Metabolic Syndrome-a constellation of insulin resistance, cardiovascular risk factors as hyperglycemia, hypertension, and dyslipidemia, and systemic metabolic dysfunction-may be driven by dysregulation of adipose tissue, which manifests as adiposopathy (pathogenic adipose tissue expansion or maldistribution), ectopic fat deposition (in the liver, muscle, pancreas, and cardiorenal systems), and altered secretion of adipokines/hepatokines. Weight gain, obesity, and/or unfavorable fat distribution create a scenario wherein the type, size, location, secretions, or even scarcity of adipocytes drive pathophysiological mechanisms leading to hepatic steatosis and steatohepatitis, type 2 diabetes, and heart and kidney disease. While recent frameworks, such as cardiovascular-kidney-metabolic syndrome, emphasize holistic staging, the central role of metabolic dysfunction-associated steatotic liver disease (MASLD) in multisystem morbidity remains underrecognized.

This narrative review synthesizes evidence linking MASLD and diabetes to cardiovascular and kidney diseases through shared pathways of adiposopathy, ectopic lipid accumulation, and dysregulated adipokine/hepatokine signaling. We propose CARDIAL-MS (CArdio-Renal-DIAbetes-Liver-Metabolic Syndrome), an expanded pathophysiological model that unifies these interactions into four progressive stages: (1) weight gain and dysfunctional adipose tissue; (2) metabolic risk factors and markers of risk; (3) cardiometabolic diseases and chronic kidney disease; and (4) advanced cardio-renal-liver-metabolic disease. By integrating MASLD as a pivotal component, CARDIAL-MS reframes metabolic syndrome as a continuum of interconnected organ injuries rather than isolated risk factors.

CARDIAL-MS provides a staging model to identify patients at critical transition points-from reversible metabolic disturbances to irreversible organ damage. This model emphasizes early interventions targeting adipose tissue health and ectopic fat deposition to mitigate the progression of metabolic cardiorenal diseases. By recognizing the syndromic nature of these conditions, CARDIAL-MS offers clinicians an actionable paradigm for risk stratification, timely diagnosis, and personalized prevention strategies.

Coronary microvascular dysfunction (CMD) is a prevalent and often underdiagnosed condition with significant implications for adverse cardiovascular outcomes. The pathophysiology of CMD includes structural and functional abnormalities in the coronary microvasculature and epicardial atherosclerosis contributes to downstream reduction in myocardial perfusion and symptoms. Diagnosis relies on advanced invasive or noninvasive imaging techniques, such as PET and cardiac magnetic resonance, capable of quantifying myocardial perfusion and myocardial blood flow reserve. Effective management includes optimizing cardiovascular risk factors and symptom control. Novel therapeutic strategies recently approved for management of diabetes, obesity, and heart failure with preserved ejection fraction offer potentially powerful options for management of CMD.

Chronic kidney disease (CKD) increases cardiac arrest (CA) risk because of renal and cardiovascular interactions.

Using Centers for Disease Control and Prevention (CDC) data from 1999 to 2020, we analyzed CKD-related CA mortality and the impact of social vulnerability index (SVI).

We identified 336 494 CKD-related CA deaths, with stable age-adjusted mortality rates over time. Disparities were observed across gender, racial/ethnic, and geographic subpopulations, with higher mortality among males, Hispanic and non-Hispanic Black populations, and those in urban and Western regions. Higher SVI correlated with increased mortality.

CKD-related CA mortality rates are stable, with disparities across demographics; higher SVI correlates with increased mortality, highlighting needed interventions.

Angiography-derived microcirculatory resistance (AMR) is proposed as a novel, pressure- temperature-wire-free and less-invasive method to evaluate coronary microvascular dysfunction (CMD). This study aims to examine the prognostic role of CMD assessed by AMR in predicting adverse events in acute coronary syndrome (ACS) patients with chronic kidney disease (CKD).

This retrospective cohort study included ACS with CKD patients in the China-Japan Friendship Hospital from January 2016 to November 2022. The patients were divided into CMD and non-CMD groups based on AMR values of less than or greater than 250 mmHg*s/m.

A total of 345 eligible patients were included in this study. During a median follow-up of 23.0 months, higher prevalence rate of MACEs (28.3% vs. 15.1%, P = 0.003) and death (20.2% vs. 4.1%, P = 0.001) were observed in the CMD group. In multivariate Cox regression analysis, patients in the group of CMD had a 1.843 times higher hazard ratio (HR) for developing MACEs (HR: 1.843, 95% CI: 1.071-3.174, P = 0.027) and 5.325 times higher HR for developing death (HR: 5.325, 95% CI: 1.979-14.327, P < 0.001) for every 10 mmHg*s/m increment in AMR. The incorporation of AMR improved the predictive accuracy of the GRACE score for MACEs and death.

This study indicates that the AMR is significantly related to poor prognosis among patients with ACS and CKD. Furthermore, AMR could improve the predictive power of the GRACE risk score. These results indicated that AMR may serve as a valuable clinical tool for classification, risk stratification or therapy individualization in these patients.

Cardiorenal syndrome (CRS) refers to the bidirectional interactions between the acutely or chronically dysfunctioning heart and kidney that lead to poor outcomes. Due to the evolving literature on renal impairment and heart failure with preserved ejection fraction (HFpEF), this review aimed to highlight the pathophysiological pathways, diagnosis using imaging and biomarkers, and management of CRS in patients with HFpEF.

The mechanism of CRS in HFpEF can be hypothesized due to the interplay of elevated central venous pressure, renin-angiotensin-aldosterone system (RAAS) activation, oxidative stress, endothelial dysfunction, coronary microvascular dysfunction, and chronotropic incompetence. The correlation between HFpEF and worsening renal function seen in both long-term trials and observational data points to the evidence for these mechanisms. Upcoming biomarkers such as cystatin C, NGAL, NAG, KIM-1, ST-2, and galectin-3, along with conventional ones, are promising for early diagnosis, risk stratification, or response to therapy. Despite the lack of specific treatment for CRS in HFpEF, the management can be discussed with similar medications used in goal-directed medical therapy for heart failure with reduced ejection fraction (HFrEF). Additionally, there is increasing evidence for the role of vasodilators, inotropes, assist devices, and renal denervation, although long-term studies are necessary.

