BACKGROUND:This study aimed to determine the prognostic impact of liver fibrosis on cardiac sympathetic innervation and renal function in patients with heart failure (HF) compared with the well-established prognostic value of cardiorenal and hepatorenal linkage. METHODS:In 525 consecutive patients with HF with left ventricular ejection fraction <50%, the fibrosis-5 index (Fib-5) was calculated to evaluate hepatic dysfunction and liver fibrosis. After 123I-metaiodobenzylguanidine (MIBG) scintigraphy, patient outcomes, with lethal cardiac events (CEs) as the primary endpoint, were evaluated for a mean interval of 36.1 ± 26.8 months. CEs were defined as sudden cardiac death, death from heart failure, detection of fatal ventricular arrhythmia, and appropriate implantable cardioverter defibrillator therapy for fatal ventricular arrhythmia. RESULTS:During follow-up, CEs were documented in 139 patients with HF. Fib-5, estimated glomerular filtration rate (eGFR), and the standardized heart-to-mediastinum ratio of MIBG activity (sHMR) were significantly reduced in CEs group compared with those in the non-CEs group. The overall multivariate analysis revealed that these parameters were significant independent determinants of CEs. Combining the cut-off values of Fib-5 (<-13.6), eGFR (<41.0 mL/min/1.73 m2), and late sHMR (<1.83), determined by receiver operating characteristic curve analysis further successfully differentiated patients with HF at higher risk for CEs from other patients with HF. CONCLUSIONS:Liver fibrosis parameters are also independent prognostic factors along with cardiac sympathetic nervous function and renal dysfunction in patients with HF, potentially enabling additive risk stratification of these patients.
Molecular hydrogen (H2) has been shown to exert antioxidant and anti-inflammatory effects across a broad spectrum of disease models and clinical trials; however, its direct reaction rate with hydroxyl radicals (•OH) in aqueous solution is exceedingly slow, and the underlying mechanism of action has remained unresolved for many years as the "hydrogen paradox". The present review delineates a paradigm shift that resolves this enigma from three distinct perspectives. First, oxidized Fe-porphyrin "hematin [Fe(III)-OH]" has been identified as a redox-related biosensor for H2, reducing •OH selectively to water through a catalytic cycle. Ab initio density functional theory calculations support the notion that H2 does not interfere with normal ferrous heme, but intervenes exclusively in pathologically hyperoxidized heme. Second, we propose a novel mechanism whereby H2 performs one-electron reduction of the high-valent ferryl iron intermediate Compound I [Fe(IV) = O·P•+] of myeloperoxidase during neutrophil extracellular trap formation, selectively arresting hypochlorous acid production and immunothrombosis without compromising normal bactericidal function. Third, we discuss how the identical concept of "high-valent iron overheat protection" applies to mitochondrial Complex IV, potentially explaining the maintenance of aerobic energy metabolism and the suppression of lactate accumulation. We present a unified paradigm shift in which H2 functions as the ultimate biological fail-safe mechanism, exerting pinpoint control exclusively over the pathological "runaway oxygen engine" driven by oxidative stress, while leaving normal enzymatic activity entirely intact.
BACKGROUND:Erythrocyte fatty acids (RBC-FAs) are objective biomarkers of longer-term fatty acid status, but their relationship with cardiovascular-kidney-metabolic (CKM) syndrome stage burden remains unclear. We aimed to derive biologically interpretable RBC-FA patterns and examine their associations with CKM stage burden. METHODS:In this population-based cross-sectional study of US adults, isometric log-ratio principal component analysis was performed among 5118 eligible nonpregnant participants with complete 21-part RBC-FA profiles to derive RBC-FA pattern scores. Associations were then evaluated in 2427 participants with positive fasting subsample weights and classifiable CKM stage. Survey-weighted logistic regression was used for the primary outcome, defined as CKM stage ≥2, and survey-weighted linear regression was used for CKM stage modeled continuously from 0 to 4. Subgroup analyses were performed by age and sex. RESULTS:Three retained principal components (PCs) explained 66.2% of total RBC-FA variance. PC1 represented an omega-3-enriched pattern, PC2 a saturated fatty acid/monounsaturated fatty acid-enriched and polyunsaturated fatty acid-depleted contrast, and PC3 a stearoyl-CoA desaturase-16/delta-6 desaturase-related desaturation proxy pattern. In fully adjusted models, PC1 was associated with lower odds of CKM stage ≥2 (OR: 0.66; 95% CI: 0.49-0.90), whereas PC3 was associated with higher odds (OR: 3.09; 95% CI: 1.61-5.92). PC2 showed no robust association. Secondary analyses using continuous CKM stage showed consistent directions, and no robust effect modification by age or sex was observed. CONCLUSION:Distinct RBC-FA patterns were differentially associated with CKM stage burden, suggesting that RBC-FA profiles may provide objective biomarker information on integrated CKM burden.
