Metabolic aspects in heart failure phenotypes : impact of biomarkers, body measurements and coronary microvascular dysfunction

<p dir="ltr"><b>Background</b>: In heart failure (HF) with preserved ejection fraction (HFpEF) phenotyping of patients, due to the heterogeneity of the syndrome, may be useful to explore underlying pathophysiology and find treatment targets. Obese-HFpEF is proposed as a phenotype and clinical characteristics may vary by region. In HFpEF coronary microvascular dysfunction (CMD) has been suggested as a unifying pathophysiological mechanism.</p><p dir="ltr">Patients with worsening HF are hospitalised and given intravenous (IV) loop diuretics to treat congestion to relieve symptoms. The evidence showing improvements in outcomes outweighing side effects is scarce. Inotropes may be administered in the acute setting but are associated with increased risk of ischemia and arrhythmia. There is no approved drug improving contractility, with long-term outcome benefits. Acyl ghrelin is a hormone with the potential to be developed to a new inotrope in HF with reduced ejection fraction (HFrEF) by improving contractility in a load-independent manner. However, this could impair the right ventricular-pulmonary arterial coupling (RVPAC).</p><p dir="ltr"><b>Aim</b>: The overall aim was to explore factors influencing metabolic health in HF patients, focusing on regional differences, body measurements, metabolic biomarkers, and HF therapies, in order to explore associations with outcomes and refine clinical management strategies. Specific aims were the following:</p><p dir="ltr">1. To determine the regional differences in clinical characteristics and prevalence of CMD in patients with HFpEF <b>(study I</b>)</p><p dir="ltr"> 2. To explore associations between body mass index (BMI)-obesity (in Whites/Blacks >30 kg/m2; in Asians >27.5 kg/m2) and waist-to-height ratio (WtHR)-obesity (>0.6) with clinical characteristics, metabolic and fibrotic biomarkers, CMD and outcomes in patients with HFpEF (<b>study II</b>) </p><p dir="ltr">3. To investigate if acyl ghrelin increases cardiac output (CO) without worsening the right-sided hemodynamics assessed by RVPAC in patients with HFrEF (<b>study III</b>) </p><p dir="ltr">4. To explore the association between IV loop diuretic-induced weight loss, patient characteristics, changes in biomarkers and outcomes in HF (<b>study IV</b>)</p><p dir="ltr"><b>Method</b>: In both <b>study I and II </b>patients with stable HFpEF were included from the multinational observational study Prevalence and Correlates of Coronary Microvascular Dysfunction (PROMIS)-HFpEF, whereof 202 patients in <b>study</b> <b>I</b> and 216 in <b>study II</b>. In <b>study III </b>22 patients with RVPAC and HFrEF were included from the randomized double-blind placebo-controlled Karolinska Acyl Ghrelin Trial, which assessed acyl ghrelin versus placebo (120-min IV infusion). In <b>study IV</b> patients hospitalised for HF (HHF) enrolled in the Swede-HF registry between 2017-2021 with administered IV loop diuretics with weight recorded at admission and discharge, surviving to discharge, were selected. Decongestion was defined as absolute weight loss of ≥2 kg between admission and discharge.</p><p dir="ltr"><b>Results</b>: In<b> study I</b> HFpEF patients from Singapore were leaner with more metabolic derangements; in Finland and Sweden the eldest, with more atrial fibrillation; and in the United States youngest and most obese. The prevalence of CMD was in Finland 88%, Singapore 80%, Sweden 77%, and United States 59%, with no association between country and CMD after adjustment. Associations between CMD and clinical characteristics did not differ by country.</p><p dir="ltr">Among the 216 patients in <b>study II</b> patients with obesity (for both BMI and WtHR) vs non-obese were younger, had more diabetes and hyperlipidemia. Higher aldosterone and insulin and lower adiponectin were independently associated with both BMI-obesity and WtHR-obesity. CFR was not associated with either BMI-obesity (odds ratio (OR) 1.75 [95% Confidence interval (CI) 0.86 - 3.61]) nor WtHR-obesity (OR 1.27 [95% CI 0.65 - 2.51]) after adjustment. First HHF or CV death was 5/100 in BMI-obesity and 8/100 patient-years in WtHR-obesity. WtHR- obesity, but not BMI-obesity, was associated with all-cause hospitalisations [hazard ratio (HR) 2.21 (95% CI 1.12-4.33)] but not after adjustments.