A new capillary-selective vasodilator that directly inhibits smooth muscle myosin in pericytes rapidly and durably reverses established capillary no-reflow in animal models.
Protein misfolding diseases impose a substantial and often under-recognized burden on both the heart and vasculature. In this Review, we outline how the failure of proteostasis drives oligomer toxicity, amyloid deposition and inflammation in cardiovascular tissues as well as microvascular injury and thrombosis, which culminate in cardiovascular dysfunction. We define the cardiovascular hallmarks of protein misfolding diseases, focusing on transthyretin amyloidosis and immunoglobulin light chain amyloidosis, and the disease-specific organ tropisms. We examine neurodegenerative proteinopathies affecting the heart–vascular–brain axis, highlighting how amyloid-β and α-synuclein accumulation contribute to dysautonomia, vascular dysfunction and adverse outcomes. We summarize diagnostic pathways and clinical indicators for early diagnosis of cardiovascular involvement in protein misfolding diseases and review established and emerging biomarkers of vascular stress and proteotoxic load. We also map the current therapeutic landscape for protein misfolding diseases, including strategies to reduce the synthesis of precursor proteins or promote the stabilization of mature proteins as well as fibril-directed therapies, and discuss remaining challenges, such as residual cardiovascular risk, that support the development of mechanism-informed therapeutic approaches. Finally, we propose a research roadmap that prioritizes systematic cardiovascular screening in at-risk populations, harmonized methods for vascular phenotyping, biomarker-anchored mechanistic clinical trials across protein misfolding diseases, and artificial intelligence-based approaches and precision medicine frameworks that integrate genotype or distinct protein conformational strain patterns, organ tropism and dynamic proteostasis measures. In this Review, the authors outline the hallmarks of cardiac and vascular involvement in protein misfolding diseases, focusing on transthyretin amyloidosis and immunoglobulin light chain amyloidosis but also discussing neurodegenerative proteinopathies affecting the heart–vascular–brain axis, including α-synucleinopathies and amyloid-β-related diseases. The authors describe clinical phenotypes, shared and disease-specific mechanisms, diagnostic and prognostic tools, and current and emerging therapies.
Centenarians — individuals aged ≥100 years — provide a unique human model for understanding resilience to cardiovascular ageing. Although cardiovascular and metabolic diseases, including hypertension, heart failure, atrial fibrillation and chronic kidney disease, are common in centenarians, their onset is typically delayed relative to that in individuals aged 80–100 years. Centenarians characteristically have structural changes in the heart and vessels, including concentric left ventricular remodelling, increased myocardial stiffness and vascular ageing, but often without the expected burden of myocardial infarction or overt heart failure. Their cardiometabolic profile is generally favourable, marked by preserved insulin sensitivity in cohorts with a low prevalence of diabetes mellitus, mid-range lipid levels and a low prevalence of obesity. Centenarians also have a distinctive inflammatory and gastrointestinal phenotype, characterized by chronic low-grade inflammation with elevated anti-inflammatory signalling, a gut microbiome that more closely resembles that of younger adults, and preserved intestinal barrier integrity. Genetically and epigenetically, exceptional longevity reflects highly polygenic contributions, selective maintenance of genomic stability and markedly younger epigenetic age compared with chronological age. In this Review, we summarize data on the cardiovascular system among centenarians by framing observations of longevity as a composite of delayed pathology, adaptive compensation and survivorship selection. Understanding the biological, behavioural and environmental mechanisms underlying cardiovascular resilience in extreme longevity might inform strategies to extend cardiovascular healthspan across all ages. In this Review, Lucia and colleagues describe the cardiometabolic, structural, genetic and inflammatory profiles of centenarians that distinguish them from their shorter-lived peers, highlighting the biological, behavioural and environmental factors driving cardiovascular resilience in extreme longevity.
Cardiac pacing has undergone a fundamental paradigm shift from conventional right ventricular apical pacing towards physiological activation of the native conduction system of the heart. Decades of evidence have established that chronic right ventricular pacing induces ventricular dyssynchrony, contributing to pacing-induced cardiomyopathy and adverse clinical outcomes. Conduction system pacing, which engages the intrinsic His–Purkinje network of the heart, has emerged as a transformative approach that preserves or restores the natural ventricular activation sequence. His bundle pacing, the earliest form of conduction system pacing, provided proof of concept but is limited by technical challenges and high capture thresholds. Left bundle branch area pacing has since become the dominant modality, offering greater procedural success, lead stability and broader applicability: from management of bradycardia and prevention of pacing-induced cardiomyopathy to cardiac resynchronization therapy in heart failure. Bachmann bundle area pacing is an emerging atrial counterpart: by capturing a preferential interatrial conduction pathway, this approach reduces interatrial conduction delay and produces a more physiological atrial activation sequence than conventional right atrial appendage pacing. Bachmann bundle area pacing might, therefore, help to prevent atrial fibrillation. In this Review, we bring these ventricular and atrial strategies together under the unifying principle of physiological pacing, describe their mechanistic basis and technical evolution, appraise the latest evidence from randomized trials and address the practical questions that arise in clinical application, indicating where more evidence is required. Conduction system pacing has transformed cardiac pacing by engaging the intrinsic His–Purkinje network, thereby preserving or restoring the natural ventricular activation sequence and avoiding pacing-induced cardiomyopathy. In this Review, Choi and colleagues discuss the various forms of ventricular and atrial physiological pacing, their mechanistic basis and technical evolution, and the latest trial evidence for clinical applications.
