{"title":"Inflammation and the Need for Biology-Driven Care in Heart Failure","authors":"Abhinav Sharma MD, PhD , Virginia Anagnostopoulou MD , Anique Ducharme MD, MSc","doi":"10.1016/j.jchf.2025.102834","DOIUrl":"10.1016/j.jchf.2025.102834","url":null,"abstract":"","PeriodicalId":14687,"journal":{"name":"JACC. Heart failure","volume":"14 2","pages":"Article 102834"},"PeriodicalIF":11.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-04-02DOI: 10.1016/j.jchf.2025.03.008
Ahmad Masri MD, MS , Martin S. Maron MD , Theodore P. Abraham MD , Michael E. Nassif MD , Roberto Barriales-Villa MD , Ozlem Bilen MD , Caroline J. Coats MD, PhD , Perry Elliott MBBS, MD , Pablo Garcia-Pavia MD, PhD , Daniele Massera MD , Iacopo Olivotto MD , Artur Oreziak MD, PhD , Anjali Tiku Owens MD , Sara Saberi MD, MS , Scott D. Solomon MD , Albree Tower-Rader MD , Stephen B. Heitner MD , Daniel L. Jacoby MD , Chiara Melloni MD, MS , Jenny Wei PhD , Mark Zenker
<div><h3>Background</h3><div>Disopyramide, used in obstructive hypertrophic cardiomyopathy (oHCM) for its negative inotropic properties mediated by its reduction in cytosolic calcium, has been recommended for decades as an option to relieve resistant obstruction. Aficamten is a selective cardiac myosin inhibitor that reduces hypercontractility directly by reducing myosin-actin interaction.</div></div><div><h3>Objectives</h3><div>This study aims to investigate the safety and efficacy of concomitant use and withdrawal of disopyramide in patients with symptomatic oHCM receiving aficamten.</div></div><div><h3>Methods</h3><div>Patients with oHCM enrolled in REDWOOD-HCM Cohort 3 (open-label), SEQUOIA-HCM (placebo-controlled), and FOREST-HCM (open-label) were analyzed. The authors identified 4 groups, each with patients symptomatic despite background therapy with disopyramide who received: 1) disopyramide plus aficamten and subsequent aficamten withdrawal per protocol (Diso-Afi Withdrawal); 2) disopyramide plus placebo (Diso-Pbo); 3) aficamten plus disopyramide with subsequent disopyramide withdrawal (Afi-Diso Withdrawal); and 4) continued both disopyramide and aficamten (Diso+Afi Continuous). Assessments were performed at baseline, after aficamten or placebo add-on therapy, and after washout (except at week 24 for Diso+Afi Continuous group).</div></div><div><h3>Results</h3><div>Overall, 50 unique patients from 3 trials enrolled, resulting in 93 subjects (segments) across 4 groups: Diso-Afi Withdrawal (n = 29), Diso-Pbo (n = 20), Afi-Diso Withdrawal (n = 17), and Diso+Afi Continuous (n = 27); mean disopyramide dose was 331 ± 146 mg/d. The addition of aficamten to disopyramide alleviated left ventricular outflow tract (LVOT) obstruction (resting: change [Δ] in least squares mean −27.0 ± 3.6, Valsalva: Δ least squares mean −39.2 ± 5.0, both <em>P <</em> 0.0001), symptoms (≥1 NYHA functional class improvement: 77.8% [95% CI: 61.0-94.5]; <em>P <</em> 0.0001; Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score: 12.3 ± 3.3 [<em>P <</em> 0.001]), and reduced N-terminal pro–B-type natriuretic peptide ratio: 0.35 [95% CI: 0.26-0.48]; <em>P <</em> 0.0001, and there was no significant change with placebo. Withdrawal of aficamten while on disopyramide resulted in return of LVOT obstruction, worsening of symptoms, and increase in NT-proBNP to baseline values. Conversely, withdrawal of disopyramide while on aficamten did not impact efficacy. There were no safety events associated with aficamten or disopyramide withdrawal, and no episodes of atrial fibrillation after disopyramide withdrawal.</div></div><div><h3>Conclusions</h3><div>In this cohort of patients with symptomatic oHCM with persistent LVOT obstruction, combination therapy with aficamten and disopyramide was safe and well tolerated but did not enhance clinical efficacy vs aficamten alone. For such oHCM patients, aficamten treatment may be considered with an option to discontinue disop