The management of CRS in HFpEF is an evolving field that currently shows promise for using diagnostic and prognostic biomarkers, conventional heart failure medications, and novel therapies such as renal denervation, interatrial shunt, and renal assist devices. Further studies are needed to understand the pathophysiological pathways, validate the use of novel biomarkers, especially for early diagnosis and prognostication, and institute new management strategies for CRS in patients with HFpEF.

While it is broadly accepted that ageing is associated with impairment of coronary microvascular function, little is known about the underlying mechanisms.

We investigated age-related changes in coronary microvascular structure in patients with stable angina without epicardial coronary stenoses.

In an analysis of the IDEAL registry, a total of 165 vessels without coronary stenosis were interrogated with combined pressure/Doppler guidewires. We calculated diastolic microvascular conductance (DMVC) and backward expansion wave (BEW), and compared them between age tertiles. We calculated the prevalence of CMD, defined by reduced coronary flow reserve (CFR), and the prevalence of low BEW and low DMVC in each group.

The three study groups were defined as having 37-53, 54-66, and 67-77 years of age, respectively. Oldest (3rd tertile) patients showed lower hyperemic flow velocity (46.7 ± 14.4 vs. 45.1 ± 12.4 vs. 38.4 ± 11.5 cm s-1, p = 0.019), lower DMVC (1.90 ± 0.71 vs. 1.44 ± 0.56 vs. 1.37 ± 0.67 cm s-1 mmHg-1, p < 0.001) and lower BEW intensity (5.9 [2.9-8.4] vs. 4.8 [2.9-6.8] vs. 4.4 [3.4-6.3] × 106 W m-2 s-1, p = 0.094). Older age was independently associated with lower BEW intensity (B: -0.10, 95% confidence interval [CI]: -0.17 to -0.09, p = 0.021) and DMVC (B: -0.25 95% CI: -0.45 to -0.09, p = 0.027). In patients with CFR < 2.5, the prevalence of BEW intensity and DMVC below the 25th percentile increased with age (25.0% vs. 52.0% vs. 72.7%, p = 0.010).

Ageing is independently associated with structural microcirculatory remodeling that is reflected in BEW intensity and DMVC measurements, and with an increased prevalence of structural CMD. These results are important to understand non-obstructive mechanisms of myocardial ischemia in the elderly.

Coronary microvascular dysfunction (CMD) has been implicated as a potential mechanism in the pathophysiology of different clinical presentations, including ischemia and no obstructive coronary artery disease (INOCA), myocardial infarction and nonobstructive coronary arteries (MINOCA), stress cardiomyopathy, heart failure, and myocarditis. There are limited data about the role of CMD in cancer therapy-related cardiovascular toxicities.

Four women with a diagnosis of active cancer receiving treatment who developed subsequent MINOCA or INOCA presented for cardiac catheterization. Upon coronary angiography showing no obstructive coronary arteries, coronary function testing was performed to evaluate for CMD.

Coronary physiology was assessed measuring non-hyperemic (resting full-cycle ratio [RFR]) and hyperemic (fractional flow reserve [FFR]) indices using a physiologic pressure wire. The wire also measured coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and RFR using thermodilution technology. CMD was confirmed if the CFR was <2.5 and the IMR was >25.

Among 4 patients with diagnosis of active cancer presenting with chest pain, there was no evidence of obstructive coronary artery disease, leading to separate diagnoses of INOCA, MINOCA, stress cardiomyopathy, and myocarditis. We found CMD in 2 patients (1 with INOCA and 1 with immune checkpoint inhibitor-related myocarditis).

CMD may play a role in cardiovascular toxicities. Further coronary physiology studies are needed to understand the mechanisms of cancer therapy-related cardiovascular toxicity and CMD, as well as optimal preventive and treatment options.

The epidemiology of coronary artery disease (CAD) has shifted, with increasing prevalence of cardiometabolic disease and decreasing findings of obstructive CAD on myocardial perfusion imaging (MPI). Coronary microvascular dysfunction (CMD), defined as impaired myocardial flow reserve (MFR) by positron emission tomography (PET), has emerged as a key mediator of risk. We aimed to assess whether PET MFR provides additive value for risk stratification of cardiometabolic disease patients compared with single-photon emission computed tomography (SPECT) MPI.

We retrospectively followed patients referred for PET, exercise SPECT, or pharmacologic SPECT MPI with cardiometabolic disease (obesity, diabetes, or chronic kidney disease) and without known CAD. We compared rates and hazards of composite major adverse cardiovascular events (MACEs) (annualized cardiac mortality or acute myocardial infarction) among propensity-matched PET and SPECT patients using Poisson and Cox regression. Normal SPECT was defined as a total perfusion deficit (TPD) of <5%, reflecting the absence of obstructive CAD. Normal PET was defined as a TPD of <5% plus an MFR of ≥2.0.

Among 21,544 patients referred from 2006 to 2020, cardiometabolic disease was highly prevalent (PET: 2308 [67%], SPECT: 9984 [55%]) and higher among patients referred to PET (P < 0.001). Obstructive CAD findings (TPD > 5%) were uncommon (PET: 21% and SPECT: 11%). Conversely, impaired MFR on PET (<2.0) was common (62%). In a propensity-matched analysis over a median 6.4-year follow-up, normal PET identified low-risk (0.9%/year MACE) patients, and abnormal PET identified high-risk (4.2%/year MACE) patients with cardiometabolic disease; conversely, those with normal pharmacologic SPECT remained moderate-risk (1.6%/year, P < 0.001 compared to normal PET).

