Sandovici M, van der Geest KSM, Reitsema RD
… +10 more, Dhaun N, Youngstein T, de Souza AWS, Grayson PC, Nielsen BD, Dweck MR, Hendrikse E, Glaudemans AWJM, Brouwer E, Slart RHJA
Circulation
· 2026 Jun · PMID 42330100
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Based on the Chapel Hill consensus criteria, the primary forms of vasculitis are classified by the predominant size of the affected blood vessels into large, medium, or small vessels. The two main forms of large vessel v...Based on the Chapel Hill consensus criteria, the primary forms of vasculitis are classified by the predominant size of the affected blood vessels into large, medium, or small vessels. The two main forms of large vessel vasculitis (LVV) are giant cell arteritis and Takayasu arteritis, both of which are more prevalent in women while showing distinct geographic patterns of prevalence. The pathogenesis of LVV is complex and multifactorial, involving a combination of genetic predisposition, environmental and geographic triggers, immune dysregulation, and aging or (premature) senescence of the immune system and blood vessels. Diagnosis based on clinical presentation alone can be challenging because of the wide variety and often nonspecific symptoms that are associated with LVV. This has prompted the development of novel diagnostic tools to aid patient management, in particular advanced vascular imaging approaches. New therapies targeting specific immune pathways are now becoming available to improve outcomes while limiting the side effects associated with traditional glucocorticoid treatment. Advances in molecular imaging techniques may also enhance our ability to objectively monitor disease and treatment response in patients with LVV. Ongoing research aims to better understand the underlying mechanisms and to develop better targeted therapies for LVV, and to improve patient assessment and life time management. This narrative review will provide an in-depth update on current challenges and future trends in LVV, enhancing our understanding of its pathogenesis, diagnostic features, and management strategies, including disease- and treatment-related cardiovascular complications.
Ahn DJ, Nakayama T, Attia A
… +6 more, White M, Eap D, Narang N, Khush KK, Parker WF, Sasaki K
Circ Heart Fail
· 2026 Jun · PMID 42329622
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BACKGROUND: In the US heart allocation system, when transplant centers submit applications for status exceptions to increase waitlist priority, patients obtain the requested status upgrades immediately while their applic...BACKGROUND: In the US heart allocation system, when transplant centers submit applications for status exceptions to increase waitlist priority, patients obtain the requested status upgrades immediately while their applications are sent to the regional review boards (RRBs) and reviewed retrospectively. How often transplants occur during this period is unknown. METHODS: Using the Scientific Registry of Transplant Recipients, we identified all adult heart transplant candidates listed between October 18, 2018, and May 31, 2025, with submitted applications for status exceptions. We assessed (1) the time elapsed between submission of exception applications and their receipt by the RRBs and (2) the rate of heart transplantation during this travel time, stratified by whether the applications were eventually approved or denied. Additionally, we estimated how many listed patients were skipped by candidates who received transplants with exceptions that were ultimately denied. RESULTS: 138 transplant centers submitted status exception requests on behalf of 11 508 adult candidates during the study period, of whom 913 (7.9%) received a denial at least once. The median time from obtaining status upgrades to application receipt by the RRBs was 3 days. Three thousand seven out of 11 508 (26.1%) patients received transplants before the RRBs even received their applications, with 174 (19.1%) among 913 with eventual denials and 2833 (26.7%) among 10 595 with approvals. The cumulative incidence of heart transplantation before application receipt for eventual denials was 19.1% (95% CI, 16.6%-21.7%), and that for approvals was 27.2% (95% CI, 26.4%-28.0%; <0.001) at 2 weeks. Candidates who received transplants despite being denied exceptions bypassed more than 11 thousand potential transplant recipients. CONCLUSIONS: More than 25% of patients with status exception requests receive heart transplants before their applications are even received by their RRBs, raising significant concerns about the fairness of retrospective review of exception requests for the allocation of donor hearts.