{"title":"Concomitant Aficamten and Disopyramide in Symptomatic Obstructive Hypertrophic Cardiomyopathy","authors":"Ahmad Masri MD, MS , Martin S. Maron MD , Theodore P. Abraham MD , Michael E. Nassif MD , Roberto Barriales-Villa MD , Ozlem Bilen MD , Caroline J. Coats MD, PhD , Perry Elliott MBBS, MD , Pablo Garcia-Pavia MD, PhD , Daniele Massera MD , Iacopo Olivotto MD , Artur Oreziak MD, PhD , Anjali Tiku Owens MD , Sara Saberi MD, MS , Scott D. Solomon MD , Albree Tower-Rader MD , Stephen B. Heitner MD , Daniel L. Jacoby MD , Chiara Melloni MD, MS , Jenny Wei PhD , Mark Zenker","doi":"10.1016/j.jchf.2025.03.008","DOIUrl":"10.1016/j.jchf.2025.03.008","url":null,"abstract":"<div><h3>Background</h3><div>Disopyramide, used in obstructive hypertrophic cardiomyopathy (oHCM) for its negative inotropic properties mediated by its reduction in cytosolic calcium, has been recommended for decades as an option to relieve resistant obstruction. Aficamten is a selective cardiac myosin inhibitor that reduces hypercontractility directly by reducing myosin-actin interaction.</div></div><div><h3>Objectives</h3><div>This study aims to investigate the safety and efficacy of concomitant use and withdrawal of disopyramide in patients with symptomatic oHCM receiving aficamten.</div></div><div><h3>Methods</h3><div>Patients with oHCM enrolled in REDWOOD-HCM Cohort 3 (open-label), SEQUOIA-HCM (placebo-controlled), and FOREST-HCM (open-label) were analyzed. The authors identified 4 groups, each with patients symptomatic despite background therapy with disopyramide who received: 1) disopyramide plus aficamten and subsequent aficamten withdrawal per protocol (Diso-Afi Withdrawal); 2) disopyramide plus placebo (Diso-Pbo); 3) aficamten plus disopyramide with subsequent disopyramide withdrawal (Afi-Diso Withdrawal); and 4) continued both disopyramide and aficamten (Diso+Afi Continuous). Assessments were performed at baseline, after aficamten or placebo add-on therapy, and after washout (except at week 24 for Diso+Afi Continuous group).</div></div><div><h3>Results</h3><div>Overall, 50 unique patients from 3 trials enrolled, resulting in 93 subjects (segments) across 4 groups: Diso-Afi Withdrawal (n = 29), Diso-Pbo (n = 20), Afi-Diso Withdrawal (n = 17), and Diso+Afi Continuous (n = 27); mean disopyramide dose was 331 ± 146 mg/d. The addition of aficamten to disopyramide alleviated left ventricular outflow tract (LVOT) obstruction (resting: change [Δ] in least squares mean −27.0 ± 3.6, Valsalva: Δ least squares mean −39.2 ± 5.0, both <em>P <</em> 0.0001), symptoms (≥1 NYHA functional class improvement: 77.8% [95% CI: 61.0-94.5]; <em>P <</em> 0.0001; Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score: 12.3 ± 3.3 [<em>P <</em> 0.001]), and reduced N-terminal pro–B-type natriuretic peptide ratio: 0.35 [95% CI: 0.26-0.48]; <em>P <</em> 0.0001, and there was no significant change with placebo. Withdrawal of aficamten while on disopyramide resulted in return of LVOT obstruction, worsening of symptoms, and increase in NT-proBNP to baseline values. Conversely, withdrawal of disopyramide while on aficamten did not impact efficacy. There were no safety events associated with aficamten or disopyramide withdrawal, and no episodes of atrial fibrillation after disopyramide withdrawal.</div></div><div><h3>Conclusions</h3><div>In this cohort of patients with symptomatic oHCM with persistent LVOT obstruction, combination therapy with aficamten and disopyramide was safe and well tolerated but did not enhance clinical efficacy vs aficamten alone. For such oHCM patients, aficamten treatment may be considered with an option to discontinue disop","PeriodicalId":14687,"journal":{"name":"JACC. Heart failure","volume":"14 2","pages":"Article 102441"},"PeriodicalIF":11.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-10-31DOI: 10.1016/j.jchf.2025.102751
João Pedro Ferreira MD, PhD , Stefan D. Anker MD, PhD , Javed Butler MD, MPH, MBA , Francisco Vasques-Nóvoa MD , Pedro Marques MD , Stuart Pocock PhD , Gerasimos Filippatos MD, PhD , Faiez Zannad MD, PhD , Milton Packer MD
Background
Magnesium plays a central role in maintaining cellular homeostasis. Limited data exist on the clinical implications of magnesium derangements in heart failure with reduced ejection fraction (HFrEF) and on the influence of sodium-glucose cotransporter 2 (SGLT2) inhibitors on serum magnesium levels.