Dilated cardiomyopathy (DCM) is characterized by progressive ventricular dilation and systolic dysfunction, yet the cellular damage that precedes intercellular fibrosis remains incompletely defined. Electron microscopy has long revealed autophagic vacuoles and myofilament lysis in cardiomyopathy, but their pathological significance has been debated for decades. Recent advances in ultrastructural analysis, including LC3 immunoelectron microscopy, have enabled more precise characterization of these changes and have renewed interest in the role of autophagy in cardiomyopathy. In this review, we integrate ultrastructural findings from a large cohort of patients with DCM with contemporary clinical imaging data to clarify the sequence of myocardial damage. Myofilament lysis consistently appears as the earliest structural abnormality, preceding intercellular fibrosis and ventricular remodeling. Autophagic vacuoles are frequently observed at sites of lysis, suggesting activation of a conserved cellular repair response rather than a mechanism of cell death. This interpretation is supported by external evidence, including LC3-based analyses demonstrating associations between autophagy and reverse remodeling, as well as experimental studies showing that sodium-glucose cotransporter 2 inhibitors enhance stress-adaptive pathways and mitochondrial energetics even in models with impaired mitophagy. By integrating electron microscopy with late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging, we further demonstrate that autophagic activity provides prognostic information beyond conventional tissue characterization. In LGE-negative myocardium, the presence of autophagic vacuoles identifies a subgroup with a lower risk of heart-failure recurrence, whereas myofilament lysis alone shows limited prognostic value. These findings highlight the importance of distinguishing structural damage from cellular repair activity when evaluating cardiomyopathy. Collectively, the evidence supports a refined framework in which myofilament lysis precedes intercellular fibrosis, and autophagy represents an adaptive response that modulates clinical outcomes. Understanding these ultrastructural processes may inform future diagnostic strategies and therapeutic approaches for cardiomyopathy.
BACKGROUND:The International ICI-myocarditis Registry Risk Score predicts major adverse cardiotoxic events (MACE), but Japanese validation is limited. METHODS AND RESULTS:In a retrospective multicenter Japanese registry (23 hospitals), 88 patients were analyzed. MACE occurred in 25 (28.4%) and increased stepwise with higher scores (0: 10%, 1: 13%, 2: 32%, 3: 50%, 4: 67%, 5: 100%; P = 0.001). Discrimination was preserved (AUC 0.76, 95% CI 0.65-0.88); a cutoff ≥2 yielded 80.0% sensitivity and 60.3% specificity. CONCLUSIONS:The score preserved discriminatory performance in Japanese cohort, but low scores did not exclude risk.
Pericoronary adipose tissue (PCAT) imaging has emerged as a promising noninvasive marker of coronary inflammation and an adjunctive risk-stratification tool beyond conventional coronary computed tomography angiography (CCTA) findings such as luminal stenosis and plaque morphology. The fat attenuation index (FAI), derived from CCTA, quantifies phenotypic changes in pericoronary fat driven by vascular inflammation. The CRISP-CT study demonstrated that elevated FAI around the right coronary artery independently predicted cardiac mortality. The ORFAN study further established that the FAI-Score-an artificial intelligence-adjusted derivative of raw PCAT attenuation-predicts cardiac events even in the absence of obstructive coronary artery disease. Multiple meta-analyses have consistently demonstrated that elevated PCAT attenuation is associated with an increased risk of major adverse cardiovascular events. It should be emphasized, however, that current evidence supports FAI/FAI-Score primarily as a prognostic marker; trial-level evidence that FAI-guided management decisions improve patient outcomes is not yet available. Beyond established prognostic applications, investigational uses include the identification of functionally significant lesions, acute coronary syndrome mechanism characterization, vasospastic angina prediction, assessment of myocardial infarction with nonobstructive coronary arteries, treatment-response monitoring, and risk stratification in diabetic populations; these emerging applications require prospective validation. The fat radiomic profile, a machine-learning-derived extension, captures structural remodeling in pericoronary fat that persists beyond the acute inflammatory changes detected by FAI alone. However, substantial technical challenges remain. Reconstruction algorithms and tube voltage introduce substantial measurement variability, underscoring the need for protocol standardization. This review provides an overview of the biological rationale, measurement methodology, prognostic evidence, emerging and investigational applications, and current limitations of PCAT-based coronary inflammation imaging.
