to discontinuation of the trial drug occurred in 23 patients (6.3%) in the tirzepatide group and in 5 patients (1.4%) in the placebo group.
CONCLUSIONS: Treatment with tirzepatide led to a lower risk of a composite of death from cardiovascular causes or worsening heart failure than placebo and improved health status in patients with heart failure with preserved ejection fraction and obesity. (Funded by Eli Lilly; SUMMIT ClinicalTrials.gov number, NCT04847557.).

DOI: https://doi.org/10.1056/NEJMoa2410027