Objectives
Using the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction; NCT03057977) population, the authors studied the association of serum magnesium with outcomes, assessed the impact of empagliflozin on serum magnesium levels, and explored the influence of serum magnesium on the effect of empagliflozin on cardiovascular and renal outcomes.
Methods
Patients with HFrEF were randomized to receive placebo or 10 mg/day of empagliflozin. Laboratory results were available at baseline, week 4, weeks 12, 32, and 52, and every 24 weeks thereafter. The median follow-up time was 16 months. The primary outcome was a composite of cardiovascular death or heart failure (HF) hospitalization.
Results
A total of 3,730 patients were included. The mean serum magnesium levels at baseline were 0.83 ± 0.11 mmol/L. The corresponding magnesium quintiles were Q1 = 0.68 ± 0.07 mmol/L (n = 878); Q2 = 0.79 ± 0.02 (n = 724); Q3 = 0.84 ± 0.01 (n = 668); Q4 = 0.88 ± 0.02 (n = 733); and Q5 = 0.97 ± 0.05 (n = 727). The patients with higher magnesium levels were older and had a lower estimated glomerular filtration rate. Conversely, the patients with lower serum magnesium had diabetes more frequently. Lower magnesium levels were modestly associated with a higher risk of HF and kidney events; such associations were attenuated with full covariate adjustment. The effect of empagliflozin (vs placebo) on the study primary outcome was more pronounced at lower baseline serum magnesium levels (Q1 HR: 0.54 mmol/L [95% CI: 0.41-0.71 mmol/L]; Q2 HR: 0.69 mmol/L [95% CI: 0.50-0.96 mmol/L]; Q3 HR: 0.82 mmol/L [95% CI: 0.58-1.15 mmol/L]; Q4 HR: 0.99 mmol/L [95% CI: 0.72-1.37 mmol/L]; and Q5 HR: 0.87 mmol/L [95% CI: 0.65-1.17 mmol/L], Pinteraction = 0.043). Empagliflozin rapidly increased magnesium levels by 0.05 mmol/L. The relative odds of experiencing lower magnesium levels were reduced with empagliflozin.
Conclusions
In EMPEROR-Reduced, low serum magnesium levels were modestly associated with poor HF and kidney outcomes. Empagliflozin increased serum magnesium levels and was associated with a more pronounced reduction of HF events among patients with low magnesium levels at baseline.
