Over the past decade, there have been significant advances in pharmacotherapy for cardiovascular diseases and related health conditions. In particular, numerous large-scale clinical trials have been conducted internationally, and remarkable progress has been made in several disease-modifying medications for diabetes, chronic kidney disease, and heart failure. These research trends have driven dynamic changes in treatment guidelines and clinical practice. At the same time, this era has given rise to the concept of cardiovascular–kidney–metabolic (CKM) syndrome, which represents a transformative shift in understanding the complex pathophysiology and therapeutics of relevant health conditions. Positioning this framework as part of a unified disease continuum could promote early intervention, multidisciplinary care, and more effective prevention and treatment strategies. Although challenges remain in validating the CKM syndrome framework and implementing the care model in Japan, this concept may provide a unique clinical tool for addressing the globally increasing burden of cardiovascular, kidney, and metabolic health issues. This review discusses the current understanding of CKM syndrome and introduces the author’s research contributions related to CKM network medicine.

Recent advances in traditional “-omics” technologies have provided deeper insights into cardiovascular diseases through comprehensive molecular profiling. Accordingly, digitalomics has emerged as a novel transdisciplinary concept that integrates multimodal information with digitized physiological data, medical imaging, environmental data, electronic health records, environmental records, and biometric data from wearables. This digitalomics-driven augmented multiomics approach can provide more precise personalized health risk assessments and optimization when combined with conventional multiomics approaches. Artificial intelligence and machine learning (AI/ML) technologies, alongside statistical methods, serve as key comprehensive analytical tools in realizing this comprehensive framework. This review focuses on two promising AI/ML applications in cardiovascular medicine: digital phonocardiography (PCG) and AI text generators. Digital PCG uses AI/ML models to objectively analyze heart sounds and predict clinical parameters, potentially surpassing traditional auscultation capabilities. In addition, large language models, such as generative pretrained transformer, have demonstrated remarkable performance in assessing medical knowledge, achieving accuracy rates exceeding 80% in medical licensing examinations, although there are issues regarding knowledge accuracy and safety. Current challenges to the implementation of these technologies include maintaining up-to-date medical knowledge and ensuring consistent accuracy of outputs, but ongoing developments in fine-tuning and retrieval-augmented generation show promise in addressing these challenges. Integration of AI/ML technologies in clinical practice, guided by appropriate validation and implementation strategies, may notably advance precision cardiovascular medicine through the digitalomics framework.

Iron is an essential requirement for normal cellular function and oxygen transport. Deficiency of iron, due to suboptimal intake, blood loss, malabsorption or maldistribution is the most common nutrient deficiency worldwide. Iron deficiency (ID) has traditionally been ignored until anemia develops. Amongst patients with cardiovascular (CV) disease, ID is common and is associated with worse symptoms, poorer quality of life, and a worse prognosis. However, the criteria used to define ID in studies and international guidelines are inconsistent and lack universal acceptance. Accordingly, we review the various criteria used to define ID in patients with CV disease, discuss how these might have influenced the results of observational studies and randomized trials and suggest areas for future research.

Background: Lipoprotein(a) [Lp(a)] is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), but the shape and potential nonlinearity of its association remain uncertain. We assessed the linear and nonlinear associations between Lp(a) levels and ASCVD risk using observational and Mendelian randomization (MR) approaches.

Methods and Results: We analyzed 351,858 UK Biobank participants (2006–2023), stratified into Lp(a) percentiles: <70th, 70th–<80th, 80th–<90th, and ≥90th. Outcomes included ASCVD events from hospital, primary care, self-report, and death registry data. Cox models estimated the hazard ratios (HRs). MR analyses used a polygenic risk score from 10 Lp(a)-associated single-nucleotide polymorphisms, with nonlinearity tested by doubly ranked MR. Higher Lp(a) levels were associated with increased ASCVD risk. Compared with the <70th percentile, adjusted HRs (95% confidence interval) were 1.11 (1.07–1.16), 1.18 (1.14–1.22), and 1.25 (1.21–1.30) for the 70th–<80th, 80th–<90th, and ≥90th groups. Kaplan-Meier curves diverged early by group. Spline models suggested nonlinearity with an inflection near 130 nmol/L (P=0.007). MR showed a 2% higher ASCVD risk per 10 nmol/L genetically predicted Lp(a) (P<2×10⁻¹⁶). Nonlinear MR suggested steeper gradients at higher levels, though not statistically significant (P=0.087).