</p><p dir="ltr">In <b>study III</b> 22 patients with HFrEF had available RVPAC (acyl ghrelin n = 12, placebo n = 10). RVPAC remained unchanged from 5.9 (5.3-7.6) to 6.3 (4.8-7.5) mm·(m/s)-1, p = 0.372, despite a 15% increase in CO in the acyl ghrelin group from 4.0 (3.5-4.6) to 4.6 (3.9-6.1) L/min, p = 0.003, while decreasing in placebo group, 5.2 (4.3-6.4) to 4.8 (4.2-5.8) mm.(m/s)-1, p = 0.035. CO change increased in the acyl ghrelin group vs placebo (p = 0.036) but RVPAC and the pressure gradient remained the same.</p><p dir="ltr"><b>Study IV </b>comprised 4979 HF patients with median age of 80 years and 57% men. During the HHF weight change was -2.5 kg. Predictors of decongestion included male sex, atrial fibrillation, and obesity. Decreasing estimated glomerular filtration rate (eGFR) did not correlate with more weight loss (r= - 0.02, p=0.095). Patients decongested (>2 kg weight loss) had a lower risk of re-HHF [HR 0.61, (95% CI 0.54-0.69)] at 30 days, but not thereafter up until one year. Decongestion did not interact with the changes in biomarkers in relation to outcomes.</p><p dir="ltr"><b>Conclusion</b>: CMD in HFpEF was equally prevalent in both regional phenotypes as well as differently assessed obese-HFpEF (<b>study I-II</b>). This suggests CMD as a therapeutic target across regions and different obese subtypes in HFpEF.</p><p dir="ltr">WtHR-obesity and BMI-obesity had similar characteristics but there were trends toward a higher risk of all-cause hospitalisation when defined by WtHR-obesity (<b>study II</b>).</p><p dir="ltr">Acyl ghrelin improves CO while preserving RVPAC which suggests it may be safe as a potential treatment in HFrEF with right ventricular failure (<b>study III</b>).</p><p dir="ltr">Finally, decongestion following diuretic therapy was associated with a lower risk of re-HHF in the short-term and this effect was regardless of changes in biomarkers (<b>study IV</b>).</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Mikael Erhardsson</b>, Ulrika Ljung Faxén, Ashwin Venkateshvaran, Sara Svedlund, Antti Saraste, Maria Lagerstrom Fermer, Li-Ming Gan, Sanjiv J Shah, Jasper Tromp, Carolyn SP Lam, Lars H. Lund, Camilla Hage. Regional differences and coronary microvascular dysfunction in heart failure with preserved ejection fraction. ESC Heart Fail. 2023 Dec;10(6):3729-3734. <a href="https://doi.org/10.1002/ehf2.14569" target="_blank">https://doi.org/10.1002/ehf2.14569</a></p><p dir="ltr">II. *<b>Mikael Erhardsson</b>, *Chanchal Chandramouli, Ulrika Ljung Faxén, Erik Michaelsson, Jasper Tromp, Ashwin Venkateshvaran, Antti Saraste, Sara Svedlund, Maria Lagerstrom Fermer, Li-Ming Gan, Sanjiv J Shah, Carolyn SP Lam, Lars H. Lund, Camilla Hage. Central and overall obesity in heart failure with preserved ejection fraction: Biomarkers, coronary microvascular dysfunction and outcomes. [Manuscript] *Shared first author. </p><p dir="ltr">III.<b> </b><b>Mikael Erhardsson</b>, Ulrika Ljung Faxén, Ashwin Venkateshvaran, Camilla Hage, Gianluigi Pironti, Tonje Thorvaldsen, Dominic-Luc Webb, Per M. Hellstrom, Daniel C. Andersson, Marcus Ståhlberg, Lars H. Lund. Acyl ghrelin increases cardiac output while preserving right ventricular-pulmonary arterial coupling in patients with heart failure. ESC Heart Fail. 2024 Feb;11(1):601-605. <a href="https://doi.org/10.1002/ehf2.14580" target="_blank">https://doi.org/10.1002/ehf2.14580</a></p><p dir="ltr">IV.<b> </b><b>Mikael Erhardsson</b>, Lina Benson, Gianluigi Savarese, Giulia Ferrannini, Ulrika Ljung Faxén, Ulf Dahlström, Lars H. Lund, Camilla Hage. Intravenous loop diuretic-induced decongestion in acute heart failure - associations with biomarker changes and 30-day and one-year outcomes. [Manuscript]</p>