{"title":"Serum Magnesium and the Effect of Empagliflozin in Heart Failure With Reduced Ejection Fraction","authors":"João Pedro Ferreira MD, PhD , Stefan D. Anker MD, PhD , Javed Butler MD, MPH, MBA , Francisco Vasques-Nóvoa MD , Pedro Marques MD , Stuart Pocock PhD , Gerasimos Filippatos MD, PhD , Faiez Zannad MD, PhD , Milton Packer MD","doi":"10.1016/j.jchf.2025.102751","DOIUrl":"10.1016/j.jchf.2025.102751","url":null,"abstract":"<div><h3>Background</h3><div>Magnesium plays a central role in maintaining cellular homeostasis. Limited data exist on the clinical implications of magnesium derangements in heart failure with reduced ejection fraction (HFrEF) and on the influence of sodium-glucose cotransporter 2 (SGLT2) inhibitors on serum magnesium levels.</div></div><div><h3>Objectives</h3><div>Using the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction; <span><span>NCT03057977</span><svg><path></path></svg></span>) population, the authors studied the association of serum magnesium with outcomes, assessed the impact of empagliflozin on serum magnesium levels, and explored the influence of serum magnesium on the effect of empagliflozin on cardiovascular and renal outcomes.</div></div><div><h3>Methods</h3><div>Patients with HFrEF were randomized to receive placebo or 10 mg/day of empagliflozin. Laboratory results were available at baseline, week 4, weeks 12, 32, and 52, and every 24 weeks thereafter. The median follow-up time was 16 months. The primary outcome was a composite of cardiovascular death or heart failure (HF) hospitalization.</div></div><div><h3>Results</h3><div>A total of 3,730 patients were included. The mean serum magnesium levels at baseline were 0.83 ± 0.11 mmol/L. The corresponding magnesium quintiles were Q1 = 0.68 ± 0.07 mmol/L (n = 878); Q2 = 0.79 ± 0.02 (n = 724); Q3 = 0.84 ± 0.01 (n = 668); Q4 = 0.88 ± 0.02 (n = 733); and Q5 = 0.97 ± 0.05 (n = 727). The patients with higher magnesium levels were older and had a lower estimated glomerular filtration rate. Conversely, the patients with lower serum magnesium had diabetes more frequently. Lower magnesium levels were modestly associated with a higher risk of HF and kidney events; such associations were attenuated with full covariate adjustment. The effect of empagliflozin (vs placebo) on the study primary outcome was more pronounced at lower baseline serum magnesium levels (Q1 HR: 0.54 mmol/L [95% CI: 0.41-0.71 mmol/L]; Q2 HR: 0.69 mmol/L [95% CI: 0.50-0.96 mmol/L]; Q3 HR: 0.82 mmol/L [95% CI: 0.58-1.15 mmol/L]; Q4 HR: 0.99 mmol/L [95% CI: 0.72-1.37 mmol/L]; and Q5 HR: 0.87 mmol/L [95% CI: 0.65-1.17 mmol/L], <em>P</em><sub>interaction</sub> = 0.043). Empagliflozin rapidly increased magnesium levels by 0.05 mmol/L. The relative odds of experiencing lower magnesium levels were reduced with empagliflozin.</div></div><div><h3>Conclusions</h3><div>In EMPEROR-Reduced, low serum magnesium levels were modestly associated with poor HF and kidney outcomes. Empagliflozin increased serum magnesium levels and was associated with a more pronounced reduction of HF events among patients with low magnesium levels at baseline.</div></div>","PeriodicalId":14687,"journal":{"name":"JACC. Heart failure","volume":"14 2","pages":"Article 102751"},"PeriodicalIF":11.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145411510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-10-13DOI: 10.1016/j.jchf.2025.102707
Diana de Oliveira-Gomes MD , Rachel M. Drazner MD, MPH , Michelle Dimza DO , Colby Ayers MS , Angela Duvalyan MD , Tiffany L. Brazile MD , Robert Morlend MD , Faris Araj MD , E. Ashley Hardin MD , Nicholas Hendren MD , Justin L. Grodin MD, MPH , Jennifer T. Thibodeau MD, MSCS , Mark H. Drazner MD, MSc
{"title":"Novel 4-Stage Classification to Estimate Right Atrial Pressure by Point-of-Care Ultrasound of Neck Vasculature","authors":"Diana de Oliveira-Gomes MD , Rachel M. Drazner MD, MPH , Michelle Dimza DO , Colby Ayers MS , Angela Duvalyan MD , Tiffany L. Brazile MD , Robert Morlend MD , Faris Araj MD , E. Ashley Hardin MD , Nicholas Hendren MD , Justin L. Grodin MD, MPH , Jennifer T. Thibodeau MD, MSCS , Mark H. Drazner MD, MSc","doi":"10.1016/j.jchf.2025.102707","DOIUrl":"10.1016/j.jchf.2025.102707","url":null,"abstract":"","PeriodicalId":14687,"journal":{"name":"JACC. Heart failure","volume":"14 2","pages":"Article 102707"},"PeriodicalIF":11.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-02-02DOI: 10.1016/j.jchf.2025.102891
Jeffrey M. Testani MD, MTR , Zachary L. Cox PharmD , Javed Butler MD