BACKGROUND:Red cell distribution width-to-albumin ratio (RAR) is associated with heart failure (HF) prognosis, but its incremental value and performance in contemporary sodium-glucose cotransporter 2 inhibitor (SGLT2i)-treated cohorts remain uncertain. METHODS:We re-audited a prospective registry and analyzed 641 unique patients with HF and baseline RAR measured before or on the day of SGLT2i initiation. The 12-month primary endpoint was all-cause death, unplanned hospitalization, or emergency department visit; event-free patients were right-censored at last contact or 365 days. RESULTS:There were 199 first events in the full time-to-event cohort. RAR remained associated with the endpoint after adjustment including N-terminal pro B-type natriuretic peptide [hazard ratio (HR) 1.42 per standard deviation, 95% confidence interval (CI) 1.24-1.61]. The HR for death or HF hospitalization was 1.57 (95% CI 1.33-1.86). Adding RAR increased Harrell's C-index modestly from 0.694 to 0.710 (likelihood-ratio p < 0.001). No statistically significant interaction was observed by SGLT2i type or initiation setting. CONCLUSIONS:Baseline RAR provides modest, confirmatory prognostic information in SGLT2i-treated HF but is not established as a treatment-response biomarker or stand-alone decision rule.
BACKGROUND:The association of epicardial obstructive coronary artery disease with major adverse cardiovascular events (MACE) is established; however, accumulating evidence emphasizes the significant role of coronary microvascular dysfunction (CMD). The aim of this meta-analysis is to summarize the available evidence on the prognostic effect of CMD in cardiovascular outcomes and mortality. METHODS:Systematic literature search in MEDLINE/PubMed and Scopus was conducted to identify studies comparing the prognosis of CMD vs non-CMD using coronary flow reserve (CFR) and/or index of microcirculatory resistance (IMR) invasive indices. A meta-analysis to calculate pooled risk ratios (RR) was performed along with sensitivity and meta-regression analyses. RESULTS:Thirty-one studies were included (n = 13,016, weighted mean age 58 years, males 57%, left ventricular ejection fraction 58%, CFR 2.6, IMR 24.4, CMD 33%). Meta-analysis of 24 studies (n = 8294) indicated a pooled RR for MACE of 2.55 (2.11, 3.10) for CMD vs non-CMD comparison. Consistent findings were observed for all-cause [1.88 (1.52, 2.33)] and cardiovascular mortality [2.76 (2.02, 3.76)], myocardial infarction [2.18 (1.56, 3.05)], revascularization [1.67 (1.06, 2.64)], heart failure hospitalization [3.46 (1.90, 6.30)], and stroke risk [1.85 (1.26, 2.71)]. The CFR and IMR-based analyses provided similar findings. Worse outcomes were observed in acute coronary syndrome patients and in those with the structural CMD endotype (abnormal CFR/abnormal IMR). CONCLUSION:Invasively diagnosed CMD is associated with a 2.5-fold increase in MACE and a 3-fold increase in cardiovascular mortality. This finding highlights the importance of a more comprehensive assessment of coronary vasculature, including both the macro- and the microcirculation.
