Given evidence on the cardiovascular disease (CVD) risk conferred by comorbidity risk factors, the American Heart Association (AHA) recently introduced a novel staging construct, named cardiovascular-kidney-metabolic (CKM) syndrome. This study examined the association of CKM syndrome stages with all-cause and cardiovascular mortality among US adults.

Data were from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 at baseline linked to the 2019 National Death Index records. For each participant, the CKM syndrome was classified into five stages: stage 0 (no CKM risk factors), 1 (excess or dysfunctional adiposity), 2 (metabolic risk factors and chronic kidney disease), 3 (subclinical CVD), or 4 (clinical CVD). The main outcomes were all-cause and cardiovascular mortality.

Among 34,809 participants (mean age: 46.7 years; male: 49.2 %), the prevalence of CKM stages 0 to 4 was 13.2 %, 20.8 %, 53.1 %, 5.0 %, and 7.8 %, respectively. During a median follow-up of 8.3 years, compared to participants with CKM stage 0, those with higher stages had increased risks of all-cause mortality (stage 2: HR 1.43, 95 % 1.13-1.80; stage 3, HR 2.75, 95 % CI 2.12-3.57; stage 4, HR 3.02, 95 % CI 2.35-3.89). The corresponding hazard ratios (95 % confidence interval) of cardiovascular mortality risks were 2.96 (1.39-6.30), 7.60 (3.50-16.5), and 10.5 (5.01-22.2). The population-attributable fractions for advanced (stages 3 or 4) vs. CKM syndrome stages (stages 0, 1, or 2) were 25.3 % for all-cause mortality and 45.3 % for cardiovascular mortality.

Higher CKM syndrome stages were associated with increased risks of all-cause and cardiovascular mortality. These findings emphasize that primordial and primary prevention efforts on promoting CKM health should be strengthened to reduce mortality risk.

Obesity, insulin resistance (IR), and diabetes are common in heart failure with preserved ejection fraction (HFpEF) and are associated with worsening heart failure, but their independent contributions remain unknown.

In this study, we sought to determine the contribution of diabetes vs obesity to left heart abnormalities in HFpEF METHODS: Indices of adiposity (body mass index [BMI], bioimpedance fat mass, waist circumference) and IR (homeostasis-model assessment [HOMA]) were measured among PVDOMICS study participants with HFpEF. Rest and exercise pulmonary capillary wedge pressure (PCWP) responses were compared, stratified by obesity (BMI ≥30 kg/m2), IR status (HOMA-IR ≥2.6), and diabetes diagnosis. Findings were also tested in an independent HFpEF cohort.

Of 276 patients with HFpEF, 246 (89%) had increased waist/height ratio, and 166 (60%) had BMI ≥30 kg/m2, with 114 (69%) of the latter having IR and 75 (45%) having diabetes. Of 110 (40%) with HFpEF and BMI <30 kg/m2, 44 (40%) had IR and 27 (25%) had diabetes (both P < 0.0001 vs obesity phenotype). The presence of IR was not associated with worse left heart remodeling or PCWP. In contrast, obesity (regardless of IR status) was associated with greater biventricular enlargement, worse exercise performance, poorer quality of life, and higher rest and exercise PCWP (P < 0.01 for all). Obesity was associated with higher rest and dynamic PCWP responses (+4.4 mm Hg; 95% CI: +2.5 to +6.4 mm Hg; P < 0.0001), even after adjustment for HOMA-IR (+4.7 mm Hg; 95% CI: +2.7 to +6.7 mm Hg; P < 0.0001). Greater fat mass, BMI, and waist circumference were associated with higher PCWP at rest and exercise (P < 0.0009 for all), but HOMA-IR was not (+0.01 mm Hg; 95% CI: -0.13 to +0.16 mm Hg; P = 0.84). Findings were similar evaluating diabetes in place of IR, and were replicated in the independent HFpEF cohort (n = 254), where BMI remained independently associated with higher rest and exercise PCWP (+0.19 mm Hg [95% CI: +0.11 to +0.27 mm Hg] per kg/m2; P < 0.0001), but diabetes was not.