Cardiometabolic disease is common among patients referred for MPI and is associated with a heterogenous level of risk. Compared with pharmacologic SPECT, PET with MFR can detect nonobstructive CAD including CMD and can more accurately discriminate low-risk from higher-risk individuals.

Coronary microvascular dysfunction has been implicated in the development of hypertensive heart disease and heart failure, with subendocardial ischemia identified as a driver of sustained myocardial injury and fibrosis. We aimed to evaluate the relationships of subendocardial perfusion with cardiac injury, structure, and a composite of major adverse cardiac and cerebrovascular events consisting of death, heart failure hospitalization, myocardial infarction, and stroke.

Layer-specific blood flow and myocardial flow reserve (MFR; stress/rest myocardial blood flow) were assessed by 13N-ammonia perfusion positron emission tomography in consecutive patients with hypertension without flow-limiting coronary artery disease (summed stress score <3) imaged at Brigham and Women's Hospital (Boston, MA) from 2015 to 2021. In this post hoc observational study, biomarkers, echocardiographic parameters, and longitudinal clinical outcomes were compared by tertiles of subendocardial MFR (MFRsubendo).

Among 358 patients, the mean age was 70.6±12.0 years, and 53.4% were male. The median MFRsubendo was 2.57 (interquartile range, 2.08-3.10), and lower MFRsubendo was associated with older age, diabetes, lower renal function, greater coronary calcium burden, and higher systolic blood pressure (P<0.05 for all). In cross-sectional multivariable regression analyses, the lowest tertile of MFRsubendo was associated with myocardial injury and with greater left ventricular wall thickness and volumes compared with the highest tertile. Relative to the highest tertile, low MFRsubendo was independently associated with an increased rate of major adverse cardiac and cerebrovascular events (adjusted hazard ratio, 2.99 [95% CI, 1.39-6.44]; P=0.005) and heart failure hospitalization (adjusted hazard ratio, 2.76 [95% CI, 1.04-7.32; P=0.042) over 1.1 (interquartile range, 0.6-2.8) years median follow-up.

Among patients with hypertension without flow-limiting coronary artery disease, impaired MFRsubendo was associated with cardiovascular risk factors, elevated cardiac biomarkers, cardiac structure, and clinical events.

Coronary microvascular disease (CMD) and impaired coronary blood flow control are defects that occur early in the pathogenesis of heart failure in cardiometabolic conditions, prior to the onset of atherosclerosis. In fact, recent studies have shown that CMD is an independent predictor of cardiac morbidity and mortality in patients with obesity and metabolic disease. CMD is comprised of functional, structural, and mechanical impairments that synergize and ultimately reduce coronary blood flow in metabolic disease and in other co-morbid conditions, including transplant, autoimmune disorders, chemotherapy-induced cardiotoxicity, and remote injury-induced CMD. This review summarizes the contemporary state-of-the-field related to CMD in metabolic and these other co-morbid conditions based on mechanistic data derived mostly from preclinical small- and large-animal models in light of available clinical evidence and given the limitations of studying these mechanisms in humans. In addition, we also discuss gaps in current understanding, emerging areas of interest, and opportunities for future investigations in this field.

Inflammation is an important contributor to excess cardiovascular risk and progressive renal injury in people with chronic kidney disease (CKD). Dysregulation of the innate and adaptive immune system is accelerated by CKD and results in increased systemic inflammation, a heightened local vascular inflammatory response leading to accelerated atherosclerosis, and dysfunction of the cardiac and renal endothelium and microcirculation. Understanding and addressing the dysregulated immune system is a promising approach to modifying cardiorenal outcomes in people with CKD. However, targeted pharmacotherapies adopted from trials of non-CKD and cardiorheumatology populations are only beginning to be developed and tested in human clinical trials. Pharmacotherapies that inhibit the activation of the NOD-like receptor protein 3 inflammasome and the downstream cytokines interleukin-1 and interleukin-6 are the most well-studied. However, most of the available evidence for efficacy is from small clinical trials with inflammatory and cardiorenal biomarker endpoints, rather than cardiovascular event endpoints, or from small CKD subgroups in larger clinical trials. Other pharmacotherapies that have proven beneficial for cardiorenal endpoints in people with CKD have been found to have pleiotropic anti-inflammatory benefits including statins, mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 agonists. Finally, emerging therapies in CKD such as interleukin-6 inhibition, small-interfering RNA against lipoproteins, aryl hydrocarbon receptor inhibitors, and therapies adopted from the renal transplant population including mammalian target of rapamycin inhibitors and T regulatory cell promoters may have benefits for cardiorenal and inflammatory endpoints but require further investigation in clinical trials.

The study aimed to investigate the potential effect of Antithrombin III (ATIII) between chronic renal insufficiency and chronic coronary artery disease (chronic CAD) in type 2 diabetes mellitus (T2DM) patients.

T2DM patients hospitalized in ZhongDa Hospital from 2013 to 2018 were enrolled. Relationships between renal function, ATIII, and chronic CAD risk were explored using multivariate regression models. Multiplicative and additive interactions were investigated between ATIII and renal function for CAD risk, and the role of ATIII was determined by bootstrap mediation analysis in patients with chronic renal dysfunction.

A total of 4197 patients were included in the study, with a chronic CAD prevalence of 23.02%. Low ATIII level was statistically associated with chronic renal insufficiency and elevated CAD risk even after adjustments (P < 0.05). A positive correlation between renal function and ATIII was demonstrated, and each 1 SD increase in renal function, ATIII increased by 2.947% (2.406-3.488%, P < 0.001) and 0.969% (0.297-1.642%, P < 0.001) in crude and adjusted models respectively. Patients with decreased renal function and ATIII were at the highest chronic CAD risk (OR = 1.51, 95%CI:1.15-1.98, P < 0.05), while no multiplicative and additive interaction effects were significant. Bootstrap mediation analysis estimated that ATIII mediated approximately 4.27% of the effect of chronic renal insufficiency on chronic CAD risk.