Conclusions: Elevated Lp(a) concentrations were causally associated with ASCVD risk, showing a predominantly graded relationship with possible nonlinearity at very high levels, supporting routine Lp(a) measurement and the development of Lp(a)-lowering therapies.

Background: We investigated associations between the low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio (L/H ratio) and cardiovascular events in high-risk type 2 diabetes (T2D) patients with diabetic retinopathy receiving statins.

Methods and Results: We conducted a post hoc analysis of the EMPATHY study, a randomized controlled trial comparing intensive vs. standard statin therapy in T2D patients with retinopathy and hypercholesterolemia without cardiovascular disease. Baseline and 12-month (12M) L/H ratios were assessed as single and serial measures. Baseline data were available for 5,006 patients (median L/H ratio 2.016), categorized as having either a high (≥2.0) or low (<2.0) L/H ratio. Over a median 36.8-month follow-up, 184 cardiovascular events occurred. The risk of cardiovascular events was higher in the group with a high than low L/H ratio, even after adjusting for age, sex, and LDL-C (hazard ratio 1.89; 95% confidence interval 1.31–2.73; P<0.001); 12M L/H ratio analysis yielded similar results. In serial categories, both low-high (baseline <2.0; 12M ≥2.0) and high-high (baseline ≥2.0; 12M ≥2.0) groups had higher risk than the low-low group (baseline <2.0; 12M <2.0). No significant interactions were observed by age, sex, LDL-C, HDL-C, or statin intensity.

Conclusions: An L/H ratio ≥2.0 identifies increased cardiovascular risk in statin-treated T2D patients with diabetic retinopathy and hypercholesterolemia without prior cardiovascular disease. Serial L/H ratio assessment may aid risk stratification in this high-risk population.

Background: Emerging evidence highlights the clinical significance of lipid variability in cardiovascular disease and adverse outcomes. This study investigated the relationship between lipid variability and incident peripheral artery disease (PAD) risk.

Methods and Results: We identified 93,948 patients in the Chang Gung Research Database in Taiwan who had been diagnosed with hyperlipidemia between 2007 and 2013 and had annual lipid measurements over 4 consecutive years. Lipid levels, including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides, as well as their visit-to-visit variability, were assessed over the 4-year period. Patients were followed until December 31, 2019 for incident PAD development. Over a mean 5.9-year follow-up, 2,735 patients (2.5%) developed PAD. Mean lipid levels were significantly associated with incident PAD. Of note, the average real variability (ARV) in HDL-C was independently associated with increased PAD risk (adjusted hazard ratio 1.13; 95% confidence interval 1.004–1.27 for highest vs. lowest quartile of HDL-C ARV; P for trend=0.002). Sensitivity analysis using variability independent of the mean as the HDL-C variability index confirmed this finding. Consistency was observed across all subgroup analyses.

Conclusions: In this multi-institutional database analysis, visit-to-visit variability in HDL-C was significantly associated with the risk of incident PAD, independent of traditional risk factors for atherosclerosis, mean lipid levels, and the use of lipid-lowering therapy.

Background: The Japanese version of the high bleeding risk (J-HBR) criteria was proposed to identify Japanese patients at HBR after percutaneous coronary intervention. However, the diagnostic ability of the J-HBR in patients with lower extremity peripheral arterial disease (LEAD) remains unclear.