{"title":"Could Mineralocorticoid Receptor Antagonists Be Harmful in Some Patients With Heart Failure?","authors":"Jeffrey M. Testani MD, MTR , Zachary L. Cox PharmD , Javed Butler MD","doi":"10.1016/j.jchf.2025.102891","DOIUrl":"10.1016/j.jchf.2025.102891","url":null,"abstract":"","PeriodicalId":14687,"journal":{"name":"JACC. Heart failure","volume":"14 2","pages":"Article 102891"},"PeriodicalIF":11.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-02-02DOI: 10.1016/j.jchf.2025.102848
Bertram Pitt MD , Gian Paolo Rossi MD
{"title":"Plasma Aldosterone Measurement to Guide Prevention and Treatment of Heart Failure in Black Adults With Hypertension","authors":"Bertram Pitt MD , Gian Paolo Rossi MD","doi":"10.1016/j.jchf.2025.102848","DOIUrl":"10.1016/j.jchf.2025.102848","url":null,"abstract":"","PeriodicalId":14687,"journal":{"name":"JACC. Heart failure","volume":"14 2","pages":"Article 102848"},"PeriodicalIF":11.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-10-10DOI: 10.1016/j.jchf.2025.102704
Isabel R. Wees MD , Colby Ayers MS , Frederick L. Ruberg MD , Mathew S. Maurer MD , Yevgeniy Brailovsky DO, MSc , Lily K. Stern MD , Jan M. Griffin MD , Michel G. Khouri MD , Lori R. Roth PA-C , Justin L. Grodin MD, MPH
{"title":"Clinical Implications of the P.V142I TTR Variant","authors":"Isabel R. Wees MD , Colby Ayers MS , Frederick L. Ruberg MD , Mathew S. Maurer MD , Yevgeniy Brailovsky DO, MSc , Lily K. Stern MD , Jan M. Griffin MD , Michel G. Khouri MD , Lori R. Roth PA-C , Justin L. Grodin MD, MPH","doi":"10.1016/j.jchf.2025.102704","DOIUrl":"10.1016/j.jchf.2025.102704","url":null,"abstract":"","PeriodicalId":14687,"journal":{"name":"JACC. Heart failure","volume":"14 2","pages":"Article 102704"},"PeriodicalIF":11.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-08DOI: 10.1016/j.jchf.2025.102822
Milton Packer MD
For the past decade, the prevailing paradigm to explain heart failure with preserved ejection fraction (HFpEF) has assumed that multiple comorbidities act in concert to trigger a systemic inflammatory state that causes coronary microvascular dysfunction, nitric oxide/cyclic guanosine monophosphate (cGMP) deficiency–dependent titin abnormalities, and load-dependent cellular inflammation and fibrosis of the myocardium. By contrast, the recently proposed adipokine hypothesis elevates one comorbidity—visceral adiposity—to explain the coexistence of systemic inflammation, multiple comorbidities, and HFpEF and identifies a specific proximal causal mechanism (ie, the secretion of a proinflammatory suite of signaling molecules from dysfunctional fat). Excess visceral adiposity and adipokine imbalances have been shown not only to produce HFpEF experimentally but also to directly cause hypertension, insulin resistance and type 2 diabetes, and chronic kidney disease. Visceral adiposity and proinflammatory adipokines can also explain features of HFpEF that are not addressed by the coronary microvascular inflammation hypothesis (eg, atrial fibrillation, skeletal muscle and pulmonary abnormalities, and renal sodium retention and plasma volume expansion). Adipokine imbalances can also cause microvascular dysfunction and defects in cGMP signaling and in titin phosphorylation, and they can directly cause cardiac hypertrophy and fibrosis independently of an effect on the microvasculature. The comorbidity-driven microvascular inflammation hypothesis did not identify a blood-borne molecular mediator that selectively targets the heart, and phenomapping based on the clustering of comorbidities has not yielded reproducible groupings. By contrast, selective silencing of specific proinflammatory adipokines only in adipose tissue causes distant effects on the heart to modulate cardiac structure and the evolution of HFpEF. Clinical trials of drugs that enhance nitric oxide/cGMP signaling or have nonspecific anti-inflammatory effects have not produced favorable effects in clinical HFpEF whereas drugs that produce benefits in HFpEF (eg, glucagon-like peptide 1 receptor agonists, sodium-glucose cotransporter 2 inhibitors) act to normalize the adipokine secretory profile. Finally, whereas coronary microvascular dysfunction is present in 60% to 70% of patients with HFpEF (with endothelium-dependent dysfunction being seen in only 30%), central obesity (assessed by an increased waist-to-height ratio) or visceral adiposity (as by mesenteric or epicardial fat) is present in >85% to 95% of patients with the disorder. Therefore, when compared with the comorbidity-driven coronary microvascular endothelial inflammation hypothesis, the adipokine hypothesis provides an explanatory framework with a stronger evidentiary support and applicable to a broader range of patients with HFpEF. Further work is needed to support these observations.