ATIII may serve as a mediator between chronic renal insufficiency and chronic CAD, providing mechanistic clues for renal-heart association and new insight into clinical therapies.

This study aimed to evaluate the bidirectional relationship between kidney and cardiovascular (CV) events in trial participants with type 2 diabetes and CV disease.

Post hoc analyses of EMPA-REG OUTCOME using Cox regression models were performed to assess the association of baseline factors with risk of a kidney event and bidirectional associations of incident kidney events and CV events. Among placebo-treated participants, baseline factors significantly associated with greater kidney event risk included lower baseline estimated glomerular filtration rate, albuminuria, higher uric acid, low-density lipoprotein cholesterol levels, and prior heart failure (HF). Coronary artery disease was not associated with increased risk. In placebo-treated participants, occurrence of an incident non-fatal kidney event increased the subsequent risk of hospitalization for HF (HHF) but not 3-point major adverse CV events (non-fatal stroke, non-fatal myocardial infarction, and CV death). Vice versa, HHF (but not myocardial infarction/stroke) increased the risk of subsequent kidney events. These associations were generally also seen in empagliflozin-treated participants and in the overall population. Interestingly, the risk of kidney events following HHF was not significantly increased in the relatively small number of placebo-treated participants already diagnosed with HF at baseline.

These findings demonstrate a bidirectional inter-relationship between HHF and kidney events. Further exploration of this relationship and strategies to optimize the use of therapies to reduce both kidney and HF outcomes is warranted.

The potential impact of renal function-related cardiovascular remodeling on associated cardiovascular risk has not been previously investigated. Hence, we conducted multiple mediation analyses in the UK Biobank study to evaluate this association. Using multiple Cox models, we found lower renal function (estimated glomerular filtration rate based on cystatin C, eGFR-cysC) was independently related to increased risks of various cardiovascular events and mortalities. Multivariable linear regression revealed a progressive relationship between declining eGFR-cysC and adverse left ventricular (LV) remodeling and impaired systolic function. In Cox models, larger LV volume, mass, as well as decreased systolic function, were significantly correlated with adverse events, particularly in heart failure. Mediation analyses showed that undesirable LV remodeling and cardiometabolic diseases were independent mediators. Our study explores the connections between reduced renal function and poor cardiovascular phenotypes, as well as their significant independent role in mediating renal function-cardiovascular outcome relationships.

To explore whether, in younger patients on dialysis with longer life expectancy, assessment of coronary artery disease (CAD) could identify individuals at higher risk of events and revascularization might improve outcomes in selected patients contrary to what had been observed in elderly patients.

From August 1997 to January 2019, 2265 patients with stage 5 chronic kidney disease were prospectively referred for cardiovascular assessment. For this study, we selected 1374 asymptomatic patients aged between 18 and 64 years. After clinical risk stratification and cardiac scintigraphy by single-photon emission computed tomography, 866 patients underwent coronary angiography. The primary end point was the composite incidence of nonfatal/fatal major adverse cardiovascular events during a follow-up period of 0.1 to 189.7 months (median, 26 months). The secondary end point was all-cause mortality.

The primary end point occurred in 327 (23.8%) patients. Clinically stratified high-risk patients had a 3-fold increased risk of the primary end point. The prevalence of abnormal findings on perfusion scans was 29.2% (n=375), and significant CAD was found in 449 (51.8%) of 866 patients who underwent coronary angiography. An abnormal finding on myocardial perfusion scan and the presence of CAD were significantly associated with a 74% and 22% increased risk of cardiovascular events, respectively. In patients undergoing percutaneous coronary intervention or coronary artery bypass grafting (n=99), there was an 18% reduction in the risk of all-cause death relative to patients receiving medical treatment (P=.03).

In this cohort of middle-aged, asymptomatic patients on dialysis, assessment of CAD identified individuals at higher risk of events, and coronary intervention was associated with reducing the risk of death in selected patients.

Advanced chronic kidney disease is associated with high cardiovascular risk, even after kidney transplant. Pretransplant cardiac testing may identify patients who require additional assessment before transplant or would benefit from risk optimization. The objective of the current study was to determine the relative prognostic utility of pretransplant positron emission tomography (PET) and single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) for posttransplant major adverse cardiovascular events (MACEs).

We retrospectively followed patients who underwent MPI before kidney transplant for the occurrence of MACE after transplant including myocardial infarction, stroke, heart failure, and cardiac death. An abnormal MPI result was defined as a total perfusion deficit >5% of the myocardium. To determine associations of MPI results with MACE, we utilized Cox hazard regression with propensity weighting for PET versus SPECT with model factors, including demographics and cardiovascular risk factors.

A total of 393 patients underwent MPI (208 PET and 185 SPECT) and were followed for a median of 5.9 years post-transplant. Most were male (58%), median age was 58 years, and there was a high burden of hypertension (88%) and diabetes (33%). A minority had abnormal MPI (n=58, 15%). In propensity-weighted hazard regression, abnormal PET result was associated with posttransplant MACE (hazard ratio, 3.02 [95% CI, 1.78-5.11]; P<0.001), while there was insufficient evidence of an association of abnormal SPECT result with MACE (1.39 [95% CI, 0.72-2.66]; P=0.33). The explained relative risk of the PET result was higher than the SPECT result (R2 0.086 versus 0.007). Normal PET was associated with the lowest risk of MACE (2.2%/year versus 3.6%/year for normal SPECT; P<0.001).

Kidney transplant recipients are at high cardiovascular risk, despite a minority having obstructive coronary artery disease on MPI. PET MPI findings predict posttransplant MACE. Normal PET may better discriminate lower risk patients compared with normal SPECT, which should be confirmed in a larger prospective study.

