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BackgroundAbnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. We tested the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF.MethodsFirst, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance 31P spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice.ResultsIn people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling.ConclusionsIn the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00181259.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a novel class of drugs with cardioprotective effects through their lipid‐lowering effects. Objective: This review aims to discuss existing and novel strategies of PCSK9 inhibition, providing an overview of established randomized controlled trials and ongoing outcome trials that assess the efficacy and long‐term safety of PCSK9 inhibitors. It also explores the evolving role of PCSK9 beyond lipid metabolism and outlines the pleiotropic actions of PCSK9 inhibition in various disorders and future directions including novel strategies to target PCSK9. Conclusion: PCSK9 inhibition shows promise not only in lipid metabolism but also in other disease processes, including atherosclerotic plaque remodeling, acute coronary syndrome, stroke, inflammation, and immune response. [ABSTRACT FROM AUTHOR]

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily recognized for its role in lipid metabolism, but recent evidence suggests that it may have broader implications due to its diverse tissue expression. Objective: This review aims to explore the multifaceted functions of PCSK9, highlighting its pro‐atherosclerotic effects, including its impact on circulating lipoprotein variables, non‐low‐density lipoprotein receptors, and various cell types involved in atherosclerotic plaque development. Conclusions: PCSK9 exhibits diverse roles beyond lipid metabolism, potentially contributing to atherosclerosis through multiple pathways. Understanding these mechanisms could offer new insights into therapeutic strategies targeting PCSK9 for cardiovascular disease management. [ABSTRACT FROM AUTHOR]

Aims Lipoprotein(a) [Lp(a)] levels are predominantly genetically determined and repeat measurements are generally considered unlikely to be clinically useful. However, the temporal variation of Lp(a) is not well characterized. Our aim was to determine the intra-individual variability of Lp(a) and whether a repeated measure reclassified Lp(a)-specific cardiovascular risk using the European Atherosclerosis Society (EAS) consensus statement risk categories. Methods and results This retrospective cohort study analysed initial and repeated serum Lp(a) levels measured using the same methodology from 609 individuals in the Nashville Biosciences database, a de-identified electronic medical records database. Baseline and follow-up paired values were significantly different (P < 0.05), with an absolute change of ≥10 mg/dL in 38.1% [95% CI 34.2–42%] and a >25% change in 40.5% [95% CI 36.6–44.3%] of individuals. Although the categories of those whose values were in the EAS low-risk and high-risk categories did not change, 53% of those in the intermediate 'grey-zone' category transitioned to either the low-risk (20%) or high-risk (33%) category. Black individuals exhibited greater variability than White individuals and women exhibited greater variability than men. There was a positive correlation between the baseline Lp(a) levels and the absolute changes in Lp(a), (r = 0.59, P < 0.01). Conclusion Temporal-related changes in Lp(a) variability were present in many individuals. A repeat Lp(a) measure may allow more precise Lp(a)-specific cardiovascular risk prediction for individuals whose initial value is in the EAS-defined intermediate 'grey-zone' category. Lp(a) variability should be included in calculating the expected effect sizes in future clinical research studies targeting Lp(a). [ABSTRACT FROM AUTHOR]

Aging is associated with a significant decline in aerobic capacity assessed by maximal exercise oxygen consumption (V̇ o 2max). The relative contributions of the specific V̇ o 2 components driving this decline, namely cardiac output (CO) and arteriovenous oxygen difference (A − V)O2, remain unclear. We examined this issue by analyzing data from 99 community-dwelling participants (baseline age: 21–96 yr old; average follow-up: 12.6 yr old) from the Baltimore Longitudinal Study of Aging, free of clinical cardiovascular disease. V̇ o 2peak, a surrogate of V̇ o 2max, was used to assess aerobic capacity during upright cycle ergometry. Peak exercise left ventricular volumes, heart rate, and CO were estimated using repeated gated cardiac blood pool scans. The Fick equation was used to calculate (A − V)O2diff,peak from COpeak and V̇ o 2peak. In unadjusted models, V̇ o 2peak, (A − V)O2diff,peak, and COpeak declined longitudinally over time at steady rates with advancing age. In multiple linear regression models adjusting for baseline values and peak workload, however, steeper declines in V̇ o 2peak and (A − V)O2diff,peak were observed with advanced entry age but not in COpeak. The association between the declines in V̇ o 2peak and (A − V)O2diff,peak was stronger among those ≥50 yr old compared with their younger counterparts, but the difference between the two age groups did not reach statistical significance. These findings suggest that age-associated impairment of peripheral oxygen utilization during maximal exercise poses a stronger limitation on peak V̇ o 2 than that of CO. Future studies examining interventions targeting the structure and function of peripheral muscles and their vasculature to mitigate age-associated declines in (A − V)O2diff are warranted. NEW & NOTEWORTHY: The age-associated decline in aerobic exercise performance over an average of 13 yr in community-dwelling healthy individuals is more closely associated with decreased peripheral oxygen utilization rather than decreased cardiac output. This association was more evident in older than younger individuals. These findings suggest that future studies with larger samples examine whether these associations vary across the age range and whether the decline in cardiac output plays a greater role earlier in life. In addition, studies focused on determinants of peripheral oxygen uptake by exercising muscle may guide the selection of preventive strategies designed to maintain physical fitness with advancing age. [ABSTRACT FROM AUTHOR]

ObjectivesThis study sought to report full 1-year results, detailed magnetic resonance imaging analysis, and determinants of efficacy in the prospective, randomized, controlled CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial.BackgroundCardiosphere-derived cells (CDCs) exerted regenerative effects at 6 months in the CADUCEUS trial. Complete results at the final 1-year endpoint are unknown.MethodsAutologous CDCs (12.5 to 25 × 10(6)) grown from endomyocardial biopsy specimens were infused via the intracoronary route in 17 patients with left ventricular dysfunction 1.5 to 3 months after myocardial infarction (MI) (plus 1 infused off-protocol 14 months post-MI). Eight patients were followed as routine-care control patients.ResultsIn 13.4 months of follow-up, safety endpoints were equivalent between groups. At 1 year, magnetic resonance imaging revealed that CDC-treated patients had smaller scar size compared with control patients. Scar mass decreased and viable mass increased in CDC-treated patients but not in control patients. The single patient infused 14 months post-MI responded similarly. CDC therapy led to improved regional function of infarcted segments compared with control patients. Scar shrinkage correlated with an increase in viability and with improvement in regional function. Scar reduction correlated with baseline scar size but not with a history of temporally remote MI or time from MI to infusion. The changes in left ventricular ejection fraction in CDC-treated subjects were consistent with the natural relationship between scar size and ejection fraction post-MI.ConclusionsIntracoronary administration of autologous CDCs did not raise significant safety concerns. Preliminary indications of bioactivity include decreased scar size, increased viable myocardium, and improved regional function of infarcted myocardium at 1 year post-treatment. These results, which are consistent with therapeutic regeneration, merit further investigation in future trials. (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction [CADUCEUS]; NCT00893360).

The vast majority of the over 18 million Americans with known coronary atherosclerosis have stable disease (i.e., they do not have nor have they recently had an acute infarction or [...]