Nguyen M, AlEssa HB, Glenn AJ
… +8 more, Tobias DK, Chavarro JE, Willett WC, Hu FB, Hanley AJ, Birken CS, Sievenpiper JL, Malik VS
Circulation
· 2026 Jun · PMID 42324999
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BACKGROUND: High intakes of fructose-containing sugars among children and adolescents is implicated in obesity and related comorbidities, including hypertension. However, sugar-sweetened beverages (SSBs), fruit juices, a...BACKGROUND: High intakes of fructose-containing sugars among children and adolescents is implicated in obesity and related comorbidities, including hypertension. However, sugar-sweetened beverages (SSBs), fruit juices, and whole fruit have different nutritional profiles and matrices, which may confer different effects on blood pressure. METHODS: GUTS (Growing Up Today Study) is a longitudinal cohort of 25 749 individuals (55% female) drawn from 2 enrollment waves, GUTS 1 (n=16 875; baseline 1996) and GUTS II (n=10 918; baseline 2004), followed up prospectively through 2021 (mean age at enrollment, 12 years; mean age at end of follow-up, 36 years). Participants provided updated information on lifestyle, health status, and habitual diet through validated food frequency questionnaires every 1 to 4 years. We conducted multivariable adjusted Cox proportional hazards regression models to estimate the associations of total fructose and SSB, fruit juice, and whole fruit intake (cumulative averages) with incident hypertension (hazard ratios [HRs] and 95% CIs), adjusting for major diet and lifestyle factors. We also modeled substitutions of SSBs or fruit juice with whole fruit, milk, and water. RESULTS: During up to 25 years of follow-up, 1625 participants (6.3%) reported a hypertension diagnosis. Total fructose intake was not associated with incident hypertension (highest versus lowest quintile HR, 1.07 [95% CI, 0.92, 1.25]; trend<0.001). However, participants with the highest intake of SSBs (≥2 servings/d versus <3 servings/week) and fruit juice (≥1.5 servings/d versus <1 serving/wk) had a higher risk of hypertension (HR, 1.52 [95% CI, 1.27, 1.83]; trend<0.001 and HR, 1.35 [95% CI, 1.06, 1.71]; trend=0.018, respectively). In contrast, whole fruit was not associated with hypertension (highest versus lowest category HR, 0.79 [95% CI, 0.59, 1.05]; trend=0.08). Replacing 1 serving/d of SSB with milk, water, or whole fruit was associated with a 13% (95% CI, 5%, 20%), 9% (95% CI, 3%, 15%), and 22% (95% CI, 11%, 31%) lower risk of hypertension, respectively. In addition, replacing fruit juice with whole fruit was associated with a 19% (95% CI, 3%, 32%) lower risk of hypertension. CONCLUSIONS: SSB and fruit juice intakes were positively associated with a higher risk of hypertension independently of overall diet quality, physical activity, and other factors. Our findings support public health guidelines to limit the overconsumption of SSBs and fruit juice starting in childhood to protect against the development of hypertension.
Howard-Quijano K, Shore-Lesserson L, Osho A
… +7 more, Raphael J, Rove JY, Panigrahi AK, Morton-Bailey V, Kamlesh Vegrecha A, Baker RA, American Heart Association Council on Cardiovascular Surgery and Anesthesia; and the Council on Clinical Cardiology
Circulation
· 2026 Jun · PMID 42324995
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Perioperative anemia and red blood cell transfusions are important risk factors for morbidity and mortality in cardiac surgery. Preoperative anemia is common, with up to 50% of patients presenting for cardiac surgery aff...Perioperative anemia and red blood cell transfusions are important risk factors for morbidity and mortality in cardiac surgery. Preoperative anemia is common, with up to 50% of patients presenting for cardiac surgery affected. Iron deficiency-the most common and potentially modifiable cause of preoperative anemia-is a major driver of blood transfusions in the cardiac surgical setting, adversely affecting both patient outcomes and resource utilization. Perioperative blood management, a patient-centered approach to blood conservation during cardiac surgery, is a multidisciplinary collaborative effort among anesthesiologists, surgeons, perfusionists, intensivists, and transfusion laboratory teams. Strategies aim to reduce blood loss and transfusions and improve patient outcomes. There has been a recent increase in research related to anemia, iron deficiency, and patient blood management in cardiac surgery. This scientific statement highlights the latest evidence on preoperative anemia assessment and intraoperative blood conservation; discusses considerations for specific patient populations regarding anemia prevalence, treatment, and outcomes; and reviews key challenges and knowledge gaps, with the goal of minimizing the impact of preoperative anemia, intraoperative blood loss, and hemodilution on cardiac surgery outcomes.