{"title":"Evolutionary History of the Comorbidity-Driven Coronary Microvascular Endothelial Inflammation Hypothesis and Its Metamorphosis to the Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction","authors":"Milton Packer MD","doi":"10.1016/j.jchf.2025.102822","DOIUrl":"10.1016/j.jchf.2025.102822","url":null,"abstract":"<div><div>For the past decade, the prevailing paradigm to explain heart failure with preserved ejection fraction (HFpEF) has assumed that multiple comorbidities act in concert to trigger a systemic inflammatory state that causes coronary microvascular dysfunction, nitric oxide/cyclic guanosine monophosphate (cGMP) deficiency–dependent titin abnormalities, and load-dependent cellular inflammation and fibrosis of the myocardium. By contrast, the recently proposed adipokine hypothesis elevates one comorbidity—visceral adiposity—to explain the coexistence of systemic inflammation, multiple comorbidities, and HFpEF and identifies a specific proximal causal mechanism (ie, the secretion of a proinflammatory suite of signaling molecules from dysfunctional fat). Excess visceral adiposity and adipokine imbalances have been shown not only to produce HFpEF experimentally but also to directly cause hypertension, insulin resistance and type 2 diabetes, and chronic kidney disease. Visceral adiposity and proinflammatory adipokines can also explain features of HFpEF that are not addressed by the coronary microvascular inflammation hypothesis (eg, atrial fibrillation, skeletal muscle and pulmonary abnormalities, and renal sodium retention and plasma volume expansion). Adipokine imbalances can also cause microvascular dysfunction and defects in cGMP signaling and in titin phosphorylation, and they can directly cause cardiac hypertrophy and fibrosis independently of an effect on the microvasculature. The comorbidity-driven microvascular inflammation hypothesis did not identify a blood-borne molecular mediator that selectively targets the heart, and phenomapping based on the clustering of comorbidities has not yielded reproducible groupings. By contrast, selective silencing of specific proinflammatory adipokines only in adipose tissue causes distant effects on the heart to modulate cardiac structure and the evolution of HFpEF. Clinical trials of drugs that enhance nitric oxide/cGMP signaling or have nonspecific anti-inflammatory effects have not produced favorable effects in clinical HFpEF whereas drugs that produce benefits in HFpEF (eg, glucagon-like peptide 1 receptor agonists, sodium-glucose cotransporter 2 inhibitors) act to normalize the adipokine secretory profile. Finally, whereas coronary microvascular dysfunction is present in 60% to 70% of patients with HFpEF (with endothelium-dependent dysfunction being seen in only 30%), central obesity (assessed by an increased waist-to-height ratio) or visceral adiposity (as by mesenteric or epicardial fat) is present in >85% to 95% of patients with the disorder. Therefore, when compared with the comorbidity-driven coronary microvascular endothelial inflammation hypothesis, the adipokine hypothesis provides an explanatory framework with a stronger evidentiary support and applicable to a broader range of patients with HFpEF. Further work is needed to support these observations.</div></div>","PeriodicalId":14687,"journal":{"name":"JACC. Heart failure","volume":"14 2","pages":"Article 102822"},"PeriodicalIF":11.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145563975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-02-02DOI: 10.1016/j.jchf.2025.102838
Eiran Z. Gorodeski MD, MPH , Shashank Shekhar MD , Robert A. Montgomery MD
{"title":"How to Rescue the Field of Heart Failure","authors":"Eiran Z. Gorodeski MD, MPH , Shashank Shekhar MD , Robert A. Montgomery MD","doi":"10.1016/j.jchf.2025.102838","DOIUrl":"10.1016/j.jchf.2025.102838","url":null,"abstract":"","PeriodicalId":14687,"journal":{"name":"JACC. Heart failure","volume":"14 2","pages":"Article 102838"},"PeriodicalIF":11.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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