Methods and Results: This multicenter registry included 818 LEAD patients undergoing endovascular treatment (EVT). Based on J-HBR major (1 point) and minor (0.5 points) criteria, patients were grouped into LEAD with (≥2.0 points) and without (1.0–1.5 points) additional J-HBR. LEAD itself is a major criterion. The primary endpoint was major bleeding events and major adverse cardiovascular and limb events (MACLE), a composite of cardiovascular death, myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation. Of the 818 patients in the study, 683 (83.5%) had LEAD with additional J-HBR. During the median follow-up period of 729 days, the risk of major bleeding events did not differ significantly between the 2 groups, although the risk of MACLE was higher in the LEAD with than without additional J-HBR group (12.4% vs. 5.9%; P=0.03). The probability of major bleeding and MACLE increased progressively with an increase in the number of J-HBR major and minor criteria.

Conclusions: Among patients with LEAD undergoing EVT, the J-HBR criteria successfully stratified ischemic and bleeding risks. This risk-predicting model may be useful in patients with LEAD.

Background: This study aimed to identify the most influential factors affecting severe respiratory failure requiring respiratory assist devices (RADs), including mechanical ventilation and non-invasive positive pressure ventilation, in patients with uncomplicated acute Stanford Type B aortic dissection (TBAD).

Methods and Results: Ninety-seven patients were retrospectively analyzed and categorized into RAD (n=15) and non-RAD (n=82) groups. The mean (±SD) time to RAD initiation was 2.1±1.2 days, with a PaO₂to fraction of inspired oxygen (FiO₂) ratio of 116±53 at initiation. Compared with the non-RAD group, patients in the RAD group were younger (56.8±13.6 vs. 70.2±12.1 years; P<0.001), had higher body mass index (27.2±7.0 vs. 23.4±3.9 kg/m²; P=0.003), more frequently had a completely patent false lumen (47% vs. 11%; P<0.001), and showed significantly higher white blood cell (WBC) counts the day after admission (12,580±2,899 vs. 9,589±2,917/μL; P<0.001). Multivariable logistic regression identified a WBC count ≥11,100/μL on the day after admission as an independent predictor of RAD requirement (odds ratio 6.17; 95% confidence interval 1.71–25.74; P=0.007). Structural equation modeling further supported the central role of an elevated WBC count (regression coefficient=0.184; P<0.05).

Conclusions: An elevated WBC count appears to be the most influential factor associated with respiratory failure requiring RAD in patients with uncomplicated acute TBAD.

Background: Outdoor air pollutants are known to have adverse health impacts, but knowledge of the relationship between exposure to air pollutant mixtures and cardiovascular health (CVH) remains limited.

Methods and Results: We examined the association of air pollutant mixtures with CVH using the American Heart Association’s Life’s Essential 8 (LE8), which is based on 4 health behaviors and 4 biometric health factors. Data from a nationally representative sample of 27,763 adults were analyzed. One-year moving average concentrations of PM₁₀, PM_2.5, SO₂, NO₂, CO, and O₃were estimated through air pollution modeling. CVH was evaluated using LE8 scores (range 0–100), with higher scores indicating superior CVH. The association of a 1-quantile increment in air pollutant mixture with the expected change in LE8 score was evaluated using Quantile g-computation. The mean LE8 score in study participants was 63.7. In the adjusted model, a 1-quantile increment in air pollutant mixture was linked to a 1.67-point (95% confidence interval −2.18, −1.16) decrease in LE8 score. CO, O₃, PM_2.5, and NO₂accounted for 43.7%, 28.7%, 23.9%, and 3.7%, respectively, of the inverse association of the air pollutant mixture with the overall LE8 score.

Conclusions: Our study revealed that long-term exposure to outdoor air pollutants is associated with poor CVH, suggesting the need for supporting policy interventions to reduce air pollutant levels and mitigate their health impacts.

Background: Because monocyte chemoattractant protein-1 (MCP-1) and high-sensitivity C-reactive protein (hs-CRP) are crucial biomarkers in the early stages of atherosclerosis, we examined the association of their serum levels with all-cause and cause-specific deaths in a healthy population.