Alkhodari M, Lapidaire W, Kart T
… +23 more, Xiong Z, Krasner S, Fletcher A, Bibi S, Savage N, Suriano K, Baumeister T, Ohuma E, Namburete AIL, Lamata P, Iturria-Medina Y, Chappell LC, Aye C, Thilaganathan B, Fraser A, Mackillop L, McManus RJ, Ntusi NAB, Khandoker AH, Hadjileontiadis LJ, Lewandowski AJ, Banerjee A, Leeson P
Circulation
· 2026 Jun · PMID 42323953
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BACKGROUND: Hypertension induces structural and functional damage in multiple organs. Evidence of subclinical damage increases risk of vascular events and death but can be difficult to identify in the clinic. We develope...BACKGROUND: Hypertension induces structural and functional damage in multiple organs. Evidence of subclinical damage increases risk of vascular events and death but can be difficult to identify in the clinic. We developed a novel machine learning approach that quantifies current hypertension-associated multiorgan damage, mapping progression from health to advanced disease, in a pseudotemporal manner and predicts organ-specific disease progression trajectories. METHODS: We analyzed 566 multimodal imaging and nonimaging variables from 27 099 participants in the UK Biobank imaging substudy to develop a semisupervised contrastive trajectory inference (cTI) framework that models multiorgan alterations associated with hypertension exposure, including heart, brain, kidneys, vasculature, lungs, liver, and metabolic information. Model stability was validated through multiple internal validation steps, and external validity was tested on 5507 participants from the Atherosclerosis Risk in Communities study (ARIC). Clinical relevance was evaluated against existing risk scores and through ability to predict survival and incident multiorgan disease for up to 7 years, across both UK Biobank and ARIC. RESULTS: In the UK Biobank (mean age 63.27±7.48 years; 53.4% women) our global organ damage score (HyperScore) achieved an area under the curve of 0.964 (0.941-0.987) for identification of individuals with severe end-organ disease and robust stability in cross-validation with a mean root mean square error of 0.104±0.084. Survival odds differed significantly across HyperScore stages (<0.001), whereas stratification by blood pressure was nonsignificant. We further revealed 6 hypertensive disease phenotypes (HyperTrajectory), characterized by predominant cardiac, lipoprotein, atherothrombosis, brain, cardiorenal, and liver features, respectively. External testing in ARIC confirmed stability of the model, with Jensen-Shannon distances as low as 0.10 for HyperScore distributions, without significant deviation in organ damage progression patterns (>0.05) and consistent end-organ and outcome characteristics between ARIC and UK Biobank across HyperTrajectories. CONCLUSIONS: Machine learning-derived global organ damage scores are feasible in hypertension and enable identification of distinct hypertension-associated organ-disease phenotypes. New frameworks for hypertension assessment and monitoring using imaging to derive personalized risk assessment and phenotype-specific intervention may be achievable.