Cardiovascular disease (CVD) and mortality is elevated in chronic kidney disease (CKD). Retinal vessel calibre in retinal photographs is associated with cardiovascular risk and automated measurements may aid CVD risk prediction.

Retrospective cohort study of 860 Chinese, Malay and Indian participants aged 40-80 years with CKD [estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2] who attended the baseline visit (2004-2011) of the Singapore Epidemiology of Eye Diseases Study. Retinal vessel calibre measurements were obtained by a deep learning system (DLS). Incident CVD [non-fatal acute myocardial infarction (MI) and stroke, and death due to MI, stroke and other CVD] in those who were free of CVD at baseline was ascertained until 31 December 2019. Risk factors (established, kidney, and retinal features) were examined using Cox proportional hazards regression models. Model performance was assessed for discrimination, fit, and net reclassification improvement (NRI).

Incident CVD occurred in 289 (33.6%) over mean follow-up of 9.3 (4.3) years. After adjusting for established cardiovascular risk factors, eGFR [adjusted HR 0.98 (95% CI: 0.97-0.99)] and retinal arteriolar narrowing [adjusted HR 1.40 (95% CI: 1.17-1.68)], but not venular dilation, were independent predictors for CVD in CKD. The addition of eGFR and retinal features to established cardiovascular risk factors improved model discrimination with significantly better fit and better risk prediction according to the low (<15%), intermediate (15-29.9%), and high (30% or more) risk categories (NRI 5.8%), and with higher risk thresholds (NRI 12.7%).

Retinal vessel calibre measurements by DLS were significantly associated with incident CVD independent of established CVD risk factors. Addition of kidney function and retinal vessel calibre parameters may improve CVD risk prediction among Asians with CKD.

To investigate the interplay between chronic kidney disease (CKD) and coronary artery disease (CAD) on the incidence of cardiovascular events in patients with suspected chronic coronary syndrome (CCS).

Patients with suspected CCS who underwent first-time coronary angiography in Western Denmark between 2003 and 2016 were included in this cohort study. Moreover, an age- and sex-matched general population cohort was established. Patients were stratified according to estimated glomerular filtration rate (eGFR). Presence of CAD was defined as ≥1 obstructive stenosis or non-obstructive diffuse disease. Major adverse cardiovascular events (MACE) were defined as a composite of myocardial infarction, ischemic stroke, and cardiac death.

A total of 42,611 patients were included with a median follow-up of 7.3 years. Patients without and with CAD had MACE rates per 100 person-years that were 0.52 and 1.67 for eGFR ≥90 mL/min/1.73 m2, 0.68 and 2.09 for eGFR 60-89 mL/min/1.73 m2, 1.27 and 3.85 for eGFR 30-59 mL/min/1.73 m2, and 2.27 and 6.92 for eGFR <30 mL/min/1.73 m2. Comparing to eGFR ≥90 mL/min/1.73 m2, the adjusted incidence rate ratios for MACE were 1.29 (1.10-1.51) for eGFR 60-89 mL/min/1.73 m2, 1.86 (1.49-2.33) for eGFR 30-59 mL/min/1.73 m2, and 3.57 (1.92-6.67) for eGFR <30 mL/min/1.73 m2 in patients without CAD, and 1.11 (1.03-1.20), 1.71 (1.55-1.90), and 2.46 (1.96-3.09) in patients with CAD. The inverse relationship between kidney function and risk of MACE was confirmed when comparing patients with and without CAD to matched individuals in the general population.

Absence of CAD is a strong negative predictor of major adverse cardiovascular events in patients with CKD.

Background Chronic kidney disease (CKD) might influence fractional flow reserve (FFR) value, potentially attenuating its prognostic utility. However, few large-scale data are available regarding clinical outcomes after FFR-guided deferral of revascularization in patients with CKD. Methods and Results From the J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry), 1218 patients were divided into 3 groups according to renal function: (1) non-CKD (estimated glomerular filtration rate ≥60 mL/min per 1.73 m2), n=385; (2) CKD (estimated glomerular filtration rate 15-59 mL/min per 1.73 m2, n=763); and (3) end-stage renal disease (ESRD) (eGFR <15 mL/min per 1.73 m2, n=70). The primary study end point was the cumulative 5-year incidence of target vessel failure (TVF), defined as a composite of cardiac death, target vessel myocardial infarction, and clinical driven target vessel revascularization. Cumulative 5-year incidence of TVF was significantly higher in the ESRD group than in the CKD and non-CKD group, whereas it did not differ between the CKD and non-CKD groups (26.3% versus 11.9% versus 9.5%, P<0.001). Although the 5-year TVF risk increased as the FFR value decreased regardless of renal function, patients with ESRD had a remarkably higher risk of TVF at every FFR value than those with CKD and non-CKD. Conclusions At 5 years, patients with ESRD showed a higher incidence of TVF than patients with CKD and non-CKD, although with similar outcomes between patients with CKD and non-CKD. Patients with ESRD had an excess risk of 5-year TVF at every FFR value compared with those with CKD and non-CKD. Registration URL: https://www.umin.ac.jp; Unique identifier: UMIN000014473.

Cardiac allograft vasculopathy (CAV) remains a common long-term complication of cardiac transplantation. While invasive coronary angiography is considered the gold standard, it is also invasive and lacks sensitivity to detect early, distal CAV. Although vasodilator stress myocardial contrast echocardiography perfusion imaging (MCE) is used in the detection of microvascular disease in non-transplant patients, there is little data guiding its use in transplant recipients. Herein is a case series of four heart transplant recipients that had vasodilator stress MCE performed in addition to invasive coronary angiography for CAV surveillance. MCE at rest and after regadenason was performed using a continuous infusion of lipid-shelled microbubbles. We describe a case of normal microvascular function, diffuse microvascular dysfunction, patchy sub-endocardial perfusion defects and a focal sub-endocardial perfusion defect. Cardiac allograft vasculopathy can be heralded by several different perfusion patterns on MCE in patients after orthotopic heart transplant. The varying prognoses and potential interventions for these different patterns require further investigation.