Methods and Results: Between 2004 and 2007, 568 participants (64% women, mean age 64.4 years) underwent health check-ups from which their serum MCP-1 and hs-CRP levels were categorized as high or low based on the median values of each biomarker. We analyzed all-cause deaths using Kaplan-Meier curves and used a multivariable Cox regression model to calculate hazard ratios for all-cause, cardiovascular disease (CVD), and cancer deaths both individually and in combination. During a median follow-up of 17.9 years, 140 deaths occurred: 43 from CVD and stroke, and 33 from cancer. The cumulative all-cause mortality rate was higher in participants with both high serum MCP-1 and hs-CRP levels than in those with lower levels. The adjusted hazard ratios for combined high serum MCP-1 and hs-CRP levels vs. low levels were 1.86 (95% confidence interval (CI): 1.09–3.17) for all-cause, 3.24 (95% CI: 1.07–9.82) for CVD and stroke, and 3.28 (95% CI: 1.06–10.18) for cancer deaths.

Conclusions: Combined serum MCP-1 and hs-CRP levels could predict all-cause and cause-specific mortality rates in the general population.

Background: Previous clinical studies reported that testosterone replacement therapy unexpectedly increased cardiovascular (CV) events in elderly men, through an unknown underlying mechanism. Because nitric oxide (NO) production is reduced in elderly men, we hypothesized that testosterone exerts harmful CV effects under reduced NO production, and examined this hypothesis using a 2/3 nephrectomized triple neuronal/inducible/endothelial NO synthases (NOS)-knockout (NX-TKO) mouse model that causes death from myocardial infarction (MI).

Methods and Results: The survival rate was markedly worse in male NX-TKO mice than in male NX-wild-type (NX-WT) mice. Orchiectomy (ORX) significantly aggravated the survival rate in NX-WT mice, but significantly improved it in NX-TKO mice. In the NX-TKO-ORX mice, long-term subcutaneous treatment with testosterone significantly deteriorated the survival rate, the incidence of MI, and CV risk factors. Furthermore, testosterone-induced aortic relaxations were significantly more impaired in the TKO than in the WT mice. RNA sequencing in the hearts of TKO-ORX mice without and with testosterone treatment indicated possible involvements of immunity- and inflammation-mediated mechanisms in the harmful CV effects of testosterone.

Conclusions: These results provide the first evidence that testosterone exerts harmful CV effects, including shorter survival, increased incidence of MI, impaired arterial relaxation, and exacerbated cardiovascular risk factors, in the absence of NOS in mice. Our findings may explain in part why testosterone replacement therapy increases CV events in elderly men.

Background: Non-home discharge (NHD) after endovascular therapy (EVT) for chronic limb-threatening ischemia (CLTI) signals frailty and higher healthcare costs.

Methods and Results: The nationwide J-EVT Registry (2021–2023) captured data for 31,025 patients with CLTI who underwent EVT. NHD, defined as transfer to chronic-care hospitals, occurred in 12.9%. Independent predictors of NHD were age ≥70 years, non-ambulatory status, and perioperative complications.

Conclusions: Because 1 in 8 Japanese CLTI patients required NHD after EVT, risk stratification and minimizing procedural invasiveness are essential to improve home-discharge rates.

Background: Cardiovascular autonomic neuropathy (CAN) is a major complication of type 2 diabetes mellitus (T2DM), but the roles of arterial stiffness and right atrial (RA) function in CAN remain unclear.

Methods and Results: In 120 patients with T2DM, we assessed short-term heart rate variability (CVR-R), cardio-ankle vascular index (CAVI), and two-dimensional speckle-tracking echocardiography (2DSTE). CAN was defined as CVR-R <2%. Multivariable analysis showed that higher CAVI and lower RA function composite scores were independently associated with CAN.

Conclusions: Both increased arterial stiffness and impaired RA function characterized CAN, indicating a key cardiovascular interaction. Combined CAVI and RA strain assessment may aid early detection.