Excess adiposity is present in most patients with HFpEF, even among those not considered obese according to BMI, calling for further study of cardiometabolic therapies among patients with HFpEF and excess adiposity with BMI <30 kg/m2. Although excess body fat is associated with IR and diabetes, cardiac remodeling, hemodynamics, and functional impairment are independently correlated with body fat, but not IR. These findings suggest that diabetes is primarily a marker of greater adiposity in HFpEF, with less direct impact on heart failure severity. (Pulmonary Vascular Disease Phenomics Program [PVDOMICS]; NCT02980887).

Definition and staging rationale of cardiovascular-kidney-metabolic syndrome were developed. The utility of cardiovascular-kidney-metabolic construct in risk stratification and target strategies of health and behavior modifications needs to be addressed. The study aims to investigate the individual and combined associations of cardiovascular-kidney-metabolic stage and cardiovascular health (CVH) by Life's Essential 8 (LE 8) with incident cardiovascular events (CVD), and determine the distribution and contribution of domain-specific CVH across cardiovascular-kidney-metabolic stages.

The study included 100,727 individuals in the China Cardiovascular Disease and Cancer Cohort with complete data on cardiovascular-kidney-metabolic factors and LE 8 metrics, with a median follow-up of 10.1 years. Cardiovascular-kidney-metabolic stages and CVH metrics (nicotine exposure, diet, physical activity, sleep, body mass index, blood lipids, blood pressure, blood glucose) were defined according to Presidential Advisory from the American Heart Association. Incident CVD events including cardiovascular death, myocardial infarction, and stroke were validated. The Fine-Gray hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of CKM stages or CVH status associated with CVD.

Compared with cardiovascular-kidney-metabolic stage 0, the adjusted competing HRs and 95% CIs of CVD events were 1.20 (0.95-1.51), 2.45 (1.97-3.04), 4.43 (3.53-5.58), and 5.95 (4.75-7.45) from stage 1 to stage 4, respectively. Optimal CVH status and each optimal CVH metric presented a significantly decreased risk of CVD events. Variation was observed in the association between cardiovascular-kidney-metabolic stage and CVD events with different CVH status or numbers of optimal CVH metrics. Compared with those in stage 0, Participants in stage 1 or 2 with optimal CVH no longer had elevated risks for incident CVD events. Suboptimal health factor contributed larger population attributable fractions to CVD events in cardiovascular-kidney-metabolic stage 0-2 (51.2%) than in stage 3-4 (25.2%), whereas suboptimal health behavior exhibited larger contribution in advanced stages (13.1% in stage 0-2 and 18.2% in stage 3-4).

The study indicated that cardiovascular-kidney-metabolic stage was associated with cardiovascular events, and optimal cardiovascular health could attenuate this risk. Health factor contributed predominantly at the early-stage, whereas health behavior exhibited consistent and slightly increased contribution along the spectrum. These findings support the utility of cardiovascular-kidney-metabolic construct and highlight the importance of target health improvement based on LE 8 framework.

Cardiovascular-Kidney-Metabolic Syndrome (CKM) has profound impacts on cardiovascular events and mortality, yet its association with dementia risk remains poorly understood.

To investigate associations between CKM and dementia risk.

The prospective cohort study is within the Health, Aging, and Body Composition study, which enrolled participants from 1997 to 1998, with a 15-year follow-up for incident dementia.

The population-based study took place in two US communities in Memphis, Tennessee, and Pittsburgh, Pennsylvania.

Of the 3,075 participants aged 70 to 79 years initially enrolled, 14 were excluded for lacking baseline cognitive assessment, 308 for baseline cognitive impairment, 4 for missing follow-up, and 108 for missing CKM data, resulting in 2,641 in the analysis.

CKM staging, as defined recently by the American Heart Association framework, was based on constructs comprising dysfunctional adiposity, metabolic risk factors, chronic kidney disease (CKD), and cardiovascular disease (CVD). Dementia was identified using hospital records, prescriptions for dementia medication, and a test of global cognition. Adjusted Cox and Fine-Gray proportional hazards models were used to estimate dementia risk and account for competing risk of death.