The frequency of heart failure and hyperuricemia is increasing worldwide. Hyperuricemia as a complication of heart failure is known to be an indicator of poor prognosis. However, no consensus exists on whether treating hyperuricemia as a complication of heart failure would alleviate symptoms or improve prognosis in patients with heart failure. There is insufficient evidence regarding whether treatment with uric acid-lowering agents can alleviate symptoms and improve prognosis in patients with heart failure. However, considering the prevention of gout, hypertension, and chronic kidney disease caused by hyperuricemia, if the serum uric acid level does not fall below 8 mg/dL with improvement in lifestyle habits, uric acid-lowering agents can be a treatment option. In an US cohort study comprising approximately 100,000 participants using Medicare data, less aggravation of heart failure was observed in patients who were administered febuxostat compared to allopurinol. Recent evidence further suggests that serum uric acid may reflect not only a biomarker of disease severity but also underlying xanthine oxidase activity and oxidative stress, which may be therapeutically targetable in selected subgroups of heart failure patients. Moreover, differential effects among uric acid-lowering agents raise the possibility that drug-specific properties, rather than uric acid reduction per se, may influence cardiovascular outcomes. In this review, we discuss clinical trials on hyperuricemia with heart failure and its treatment. Further large-scale, high-quality, prospective intervention studies on the efficacy of treating hyperuricemia as a complication of heart failure are required.
BACKGROUND:Cell therapy using pluripotent stem cell-derived cardiomyocytes (PSC-CMs) has emerged as a promising strategy for cardiac regeneration. Although transplanted PSC-CMs can contribute to remuscularization, accumulating evidence suggests that paracrine mechanisms also play an important role in functional recovery. Among potential paracrine factors, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are highly expressed in PSC-CMs; however, whether PSC-CM-derived ANP and BNP contribute to cardiac repair after transplantation remains to be determined. METHODS:In this study, we generated human induced pluripotent stem cell (hiPSC) lines deficient in ANP (NPPA knockout), BNP (NPPB knockout), or both peptides using CRISPR-Cas9 genome editing. These iPSCs were differentiated into cardiomyocytes, and their characteristics and paracrine effects were then examined in vitro using endothelial cell assays and co-culture with cardiac fibroblasts. RESULTS:ANP- and/or BNP-deficient hiPSC-derived cardiomyocytes (hiPSC-CMs) showed comparable cardiac differentiation efficiency, cell size, proliferative capacity, and susceptibility to apoptosis compared with wild-type hiPSC-CMs. In trans-well migration and Matrigel tube formation assays, conditioned medium from wild-type hiPSC-CMs significantly enhanced endothelial cell migration and tube formation compared with medium from double-knockout hiPSC-CMs lacking both ANP and BNP, suggesting that natriuretic peptides contribute to the pro-angiogenic effects of hiPSC-CMs in vitro. In contrast, co-culture with hiPSC-CMs attenuated TGF-β1-induced myofibroblast gene expression in cardiac fibroblasts regardless of natriuretic peptide deficiency, possibly reflecting minimal expression of the natriuretic peptide receptor NPRA in fibroblasts under in vitro conditions. CONCLUSIONS:These findings suggest that ANP and BNP are involved in the pro-angiogenic paracrine activity of hiPSC-CMs in vitro. This study provides genetically modified hiPSC-CM models that may serve as a platform for future in vivo transplantation studies to determine whether PSC-CM-derived natriuretic peptides contribute to cardiac repair after transplantation.
Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Accumulating pathological evidence indicates that rapid plaque progression is driven not only by recurrent subclinical plaque rupture with healing but also by intraplaque hemorrhage (IPH), which can occur independently of overt luminal thrombosis. IPH is no longer regarded as a passive process that merely enlarges plaque volume through deposition of erythrocyte-derived lipids, hemoglobin, and iron. Instead, contemporary pathological studies have revealed that IPH initiates a cascade of molecular and cellular responses that actively promote plaque destabilization. Within hemorrhagic plaques, erythrocyte lysis generates oxidative stress and cholesterol crystallization, accelerating necrotic core expansion and inflammatory signaling. In parallel, hemoglobin-haptoglobin complex uptake by CD163+ macrophages induces a distinct macrophage phenotype characterized by vascular endothelial growth factor and pro-inflammatory cytokines secretion, increased microvascular permeability, and propagation of intraplaque angiogenesis. These macrophage-driven processes amplify endothelial dysfunction, promote proapoptotic endothelial-to-mesenchymal transition, impair fibrous-cap integrity, and paradoxically suppress stabilizing calcification, thereby creating a microenvironment highly susceptible to rupture. Importantly, these IPH-driven cellular responses do not act in isolation but converge to amplify plaque vulnerability through interconnected inflammatory, angiogenic, and structural pathways. Advances in vascular imaging have enabled in vivo detection of IPH-related plaque features, providing a translational bridge between pathological observations and clinical phenotyping. Across carotid and coronary arterial beds, imaging-detected IPH consistently correlates with accelerated lesion progression and adverse cardiovascular outcomes. Together, current evidence positions IPH as a central biological driver of plaque progression and destabilization rather than a secondary epiphenomenon. A deeper understanding of IPH-related cellular mechanisms may identify novel therapeutic targets beyond lipid lowering and improve identification of patients with intrinsically unstable atherosclerotic disease.
BACKGROUND:Worsening renal function (WRF) in acute heart failure (AHF) has been associated with poor outcomes; however, when accompanied by hemoconcentration, WRF is not necessarily associated with adverse outcomes. The associations of WRF and hemoconcentration with renal outcomes and longitudinal changes in renal function remain unclear. METHODS:In this multicenter retrospective study, 2556 hospitalized patients with AHF (median 80 years; 60% male) were categorized into four groups according to WRF and hemoconcentration status. WRF was defined as a ≥20% decrease in estimated glomerular filtration rate (eGFR) from admission to discharge. Hemoconcentration was defined as concurrent increases in hemoglobin and hematocrit levels from admission to discharge. The primary outcome was a composite of initiation of maintenance dialysis, decline in eGFR to <10 mL/min/1.73 m2, or ≥40% reduction in eGFR within one year after discharge. RESULTS:The WRF/hemoconcentration group had less frequent inotrope use and lower N-terminal pro-B-type natriuretic peptide levels at discharge. The cumulative incidence of the primary outcome was 18.4%, 15.9%, and 20.0% in the No WRF/No hemoconcentration, No WRF/hemoconcentration, and WRF/No hemoconcentration groups, respectively, and was lowest at 9.5% in the WRF/Hemoconcentration group. In multivariable analysis, this group was significantly associated with a lower risk of the primary outcome, compared with the No WRF/No hemoconcentration group (subdistribution hazard ratio 0.58, 95% confidence interval 0.36 to 0.93, p = 0.025). The longitudinal changes in renal function differed significantly across the groups; the WRF/Hemoconcentration group showed an attenuated decline or even improvement in eGFR (+3.6 mL/min/1.73 m2/year), whereas the No WRF/No hemoconcentration group exhibited the steepest decline (-6.2 mL/min/1.73 m2/year). CONCLUSIONS:Renal function changes after AHF hospitalization were heterogeneous, and WRF accompanied by hemoconcentration was associated with favorable renal outcomes within one year after discharge.
Cardiovascular disease (CVD) is the leading cause of mortality globally and imposes a substantial disease burden. Addressing the social determinants of health (SDOH) presents a critical opportunity to reduce CVD-related mortality and disability. In Japan, CVD constitutes a major cause of death and necessitates long-term care, with current guidelines now incorporating SDOH related to CVD, indicative of a growing interest in these determinants. This review outlines the definition and conceptual frameworks of SDOH, along with its key domains: (1) Economic stability, (2) Education access and quality, (3) Social and community context, (4) Health care access and quality, and (5) Neighborhood and built environment. In addition to these established determinants, we discuss emerging SDOH such as climate change and digital health technologies, which may reshape cardiovascular risk and potentially widen existing disparities. We also summarize existing epidemiological findings and implications for intervention strategies, and outline future perspectives, including the implications of genetic testing and related ethical, legal, and social issues, as well as strategies aimed at reducing health disparities. Overall, advancing equitable cardiovascular health will require continued research, greater recognition of the role of SDOH, and efforts to address these determinants, including improving understanding of SDOH among health care professionals and the public and strengthening the evidence base for CVD and SDOH.