Given the central importance of cardiorenal interactions, mechanistic tools for evaluating cardiorenal physiology are needed. In the heart and kidneys, shared pathways of neurohormonal activation, hypertension, and vascular and interstitial fibrosis implicate the relevance of systemic vascular health. The availability of a long axial field of view positron emission tomography (PET)/computed tomography (CT) system enables simultaneous evaluation of cardiac and renal blood flow.

This study evaluated the feasibility of quantification of renal blood flow using data acquired during routine, clinically indicated 13N-ammonia myocardial perfusion PET/CT. Dynamic PET image data were used to calculate renal blood flow. Reproducibility was assessed by the intraclass correlation coefficient among 3 independent readers. PET-derived renal blood flow was correlated with imaging and clinical parameters in the overall cohort and with histopathology in a small companion study of patients with a native kidney biopsy.

Among 386 consecutive patients with myocardial perfusion PET/CT, 296 (76.7%) had evaluable images to quantify renal perfusion. PET quantification of renal blood flow was highly reproducible (intraclass correlation coefficient 0.98 [95% CI, 0.93-0.99]) and was correlated with the estimated glomerular filtration rate (r=0.64; P<0.001). Compared across vascular beds, resting renal blood flow was correlated with maximal stress myocardial blood flow and myocardial flow reserve (stress/rest myocardial blood flow), an integrated marker of endothelial health. In patients with kidney biopsy (n=12), resting PET renal blood flow was strongly negatively correlated with histological interstitial fibrosis (r=-0.85; P<0.001).

Renal blood flow can be reliably measured from cardiac 13N-ammonia PET/CT and allows for simultaneous assessment of myocardial and renal perfusion, opening a potential novel avenue to interrogate the mechanisms of emerging therapies with overlapping cardiac and renal benefits.

Coronary microvascular dysfunction (CMD) is a high-risk factor for a variety of cardiovascular events. Due to its complex aetiology and concealability, knowledge of the pathophysiological mechanism of CMD is still limited at present, which greatly restricts its clinical diagnosis and treatment. Studies have shown that CMD is closely related to a variety of cardiovascular diseases, can aggravate the occurrence and development of cardiovascular diseases, and is closely related to a poor prognosis in patients with cardiovascular diseases. Improving coronary microvascular remodelling and increasing myocardial perfusion might be promising strategies for the treatment of cardiovascular diseases. In this paper, the pathogenesis and functional assessment of CMD are reviewed first, along with the relationship of CMD with cardiovascular diseases. Then, the latest strategies for the treatment of CMD and cardiovascular diseases are summarized. Finally, urgent scientific problems in CMD and cardiovascular diseases are highlighted and future research directions are proposed to provide prospective insights for the prevention and treatment of CMD and cardiovascular diseases in the future.

To investigate abnormalities in myocardial strain and classic echocardiographic indices and coronary flow reserve (CFR), in younger versus older CKD patients.

Sixty consecutive CKD patients (<60 years old n = 30, ≥60 years old n = 30) and 30 healthy controls (age- and gender-matched with younger CKD patients) were recruited. An echocardiographic assessment including myocardial strain indices (i.e. global longitudinal strain -GLS -, TWIST, UNTWIST rate) was performed at baseline and following dipyridamole administration in all participants.

Younger CKD patients had higher E/e', left ventricular mass index and relative wall thickness and lower E' (p < .005 for all) compared to healthy controls. Older CKD patients had lower E/A and E' (p < .05 for both) compared to younger CKD patients; these differences did not remain significant after adjustment for age. CFR was higher in healthy controls compared to younger and older CKD patients (p < .05 for both) without a significant difference between CKD groups. There were no significant differences in GLS, TWIST or UNTWIST values among the three groups of patients. Dipyridamole-induced changes did not differ significantly among the three groups.

Compared to healthy controls, impaired coronary microcirculation and left ventricular diastolic function, but not myocardial strain abnormalities, are found in young CKD patients and deteriorate with aging.

Persistent coronary microcirculatory dysfunction (CMD) and elevated trimethylamine N-oxide (TMAO) levels after ST-elevation myocardial infarction (STEMI) may drive negative structural and electrical cardiac remodeling, resulting in new-onset atrial fibrillation (AF) and a decrease in left ventricular ejection fraction (LVEF).

TMAO and CMD are investigated as potential predictors of new-onset AF and left ventricular remodeling following STEMI.

This prospective study included STEMI patients who had primary percutaneous coronary intervention (PCI) followed by staged PCI three months later. Cardiac ultrasound images were obtained at baseline and after 12 months to assess LVEF. Coronary flow reserve (CFR), and index of microvascular resistance (IMR) were assessed using the coronary pressure wire during the staged PCI. Microcirculatory dysfunction was defined as having an IMR value ≥25 U and CFR value <2.5 U.

A total of 200 patients were included in the study. Patients were categorized according to whether or not they had CMD. Neither group differed from the other with regards to known risk factors. Despite making up only 40.5% of the study population, females represented 67.4% of the CMD group p < 0.001. Similarly, CMD patients had a much higher prevalence of diabetes than those without CMD (45.7% vs. 18.2%; p < 0.001). At the one-year follow-up, the LVEF in the CMD group had decreased to significantly lower levels than those in the non-CMD group (40% vs. 50%; p < 0.001), whereas it had been higher in the CMD group at baseline (45% vs. 40%; p = 0.019). Similarly, during the follow-up, the CMD group had a greater incidence of AF (32.6% vs. 4.5%; p < 0.001). In the adjusted multivariable analysis, the IMR and TMAO were associated with increased odds of AF development (OR: 1.066, 95% CI: 1.018-1.117, p = 0.007), and (OR: 1.290, 95% CI: 1.002-1.660, p = 0.048), respectively. Similarly, elevated levels of IMR and TMAO were linked with decreased odds of LVEF improvement, while higher CFR values are related to a greater likelihood of LVEF improvement.