The 2,641 participants had a mean (SD) age of 74 (2.8) years at baseline; 53 % were female, 36 % were of Black race, and had a range of baseline CKM: 3 % Stage 0 (no CKM), 4 % Stage 1 (excess/dysfunctional adiposity), 26 % Stage 2 (metabolic risk factors), 24 % Stage 3 (subclinical CVD and CKD), and 43 % Stage 4 (clinical CVD and CKD). Compared to participants with CKM Stages 0-2, those with CKM Stages 3-4 had a 50 % increase in dementia risk (hazard ratio 1.50, 95 % CI 1.20 to 1.86) in the fully adjusted model. The association remained significant after additional adjustment for metabolic risk factors, CVD, and CKD, both separately and together. Accounting for competing risk of death yielded similar results.

Among community-dwelling older adults, advanced CKM is associated with an increased risk of dementia. Older adults with CKM may need to be followed closely for adverse cognitive outcomes, and modifiable risk factors should be managed proactively.

Estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio are complementary domains of kidney disease staging and independently associated with heart failure (HF) progression.

The purpose of this study was to evaluate whether the efficacy and safety of finerenone varies according to kidney risk among patients with HF with mildly reduced or preserved ejection fraction.

In this prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure), clinical outcomes and treatment effects of finerenone on the primary endpoint (cardiovascular death and total [first and recurrent] HF events) and key secondary endpoints were evaluated according to baseline KDIGO (Kidney Disease: Improving Global Outcomes) risk category (low, moderately increased, and high or very high). Key exclusion criteria in FINEARTS-HF were eGFR <25 mL/min/1.73 m2 or serum potassium >5.0 mmol/L.

Overall, 5,797 (97%) FINEARTS-HF participants had classifiable KDIGO risk category at baseline, of whom 2,022 (35%), 1,688 (29%), and 2,087 (36%) were low, moderate, and high/very high risk, respectively. Over a median follow-up of 2.7 years, higher kidney risk was associated with a higher rate of primary outcome events, with similar findings for other key endpoints, including the composite kidney outcome, new-onset atrial fibrillation, and vascular events. Benefits of finerenone vs placebo on the primary endpoint (Pinteraction = 0.24) and Kansas City Cardiomyopathy Questionnaire-Total Symptom Score at 12 months (Pinteraction = 0.36) were consistent irrespective of baseline kidney risk category. Participants with higher kidney risk experienced greater reductions in urine albumin-to-creatinine ratio after 6 months (Pinteraction = 0.031), without differences in eGFR slope. Risks of safety events, including hyperkalemia, with finerenone vs placebo were not enhanced among participants with higher kidney risk.

Finerenone appears to consistently improve clinical outcomes, HF-related health status, and albuminuria across a broad spectrum of kidney risk in patients with HF with mildly reduced or preserved ejection fraction. (Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone on Morbidity [Events Indicating Disease Worsening] and Mortality [Death Rate] in Participants With Heart Failure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke] Greater or Equal to 40% [FINEARTS-HF]; NCT04435626).

Cardiac, renal, and metabolic (CRM) conditions are major causes of morbidity and mortality globally. This study aims to explore the relationship between serum uric acid (SUA), hyperuricemia, gout, and CRM conditions in middle-aged and elderly populations.

Sample 1 included participants from CHARLS (China Health and Retirement Longitudinal Study, n=9341), and Sample 2 from NHANES (National Health and Nutrition Examination Survey, unweighted n=17 913; weighted n=115 646 390). Ordinal logistic regression, Cox regression, and restricted cubic spline analyses were used to assess the relationship between SUA, hyperuricemia, gout, and CRM conditions. A 2-sample Mendelian randomization analysis was conducted to explore causal associations between SUA and CRM conditions.

In both samples, SUA, hyperuricemia, and gout were positively correlated with the risk of CRM conditions. Among participants with 3 or ≥1 CRM condition(s), SUA, asymptomatic hyperuricemia, and gout with poorly controlled hyperuricemia showed significant positive associations with all-cause mortality, whereas these associations were not observed in patients with gout with normal SUA levels. The restricted cubic spline analysis revealed a positive relationship between SUA levels and the risk of all-cause mortality in participants with ≥1 CRM condition(s), demonstrating a nonlinear dose-response relationship across both samples (P for nonlinearity <0.05). Mendelian randomization analysis indicated that SUA was causally associated with cardiovascular disease, chronic kidney disease, and diabetes.

Hyperuricemia and gout are strong predictors of increased prevalence and mortality of CRM conditions, emphasizing the importance of managing hyperuricemia and gout in these patients.