Reddy YNV, Frantz RP, Egbe AC
… +15 more, Miranda WR, Asokan AK, Hassoun PM, Hemnes AR, Horn E, Leopold JA, Rischard F, Rosenzweig EB, Hill NS, Erzurum SC, Finet JE, Mukherjee M, Tang WHW, Nair KS, Borlaug BA
Circ Heart Fail
· 2026 Jun · PMID 42318624
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BACKGROUND: Some symptomatic patients manifest pulmonary hypertension (PH), despite normal pulmonary vascular resistance and pulmonary artery wedge pressure-a condition termed unclassified PH. Although hypothesized to re...BACKGROUND: Some symptomatic patients manifest pulmonary hypertension (PH), despite normal pulmonary vascular resistance and pulmonary artery wedge pressure-a condition termed unclassified PH. Although hypothesized to reflect increased flow as seen in congenital heart disease, broader clinical implications remain unknown. METHODS: The current analysis included PVDOMICS participants with either no PH or unclassified PH who underwent dynamic right heart catheterization and transpulmonary metabolomics. In a validation cohort, patients with no PH or unclassified PH underwent exercise right heart catheterization. In exploratory cohorts to understand the impact of increased flow, the prevalence of unclassified PH was assessed in (1) adult congenital heart disease and (2) high output heart failure. RESULTS: The overall prevalence of unclassified PH in PVDOMICS (n=1046) and the validation cohort (n=1202) was 7.8% (175/2248), which was comparable to the 6.6% (66/1005) prevalence in adult congenital heart disease (n=1005), and lower than high output heart failure (n=159, prevalence 14.5% [23/159]; =0.006). Increased flow occurred in a minority of unclassified PH from both PVDOMICS (28%; 15/53) and the validation cohort (11%; 13/122). Unclassified PH (n=53) was associated with greater adiposity, higher heart failure with preserved ejection fraction (HFpEF)-age, body mass index, atrial fibrillation score probability, and more left heart remodeling compared with those with no PH (n=216). Metabolomics revealed lower glycine metabolites in unclassified PH indicative of metabolic dysfunction. Left heart remodeling, quality of life, exercise capacity, and glycine levels were all abnormal in unclassified PH relative to healthy controls (n=96). In the validation cohort, pulmonary artery wedge pressure, pulmonary vascular resistance, and pulmonary artery compliance were subtly abnormal at rest in unclassified PH (n=122) compared with no PH (n=312). With exercise testing, 59% (72/122) with unclassified PH had exertional pulmonary artery wedge pressure elevation consistent with undiagnosed HFpEF. CONCLUSIONS: The presence of PH without obvious cause most often reflects subclinical left heart and metabolic dysfunction consistent with unrecognized early-stage HFpEF. Dynamic provocation during right heart catheterization can unmask unrecognized HFpEF in over half of unclassified PH, which may help guide appropriate initiation of proven HFpEF therapies to improve symptoms and functional status. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02980887.
Lee SY, Kim GB, Carminati M
… +18 more, Giugno L, Çelebi A, Yucel IK, Eicken A, Ewert P, Georgiev S, Choi JY, Kim CS, Gutiérrez-Larraya F, Balbacid Domingo E, Odemis E, Kizilkaya MH, Luis Zunzunegui J, Ballesteros Tejerizo F, Kim SH, Jang SI, Krasemann T, Krings G
BACKGROUND: Patients with congenital or acquired right ventricular outflow tract dysfunction frequently require pulmonary valve replacement and are exposed to repeated surgical interventions due to prosthetic valve degen...BACKGROUND: Patients with congenital or acquired right ventricular outflow tract dysfunction frequently require pulmonary valve replacement and are exposed to repeated surgical interventions due to prosthetic valve degeneration. The PULSTA self-expanding transcatheter pulmonary valve was designed to address a broad spectrum of native and surgically repaired right ventricular outflow tract anatomies. This study reports the midterm safety, hemodynamic performance, and durability outcomes of the prospective, multinational PULSTA CE approval trial (PULSTA Carpentier Edwards). METHODS: This premarket, multicenter, nonrandomized study enrolled 58 patients across 11 centers in 6 countries. Successful PULSTA implantation was achieved in 57 patients (98.3%), including 4 valve-in-valve procedures. Patients were followed for a median duration of 4.1 years. Primary end points included procedural or device-related serious adverse events, hemodynamic improvement, and sustained valve function. RESULTS: At 6 months, cardiac magnetic resonance imaging demonstrated significant reverse right ventricular remodeling, with marked reductions in right ventricular end-diastolic volume index, end-systolic volume index, and pulmonary regurgitation fraction (all <0.001). Valve performance remained stable throughout follow-up, with 93.8% of patients exhibiting mild or less pulmonary regurgitation at 4.1 years. Freedom from reintervention was 98.2% at 5 years. One patient required a PULSTA-in-PULSTA implantation due to paravalvular leakage, and one case of infective endocarditis was successfully managed with antibiotic therapy. No stent fractures or structural valve deterioration were observed. CONCLUSIONS: The PULSTA transcatheter pulmonary valve demonstrated high procedural success, durable valve function, and sustained hemodynamic benefits. Its adaptability to diverse right ventricular outflow tract anatomies and favorable safety profile supports its role as an effective therapeutic option for patients with right ventricular outflow tract dysfunction. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03983512.