BACKGROUND:Post-discharge risk stratification remains challenging in patients with heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), where natriuretic peptides incompletely capture residual renal and microvascular stress. Albuminuria integrates glomerular and microvascular injury, yet whether its prognostic value depends on measurement timing-admission versus discharge-and whether this relationship differs by ejection fraction (EF) phenotype, has not been established. METHODS:In 290 patients hospitalized for acute decompensated HF [126 HF with reduced ejection fraction (HFrEF), 164 HFmrEF/HFpEF], the urine albumin-to-creatinine ratio (UACR) was measured at admission and discharge. The primary outcome was the 1-year composite of all-cause death or HF rehospitalization. Sensitivity analyses sequentially adjusted for individual medication classes, and the interaction between UACR and EF phenotype was formally tested. RESULTS:UACR decreased markedly during hospitalization (median 96.8 to 24.7 mg/gCr; p < 0.001), yet residual albuminuria was greater in HFmrEF/HFpEF at discharge (28.5 mg/gCr vs 18.7 mg/gCr; p = 0.038). During a 1-year follow-up, 98 patients (34%) experienced the composite endpoint. Per 1-SD increase in log-transformed discharge UACR, discharge UACR was independently associated with outcomes in HFmrEF/HFpEF across all four medication-adjusted models (HR range 1.37-1.40, all p ≤ 0.008), whereas admission UACR lost significance after adjustment. No meaningful associations were observed in HFrEF. The interaction between discharge UACR and EF phenotype was of borderline significance after adjustment (p for interaction = 0.047). CONCLUSIONS:Discharge UACR independently predicts adverse outcomes in HFmrEF/HFpEF, with associations that remained consistent after adjustment for individual HF medication classes. Predischarge UACR measurement may refine post-discharge risk stratification in HFmrEF/HFpEF in addition to natriuretic peptides.
Digital therapeutics using mobile technology offer potential advantages for facilitating patient-centered care. Driven by an increasing demand for digital health in the care of individuals with heart failure (HF), numerous mobile health applications (mHealth apps) have been developed to enhance self-care behaviors in patients with chronic HF. The key functional elements of HF apps include self-monitoring support, medication tracking and reminders, lifestyle modification guidance, sensor device connectivity and data transmission, educational materials, automated health status checks with alerts for potential HF exacerbation, and motivational support and feedback. Several randomized clinical trials (RCTs) have evaluated the efficacy and feasibility of self-care interventions for patients with chronic HF that use smartphone- or tablet-based apps designed as standalone or near-standalone systems. Although it has been observed that mHealth apps can improve patients' self-care behaviors, the evidence regarding the apps' impact on hard clinical endpoints (e.g. mortality and hospitalization) remains limited and inconsistent. The results of RCTs have demonstrated potential benefits, but it remains essential to address barriers to mHealth app adoption among both patients and healthcare professionals in order to successfully implement such apps into routine clinical practice. This narrative review examines mobile app-based self-care interventions and evaluates the evidence concerning their efficacy and feasibility in chronic HF patient populations.
Calcified nodule (CN) is a unique calcified plaque morphology that is pathologically characterized by fibrous-cap disruption and luminal thrombus associated with eruptive, dense calcific nodules. Although CNs account for a small proportion of acute coronary syndrome, they remain challenging substrates for percutaneous coronary intervention (PCI) due to high risks of underexpansion and in-stent restenosis. To understand their unpredictable mechanical behavior, it is crucial to recognize their origin: CNs typically arise from the fragmentation of mechanically vulnerable necrotic core calcification under mechanical stress, often exacerbated by adjacent rigid sheet calcium. Crucially, while intravascular imaging typically classifies CNs into "eruptive" or "non-eruptive" forms, this binary classification alone is sometimes insufficient to predict lesion compliance or "softness." A deeper understanding of the underlying pathological evolution-from fresh, thrombus-covered nodules to mature, ossified masses-is essential to distinguish deformable lesions from rigid ones. This review bridges this gap by proposing a pathology-imaging continuum that links histological maturity to mechanical behavior, enabling more precise phenotyping beyond surface appearance. We finally discuss how this integrated approach informs contemporary PCI strategies, including atherectomy, intravascular lithotripsy, and lifetime management, to optimize clinical outcomes.