The cardiovascular-kidney-metabolic index (CKMI), a novel functional indicator proposed in this study, aims to accurately reflect the functional status of the heart, kidneys, and metabolism. However, its ability to predict mortality risk in critically ill patients during their stay in the intensive care unit (ICU) remains uncertain. Therefore, this study aims to validate the correlation between the CKMI during hospitalization and all-cause mortality.

The study utilized the Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV) dataset for a retrospective analysis of cohorts. The cohorts were divided into quartiles based on CKMI index levels. The primary endpoint was all-cause mortality during ICU and hospital stay, while secondary endpoints included the duration of ICU stay and overall hospitalization period. We established Cox proportional hazards models and employed multivariable Cox regression analysis and restricted cubic spline (RCS) regression analysis to explore the relationship between CKMI index and all-cause mortality during hospitalization in critically ill patients. Additionally, subgroup analyses were conducted based on different subgroups.

The study enrolled 1,576 patients (male 60.79%). In-patient and ICU mortality was 11.55% and 6.73%. Multivariate COX regression analysis demonstrated a significant negative correlation between CKMI index and the risk of hospital death [HR, 0.26 (95% CI 0.07-0.93), P = 0.038] and ICU mortality [HR, 0.13 (95% CI 0.03-0.67), P = 0.014].RCS regression model revealed that in-hospital mortality (P-value =0.015, P-Nonlinear =0.459) and ICU mortality (P-value =0.029, P-Nonlinear =0.432) increased linearly with increasing CKMI index. Subgroup analysis confirmed consistent effect size and direction across different subgroups, ensuring stable results.

Our research findings suggest that a higher CKMI index is associated with a significant reduction in both in-hospital and ICU mortality among critically ill patients. Therefore, CKMI index emerges as a highly valuable prognostic indicator for predicting the risk of in-hospital death in this population. However, to strengthen the validity of these results, further validation through larger-scale prospective studies is imperative.

Cardiovascular-kidney-metabolic (CKM) multimorbidity is prevalent among individuals with heart failure (HF), but whether cardiac structure and function, clinical outcomes, and treatment response to sacubitril/valsartan vary in relation to CKM status is unknown.

In this PARAGON-HF post-hoc analysis, we evaluated the impact of CKM multimorbidity (atherosclerotic cardiovascular [CV] disease, chronic kidney disease, and type 2 diabetes) on cardiac structure and function, clinical outcomes, and treatment effects of sacubitril/valsartan versus valsartan. The primary outcome was a composite of total HF hospitalizations and CV death. Secondary outcomes included the individual components of the primary outcome and a composite kidney outcome (sustained estimated glomerular filtration rate reduction of ≥50%, end-stage kidney disease, or kidney-related death). At baseline, 35.2% had one CKM condition, 33.3% had two, 15.9% had three, and only 15.6% had HF alone. CKM multimorbidity was associated with higher septal and posterior wall thickness, lower global longitudinal strain, higher E/e', and worse right ventricular function. Total HF hospitalizations or CV death increased with greater CKM multimorbidity, with the highest relative risk observed with three CKM conditions (rate ratio 3.06, 95% confidence interval 2.33-4.03), compared with HF alone. Treatment effects of sacubitril/valsartan were consistent irrespective of the number of CKM conditions for the primary endpoint (pinteraction = 0.75), CV death (pinteraction = 0.82), total HF hospitalizations (pinteraction = 0.67), and the composite kidney endpoint (pinteraction = 0.99).

Cardiovascular-kidney-metabolic multimorbidity was common in PARAGON-HF and associated with adverse changes in cardiac structure and function and with a stepwise increase in risk of clinical outcomes. Treatment effects of sacubitril/valsartan were consistent irrespective of CKM burden.

ClinicalTrials.gov NCT01920711.

Heart failure (HF), especially HF with reduced ejection fraction (HFrEF), presents complex challenges, particularly in the aging population where it often coexists with type 2 diabetes mellitus (T2DM).

To analyze the effect of dapagliflozin treatment on cardiac, renal function, and safety in patients with HFrEF combined with T2DM.