CMD and elevated TMAO levels were highly prevalent three months after STEMI. Patients with CMD had an increased incidence of AF and a lower LVEF 12 months after STEMI.

Chronic cadmium (Cd) exposure severely affects the structural integrity of the heart, leading to cardiovascular disease. This study investigates the protective role of ascorbic acid (AA) and resveratrol (Res) in cellular defense against Cd-induced cardiomyocyte damage and myocardial hypertrophy in H9c2 cardiomyocytes. Experimental results showed that AA and Res treatment significantly increased cell viability, reduced ROS production, attenuated lipid peroxidation, and increased antioxidant enzyme activity in Cd-induced H9c2 cells. AA and Res decreased the mitochondrial membrane permeability and protected the cells from Cd induced cardiomyocyte damage. This also suppressed the pathological hypertrophic response triggered by Cd, which increased the cell size of cardiomyocytes. Gene expression studies revealed that cells treated with AA and Res decreased the expression of hypertrophic genes ANP (two-fold), BNP (one-fold) and β- MHC (two-fold) compared to Cd exposed cells. AA and Res promoted the nuclear translocation of Nrf2 and increased the expression of antioxidant genes (HO-1, NQO1, SOD and CAT) during Cd mediated myocardial hypertrophy. This study proves that AA and Res play a significant role in improving Nrf2 signaling, thereby reversing stress-induced injury, and facilitating the regression of myocardial hypertrophy.

This paper looks to validate the risk score from the Heart Failure Association of the European Society of Cardiology and the International Cardio-Oncology Society (HFA-ICOS) for predicting potential cardiotoxicity from anticancer therapy for patients positive for human epidermal growth factor receptor 2.

A total of 507 patients with at least five years since index diagnosis of breast cancer were retrospectively divided according to the HFA-ICOS risk proforma. According to level of risk, these groups were assessed for rates of cardiotoxicity via mixed-effect Bayesian logistic regression model.

A follow-up of five years observed cardiotoxicity of 3.3% (n = 3) in the low-risk, 3.3% (n = 10) in the medium-risk, 4.4% (n = 6) in the high-risk, and 38% (n = 6) in the very-high-risk groups respectively. For cardiac events related to treatment, the risk was significantly higher for the very-high-risk category of HFA-ICOS compared to other categories (Beta = 3.1, 95% CrI: 1.5, 4.8). For overall cardiotoxicity related to treatment, the area under the curve was 0.643 (CI 95%: 0.51, 0.76), with 26.1% (95% CI: 8%, 44%) sensitivity and 97.9% (95% CI: 96%, 99%) specificity.

The HFA-ICOS risk score has moderate power in predicting cancer therapy-related cardiotoxicity in HER2-positive breast cancer patients.

Diabetes and hepatitis B are both global problems. The influence of diabetes on complications and prognosis of hepatitis B has been widely studied. However, the association between hepatitis B virus (HBV) infection and the prevalence of diabetes-related complications is less documented and is uncertain.

This was a retrospective study. We collected information from a large clinical database. A total of 1,090 Chinese inpatients with type 2 diabetes were included.

The participants were divided into two groups, including 135 patients with HBV infection and 955 patients without HBV infection. Patients with HBV infection were younger and had worse control of blood glucose than those without HBV infection. No significant difference was found in the prevalence of diabetic retinopathy, neuropathy, nephropathy, diabetic ketosis or diabetic ketoacidosis between the patients with HBV infection and the patients without HBV infection. The prevalence of macrovascular complications was 54.1% and 64.4% in diabetes patients complicated with HBV infection and without HBV infection, respectively. The P-value was <0.05. However, through the logistic regression analysis, we found HBV infection was not an independent risk factor for macrovascular complications of diabetes.

There was no significant correlation between the prevalence of macrovascular complications, microvascular complications of diabetes, diabetic ketosis or diabetic ketoacidosis and HBV infection status.

Impaired MFR in the absence of flow-limiting CAD is associated with adverse events. Cardiovascular disease is an important cause of morbidity and mortality in patients with breast cancer. We sought to test the utility of MFR to predict outcomes in a cohort of patients with breast cancer.

We retrospectively studied consecutive patients with breast cancer or breast cancer survivors who underwent cardiac stress PET imaging from 2006 to 2017 at Brigham and Women's Hospital. Patients with a history of clinically overt CAD, LVEF < 45%, or abnormal myocardial perfusion were excluded. Subjects were followed from time of PET to the occurrence of a first major adverse cardiovascular event (MACE) and all-cause death.

The final cohort included 87 patients (median age 69.0 years, 98.9% female, mean MFR 2.05). Over a median follow-up of 7.6 years after PET, the lowest MFR tertile was associated with higher cumulative incidence of MACE (adjusted subdistribution hazard ratio 4.91; 95% CI 1.68-14.38; p = 0.004) when compared with the highest MFR tertile.

In patients with breast cancer, coronary vasomotor dysfunction was associated with incident cardiovascular events. MFR may have potential as a risk stratification biomarker among patients with/survivors of breast cancer.

Coronary microvascular dysfunction (CMD) is a leading cause of ischemic heart disease. Over the past few decades, considerable progress has been made with respect to research on CMD. The present study summarized the current research hotspots and trends on CMD by applying a bibliometric approach.

Relevant publications between 2002 and 2022 were extracted from the Web of Science Core Collection. Visualization network maps of countries, institutions, authors, and co-cited authors were built using VOSviewer. CiteSpace was used for keyword analysis and the construction of a dual-map overlay of journals and a timeline view of co-cited references.