Lewsey SC, Martyn T, Blumer V
… +9 more, Brownell NK, Denfeld QE, Dunlay SM, Goyal P, Halloway S, Matlock D, Vardeny O, Van Spall HGC, American Heart Association Cardiovascular Disease in Older Populations Committee of the Council on Clinical Cardiology and Council on Cardiovascular and Stroke Nursing; Council on Basic Cardiovascular Sciences; Council on Lifelong Congenital Heart Disease and Heart Health in the Young; and Heart Failure and Transplantation Committee of the Council on Clinical Cardiology
Circulation
· 2026 Jun · PMID 42312386
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Heart failure prevalence is increasing and has a disproportionate burden on older adults. Older adults, however, may encounter unique challenges in accessing and navigating comprehensive disease-modifying, guideline-dire...Heart failure prevalence is increasing and has a disproportionate burden on older adults. Older adults, however, may encounter unique challenges in accessing and navigating comprehensive disease-modifying, guideline-directed therapies, thus limiting use among those at highest risk of cardiovascular death or worsening heart failure. Care of the older adult with heart failure requires tailored treatment plans to overcome barriers to effective therapies in this population. This scientific statement reviews the literature on care optimization for older adults (≥65 years of age) living with heart failure and highlights strategies for clinicians who aim to deliver patient-centered, evidenced-based heart failure care in the context of common comorbidities seen in older adults. We discuss the consistent treatment effect and safety profiles of guideline-directed therapies for heart failure in older adults and how to manage multimorbidity, polypharmacy, frailty, and social needs using a shared decision-making framework. In consideration of the complexity of heart failure care of the older adult, we highlight a structured framework for therapeutic considerations in the context of benefit-to-risk ratio, multimorbidity, and social needs. We offer practical guidance on the care of older adults with advanced comorbidities who may not have been adequately represented in landmark trials. We also consider implementation strategies, health services interventions, and supportive tools that may foster optimal care in older adults with heart failure. This work is aimed at informing the practice of clinicians and health systems alike to improve outcomes and to reduce the morbidity of heart failure in older adults.
BACKGROUND: Recent observational studies have suggested that early treatment (<12 hours from diagnosis) of intermediate risk pulmonary embolism (PE) with catheter-based therapies may reduce morbidity and mortality. Howev...BACKGROUND: Recent observational studies have suggested that early treatment (<12 hours from diagnosis) of intermediate risk pulmonary embolism (PE) with catheter-based therapies may reduce morbidity and mortality. However, the effect of early versus late mechanical thrombectomy on acute pulmonary hemodynamics and right ventricular mechanics is less well defined. METHODS: Patients enrolled in SYMPHONY-PE were divided into one of 2 groups based on the time from baseline CT pulmonary angiography to mechanical thrombectomy: Early <12 hours versus late ≥12 hours. The primary safety end point was the rate of major adverse events within 48 hours, as adjudicated by an academic independent safety board. The primary efficacy end point was the core-lab assessed mean change in right ventricle-to-left ventricle ratio from baseline to 48 hours. RESULTS: Early thrombectomy was performed in 44% (48/109) of patients and was associated with a larger reduction, approaching statistical significance, in right ventricle-to-left ventricle ratio (0.52±0.50 versus 0.37±0.34; =0.071). Mean pulmonary artery pressure decreased significantly more in patients receiving early thrombectomy (8.6±5.2 versus 5.8±5.0 mm Hg; =0.006). The major adverse events rate was similar (=0.431) between groups, and there were no mortalities. The differences in efficacy outcomes were greatest in higher-risk patients per the Composite Pulmonary Embolism Shock score. CONCLUSIONS: Early mechanical thrombectomy was associated with larger reductions in right ventricle-to-left ventricle ratio and mean pulmonary artery pressure, with no significant differences in safety event rates compared with patients who underwent late thrombectomy. Randomized trials are needed to test these associations. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06062329.