Patients with T2DM complicated with HFrEF who underwent treatment in our hospital from February 2018 to March 2023 were retrospectively analyzed as the subjects of this study. The propensity score matching method was used, and a total of 102 eligible samples were scaled. The clinical efficacy of the two groups was evaluated at the end of the treatment, comparing the results of blood glucose, insulin, cardiac function, markers of myocardial injury, renal function indexes, and 6-min walk test (6MWT) before and after the treatment. We compared the occurrence of adverse effects on the treatment process of the two groups of patients. The incidence of adverse outcomes in patients within six months of treatment was counted.

The overall clinical efficacy rate of patients in the study group was significantly higher than that of patients in the control group (P = 0.013). After treatment, the pancreatic beta-cell function index, left ventricular ejection fraction, and glomerular filtration rate of patients in the study group were significantly higher than control group (P < 0.001), while their fasting plasma glucose, 2-h postprandial glucose, glycosylated hemoglobin, insulin resistance index, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, cardiac troponin I, creatine kinase-MB, N-terminal pro b-type natriuretic peptide, serum creatinine, and blood urea nitrogen were significantly lower than those of the control group. After treatment, patients in the study group had a significantly higher 6MWT than those in the control group (P < 0.001). Hypoglycemic reaction (P = 0.647), urinary tract infection (P = 0.558), gastrointestinal adverse effect (P = 0.307), respiratory disturbance (P = 0.558), and angioedema (P = 0.647) were not statistically different. There was no significant difference between the incidence of adverse outcomes between the two groups (P = 0.250).

Dapagliflozin significantly enhances clinical efficacy, cardiac and renal function, and ambulatory capacity in patients with HFrEF and T2DM without an increased risk of adverse effects or outcomes.

To assess the cost-effectiveness of dapagliflozin in addition to usual care, compared with usual care alone, in a large population of patients with heart failure (HF), spanning the full range of left ventricular ejection fraction (LVEF).

Patient-level data were pooled from HF trials (DAPA-HF, DELIVER) to generate a population including HF with reduced, mildly reduced and preserved LVEF, to increase statistical power and enable exploration of interactions among LVEF, renal function and N-terminal pro-B-type natriuretic peptide levels, as they are relevant determinants of health status in this population. Survival and HF recurrent event risk equations were derived and applied to a lifetime horizon Markov model with health states defined by Kansas City Cardiomyopathy Questionnaire total symptom score quartiles; costs and utilities were in the UK setting. The base case incremental cost-effectiveness ratio (ICER) was £6470 per quality-adjusted life year (QALY) gained, well below the UK willingness-to-pay (WTP) threshold of £20 000/QALY gained. In interaction sensitivity analyses, the highest ICER was observed for elderly patients with preserved LVEF (£16 624/QALY gained), and ranged to a region of dominance (increased QALYs, decreased costs) for patients with poorer renal function and reduced/mildly reduced LVEF. Results across the patient characteristic interaction plane were mostly between £5000 and £10 000/QALY gained.

Dapagliflozin plus usual care, versus usual care alone, yielded results well below the WTP threshold for the UK across a heterogeneous population of patients with HF including the full spectrum of LVEF, and is likely a cost-effective intervention.

The correlation between obesity, type 2 diabetes mellitus (DM), cardiovascular disease (CVD), and chronic kidney disease (CKD) is an escalating and widely acknowledged epidemic in industrialized nations. Recently, this complex web of interrelated health conditions has been collectively defined as the Cardiovascular-Kidney-Metabolic (CKM) syndrome by the American Heart Association (AHA). The molecular mechanisms underlying CKM disease contain a spectrum of interconnected factors, including hyperglycemia, insulin resistance, heightened activity of the renin-angiotensin-aldosterone system (RAAS), the generation of advanced glycation end-products, oxidative stress, lipotoxicity, endoplasmic reticulum stress, abnormalities in calcium handling, malfunctioning of mitochondria and impaired energy production, as well as persistent chronic inflammation. Addressing their prevention, management, and treatment is of paramount importance to promote better patient health outcomes. The objective of this review is to provide a comprehensive and critical examination of the current state-of-the-art regarding the recently defined CKM syndrome. This includes an exploration of epidemiological evidence establishing connections between cardio-renal-metabolic diseases, an examination of the underlying pathophysiological mechanisms, and a comprehensive overview of existing treatment modalities.