1539 CMD-related publications were extracted for bibliometric analysis. The annual publications generally showed an upward trend. The United States of America was the most prolific country, with 515 publications (33.5%). Camici P. G. was the most influential author, whereas the European Heart Journal, Circulation, and Journal of the American College of Cardiology were the most authoritative journals. Research hotspot analysis revealed that endothelial dysfunction as well as reduced nitric oxide production or bioavailability played critical roles in CMD development. Positron emission tomography was the most widely used imaging method for diagnosis. In addition, microvascular angina, hypertrophic cardiomyopathy, and heart failure have attracted much attention as the main clinical implications. Furthermore, international standards for CMD diagnosis and management may be the future research directions.

This study offers a comprehensive view about the hotspots and development trends of CMD, which can assist subsequent researchers and guide future directions.

Both coronary flow reserve (CFR) and chronic kidney disease (CKD) are known to be associated with adverse cardiac events. However, it is unclear how these prognostic factors are interrelated. This study evaluated the association between intracoronary physiologic indexes and CKD and their prognostic implications.

A total of 351 patients without left ventricular systolic dysfunction (ejection fraction ≥ 40%) and not on dialysis whose revascularization was deferred based on fractional flow reserve (FFR) > 0.80 were analyzed. Depressed CFR was defined as CFR ≤ 2.0. The primary outcome was a composite of cardiac death or hospitalization for heart failure at 3 years.

Patients with CKD showed lower CFR than the non-CKD population (3.28 ± 1.77 vs. 2.60 ± 1.09, P < 0.001), mainly driven by increased resting coronary flow. There was no significant difference in hyperemic coronary flow, FFR, and index of microvascular resistance between the 2 groups. CFR was significantly associated with estimated glomerular filtration rate (eGFR) (P = 0.045), and the proportion of depressed CFR was significantly increased with higher CKD stages (P = 0.011). The risk of cardiac death or hospitalization for heart failure was the lowest in the non-CKD and preserved CFR group (11.9%) and the highest in the CKD and depressed CFR group (60.0%, overall log rank P < 0.001). Both CKD (adjusted hazard ratio [HR_adj] 2.614, 95% confidence interval [CI] 1.505-4.539, P < 0.001) and depressed CFR (HR_adj 3.237, 95% CI 2.015-5.199, P < 0.001) were independently associated with the risk of the primary outcome.

There was a significant association between severity of CKD and CFR. Both CKD and depressed CFR showed independent association with higher risk of cardiac death or hospitalization for heart failure.

Coronary vasomotion abnormalities have been described in small studies but not studied systematically. We aimed to review the present literature and analyze it to improve our understanding of chronic kidney disease (CKD) related-coronary microvascular dysfunction.

Coronary flow reserve (CFR) is a well-known measure of coronary vasomotion. We aimed to assess the difference in CFR among participants with and without CKD.

PubMed, Embase, and Cochrane CENTRAL were systematically reviewed to identify studies that compared CFR in participants with and without CKD. We estimated standardized mean differences in mean CFR reported in these studies. We performed subgroup analyses according to imaging modality, and the presence of significant epicardial coronary artery disease.

In 14 observational studies with 5966 and 1410 patients with and without CKD, the mean estimated glomerular filtration rate (eGFR) was 29 ± 04 and 87 ± 25 ml/min/1.73 m² , respectively. Mean CFR was consistently lower in patients with CKD in all studies and the cumulative mean difference was statistically significant (2.1 ± .3 vs. 2.7 ± .5, standardized mean difference -.8, 95% CI -1.1, -.6, p < .05). The lower mean CFR was driven by both significantly higher mean resting flow velocity (.58 cm/s, 95% CI .17, .98) and lower mean stress flow velocity (-.94 cm/s, 95% CI -1.75, -.13) in studies with CKD. This difference remained significant across diagnostic modalities and even in absence of epicardial coronary artery disease. In meta-regression, there was a significant positive relationship between mean eGFR and mean CFR (p < .05).

Patients with CKD have a significantly lower CFR versus those without CKD, even in absence of epicardial coronary artery disease. There is a linear association between eGFR and CFR. Future studies are required to understand the mechanisms and therapeutic implications of these findings.

In this meta-analysis of observational studies, there was a significant reduction in coronary flow reserve in studies with chronic kidney disease versus those without. This difference was seen even in absence of epicardial coronary artery disease. In meta-regression, a lower estimate glomerular filtration rate was a significant predictor of lower coronary flow reserve. Coronary microvascular dysfunction, rather than atherosclerosis-related epicardial disease may underly increase cardiovascular risk in a patient with chronic kidney disease.

Coronary microvascular dysfunction (CMD) may precede clinically overt coronary artery disease (CAD). Overall and central obesity (CO) are major risk factors for CAD. This study sought to investigate the subclinical significance of body adiposity patterns based on the CMD risk.

A total of 128 patients with non-obstructive CAD were prospectively enrolled. Patients were categorized into 4 anthropometric groups: normal weight and non-CO (NWNCO, n = 41), normal weight and CO (NWCO, n = 20), excess weight and non-CO (EWNCO, n = 26), and excess weight and CO (EWCO, n = 41). Patients underwent rest/stress electrocardiography-gated 13N-ammonia positron emission tomography to measure absolute myocardial blood flow (MBF), myocardial flow reserve (MFR), hemodynamic parameters, and cardiac function.

Resting MBF did not differ between groups (P = .36). Compared with the NWNCO group, hyperemic MBF and MFR were significantly lower in the NWCO and EWCO groups. Notably, patients with NWCO presented the lowest hyperemic MBF and MFR and the highest incidence of CMD. Waist circumference was an independent risk factor for CMD (OR 1.05, 95% CI 1.01 to 1.10, P = .02).

In patients with non-obstructive CAD, CO may be associated with an increased risk of CMD to better fit the study findings which did not assess management or monitoring of MBF and MFR.