Chan PS, McNally BF, Fu Z
… +2 more, Al-Araji R, Girotra S
Circulation
· 2026 Jun · PMID 42312381
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BACKGROUND: Cardiopulmonary resuscitation (CPR) by health care responders is often suboptimal during out-of-hospital cardiac arrest (OHCA). Mechanical CPR devices have been promoted as a strategy to improve CPR quality....BACKGROUND: Cardiopulmonary resuscitation (CPR) by health care responders is often suboptimal during out-of-hospital cardiac arrest (OHCA). Mechanical CPR devices have been promoted as a strategy to improve CPR quality. Whether their use in routine care is associated with improved OHCA survival at emergency medical service (EMS) agencies is unclear. METHODS: Within the Cardiac Arrest Registry to Enhance Survival, we assessed agency-level rates of OHCA survival at EMS agencies with ≥2 years of OHCA data before and after their first documented use of a mechanical CPR device from 2013 to 2019 using an observational cohort study design. Temporal trends in favorable neurological survival (without severe neurological disability) and survival to discharge were first assessed in EMS agencies that did not initiate mechanical CPR device use (control agencies) using multivariable hierarchical logistic regression. Then an interrupted time series analysis evaluated whether introduction of mechanical CPR devices at EMS agencies was associated with higher OHCA survival. RESULTS: Among 51 994 patients with OHCA at 73 control agencies, there were no temporal trends in risk-adjusted rates of favorable neurological survival (annual rates ranged between 9.6% and 10.6%; =0.23) or survival to discharge (annual rates ranged between 11.1% and 12.0%; =0.31). At 49 EMS agencies that introduced mechanical CPR devices (14 110 OHCAs before and 17 804 OHCAs after), the mean EMS agency risk-adjusted rate of favorable neurological survival was 8.9%±2.2% before mechanical CPR device introduction and 8.3%±1.3% after, with no change in model intercept (adjusted odds ratio, 0.94 [95% CI, 0.80-1.11]; =0.48) or slope after introduction of mechanical CPR devices (adjusted odds ratio per year, 1.03 [95% CI, 0.96-1.12]; =0.41). Similarly, the mean EMS agency risk-adjusted rate of survival to discharge was 11.0%±2.2% before and 10.0%±1.0% after device introduction, with no significant change in model intercept or slope after device introduction. CONCLUSIONS: In a large US registry of OHCA, EMS agency rates of favorable neurological survival and survival to discharge were not higher after the initiation of mechanical CPR device use.
The assessment of left ventricular diastolic function started with invasive pressure measurements and is currently primarily based on echocardiographic imaging. The current approach to the diagnosis of diastolic function...The assessment of left ventricular diastolic function started with invasive pressure measurements and is currently primarily based on echocardiographic imaging. The current approach to the diagnosis of diastolic function relies on mitral inflow velocities, tissue Doppler early diastolic velocity of the mitral annulus, peak velocity of tricuspid regurgitation, pulmonary vein flow, left atrial size and function, and the noninvasive estimation of right atrial pressure. The recommended algorithm in the 2025 American Society of Echocardiography guidelines for estimation of mean left atrial pressure has been validated in a large multicenter study that included 951 patients. Further, that algorithm has shown incremental value to triaging clinical scores in achieving accurate heart failure with preserved ejection fraction diagnosis, against the invasive gold standard. Newer promising approaches have been developed over the past few years to study left ventricular diastolic function, including shear wave propagation velocity, left atrial conduit volume, and timing of mitral and tricuspid valve opening in the apical 4-chamber view. Artificial intelligence has been applied to this field as a rule-based decision tree algorithm, and as deep-learning neural networks to train models for diagnosing and grading diastolic dysfunction, and for diagnosing heart failure with preserved ejection fraction.
Tie H, Hou M, Li Y
… +11 more, Pan M, Neumann D, Liu R, Zhang J, Hoes MF, Nabben M, Glatz JFC, Li X, Wu X, Luiken JJFP, Wang S
Circulation
· 2026 Jun · PMID 42305091
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BACKGROUND: Cardiac aging involves progressive mitochondrial dysfunction, contributing to heart failure. Cardiolipin (CL), essential for mitochondrial function, is increasingly depleted in aging cardiomyocytes, promoting...BACKGROUND: Cardiac aging involves progressive mitochondrial dysfunction, contributing to heart failure. Cardiolipin (CL), essential for mitochondrial function, is increasingly depleted in aging cardiomyocytes, promoting mitochondrial decline. Lysosomal degradation relies on v-ATPase (vacuolar-type H+-ATPase)-mediated acidification, and although lysosomes regulate phospholipid metabolism, their roles in CL homeostasis during aging remains unclear. This study examines whether v-ATPase dysfunction drives age-related cardiac changes by disrupting CL metabolism and mitochondrial function. METHODS: To investigate underlying mechanisms and causality, we use RNA sequencing, targeted lipidomics, immunofluorescence microscopy, (co)immunoprecipitation, proximity ligation assays, subcellular fractionation, mitochondrial respiration analysis and echocardiography, a cardiolipin synthase-1 () knockout mouse model, and 2 v-ATPase knockout models. In addition, we assess whether a nutraceutical intervention targeting v-ATPase dysfunction can mitigate heart failure in aging mouse models and elderly people. RESULTS: Our present findings reveal a sequence of events driving age-related cardiomyopathy: declining cardiac nicotinamide adenine dinucleotide levels impair v-ATPase-mediated lysosomal acidification by weakening the interaction between nicotinamide adenine dinucleotide-dependent glycolytic enzyme aldolase and v-ATPase. This disruption increases lysosomal membrane permeability by reducing lysosomal acidification, allowing cathepsin B to leak into mitochondria. There, cathepsin B disrupts mitochondrial CRLS1 (cardiolipin synthase I), impairing CL synthesis and remodeling. The resulting CL deficiency causes mitochondrial oxidative stress and programmed cell death, leading to mitochondrial and cardiac dysfunction. Genetic or chemical inhibition of v-ATPase and of CRLS1 in mouse models reproduce these age-related defects, highlighting their central roles in cardiac aging. Restoring nicotinamide adenine dinucleotide levels rescues lysosomal acidification and CL metabolism, protecting against age-related cardiomyopathy in rodents and humans. CONCLUSIONS: Augmenting v-ATPase-mediated lysosomal acidification offers novel therapeutic strategies to combat age-related cardiomyopathy by rewiring CL homeostasis.
Aortic stenosis (AS) is increasingly recognized as a disease of both the valve and the myocardium. Beyond valvular obstruction, many patients with aortic stenosis develop extra-valvular abnormalities, including left vent...Aortic stenosis (AS) is increasingly recognized as a disease of both the valve and the myocardium. Beyond valvular obstruction, many patients with aortic stenosis develop extra-valvular abnormalities, including left ventricular hypertrophy, diastolic dysfunction, and atrial and pulmonary vascular remodeling, which have emerged as major determinants of symptoms and prognosis. These abnormalities share many similarities with heart failure with preserved ejection fraction (HFpEF), a condition that is also prevalent in the same aging population. Emerging data suggest that AS and HFpEF frequently coexist and interact, compounded by shared cardiometabolic risk factors, producing convergent phenotypes that complicate diagnosis and influence treatment response. Residual HFpEF appears to underlie much of the persistent heart failure burden after aortic valve replacement, while even mild AS portends worse outcomes in patients with HFpEF. Recent studies have shown that HFpEF-directed therapies, such as sodium-glucose cotransporter 2 inhibitors, may benefit selected patients with AS. As both conditions increase in prevalence and valve interventions are offered to increasingly complex patients, a clearer understanding of the ways in which AS and HFpEF overlap and interact is essential. This review integrates epidemiological, pathophysiological, and clinical perspectives to synthesize emerging evidence on the AS-HFpEF overlap and outlines implications for diagnosis, prognosis, and management.