Empagliflozin's role in reducing ventricular repolarization heterogeneity: insights into cardiovascular mortality decline from the EMPATHY-HEART trial.

BACKGROUND: The incidence of myocardial infarction (MI) and sudden cardiac death (SCD) is significantly higher in individuals with Type 2 Diabetes Mellitus (T2DM) than in the general population. Strategies for the prevention of fatal arrhythmias are often insufficient, highlighting the need for additional non-invasive diagnostic tools. The T-wave heterogeneity (TWH) index measures variations in ventricular repolarization and has emerged as a promising predictor for severe ventricular arrhythmias. Although the EMPA-REG trial reported reduced cardiovascular mortality with empagliflozin, the underlying mechanisms remain unclear. This study investigates the potential of empagliflozin in mitigating cardiac electrical instability in patients with T2DM and coronary heart disease (CHD) by examining changes in TWH. METHODS: Participants were adult outpatients with T2DM and CHD who exhibited TWH > 80 µV at baseline. They received a 25 mg daily dose of empagliflozin and were evaluated clinically including electrocardiogram (ECG) measurements at baseline and after 4 weeks. TWH was computed from leads V4, V5, and V6 using a validated technique. The primary study outcome was a significant (p < 0.05) change in TWH following empagliflozin administration. RESULTS: An initial review of 6,000 medical records pinpointed 800 patients for TWH evaluation. Of these, 412 exhibited TWH above 80 µV, with 97 completing clinical assessments and 90 meeting the criteria for high cardiovascular risk enrollment. Empagliflozin adherence exceeded 80%, resulting in notable reductions in blood pressure without affecting heart rate. Side effects were generally mild, with 13.3% experiencing Level 1 hypoglycemia, alongside infrequent urinary and genital infections. The treatment consistently reduced mean TWH from 116 to 103 µV (p = 0.01). CONCLUSIONS: The EMPATHY-HEART trial preliminarily suggests that empagliflozin decreases heterogeneity in ventricular repolarization among patients with T2DM and CHD. This reduction in TWH may provide insight into the mechanism behind the decreased cardiovascular mortality observed in previous trials, potentially offering a therapeutic pathway to mitigate the risk of severe arrhythmias in this population. TRIAL REGISTRATION: NCT: 04117763.

Left atrial stiffness index - an early marker of left ventricular diastolic dysfunction in patients with coronary heart disease.

AIMS: To evaluate the correlation between left atrial stiffness index (LASI) and left ventricular diastolic function in patients with coronary heart disease (CHD) by Autostrain LA technique. METHODS: This was a retrospective analysis that included a total of 82 CHD patients who had suitable image quality for left atrial strain measurement. According to the 2016 ASE/EACVI guidelines for the echocardiographic assessment of diastolic dysfunction, the patients were divided into three groups: normal left ventricular diastolic function group (n = 26), indeterminate left ventricular diastolic function (n = 36), and left ventricular diastolic dysfunction (LVDD) (n = 20). The left atrial conduit strain (LAScd), Left atrial contractile strain (LASct), left atrial reservoir strain (LASr) and its derived parameters, including LASI and left atrial filling index (LAFI), were compared among the three groups. Furthermore, we conduct a correlation analysis between LASI and left ventricular diastolic function in patients with CHD. RESULTS: LASr and LAScd in normal group were higher than those in indeterminate group, LASr and LAScd in indeterminate group were higher than those in LVDD group, LASI in normal group was lower than that in indeterminate group, and LASI in indeterminate group was lower than that in LVDD group (P < 0.001). LASct in both normal and indeterminate groups was higher than that in LVDD group (P < 0.05). The LAFI of normal group was lower than that of indeterminate group and LVDD group (P < 0.001). LASI was positively correlated with E/e'(r = 0.822) (P < 0.001). LASr and E/e' were negatively correlated (r = -0.637) (P < 0.001). CONCLUSION: LASI is closely related to the changes of left ventricular diastolic function in CHD patients.

Diagnostic value of nocturnal trend changes in a dynamic electrocardiogram for coronary heart disease.

OBJECTIVE: To explore the diagnostic value of intermittent changes in the nocturnal ST segment trend graph in a dynamic electrocardiogram (ECG) for coronary heart disease (CHD). METHODS: A total of 205 patients who underwent coronary angiography were included in this retrospective study. The study sample was determined through a power analysis aimed at achieving power of 80% with a significance level of 0.05. The participants were divided into the CHD (n = 101) and the non-CHD (n = 104) group, based on the degree of coronary artery diameter stenosis. The morphological changes in the ST segment trend graph were observed and divided into two categories: 'wall-shaped' and 'peak-shaped' changes. RESULTS: Among the 205 patients, 94 had nocturnal ST segment dynamic changes and 111 did not. The detection rate of CHD without nocturnal ST segment dynamic changes was 21.59%, significantly lower than the detection rate of 93.18% in those with nocturnal ST segment changes, reflecting a statistically significant difference (P < 0.05). The positive rate of ST segment in patients with single-vessel disease (71.88%) was lower than in patients with multi-vessel disease (78.57%), and both differences were statistically significant (P < 0.05). The duration of ST segment trend graph changes in 94 cases in the CHD group with intermittent changes in the nocturnal ST segment trend graph was higher than in the non-CHD group, but no significant difference was observed (P > 0.05). The detection rate of CHD in the peak-shaped dynamic change group of the nocturnal ST segment trend graph was significantly higher (76/82) than in the wall-shaped (6/82) dynamic change group (P < 0.05). CONCLUSION: Peak-shaped changes in the nocturnal ST segment trend graph indicate coronary artery lesions. Nocturnal ST segment changes observed through dynamic ECG monitoring can serve as a valuable non-invasive predictor for CHD, providing a feasible method for early diagnosis and intervention in clinical practice.

Impaired sensitivity to thyroid hormones is associated with different grades of hypertension: A multicenter cross-sectional study.

BACKGROUND AND AIM: Accumulating evidence suggests a potential link between thyroid function with hypertension. However, the research results are limited, and there is no research to explore the relationship between central and peripheral thyroid hormones (THs) sensitivity and different grades of hypertension in patients with coronary heart disease (CHD). This study aims to prove the complex interaction between thyroid system and blood pressure, and provides new ideas for the assessment of hypertension in patients with CHD. METHODS AND RESULTS: Calculate parameters representing central and peripheral sensitivity to THs. Logistic regression analysis was used to analyze the relationship between central and peripheral THs sensitivity of CHD patients and different grades of hypertension, especially in different ages, sexes, blood glucose levels, smoking, and drinking statuses. Among the 34,310 participants, 19,610 (57.16 %) were diagnosed with hypertension. The risk of hypertension and TSHI (OR: 0.88; 95 % CI: 0.87-0.90; P < 0.001), TT4RI (OR: 0.998; 95 % CI: 0.998-0.999; P < 0.001), TFQI (OR: 0.63; 95 % CI: 0.60-0.67; P < 0.001), PTFQI (OR: 0.63; 95 % CI: 0.59-0.67; P < 0.001) was negatively associated. The risk of hypertension was positively associated with FT3/FT4 (OR: 1.20; 95 % CI: 1.17-1.22; P < 0.001). After stratified analysis, these associations remained significant at different ages, sexes, blood glucose levels, grades of hypertension, smoking, and drinking statuses (P < 0.001). CONCLUSIONS: This study shows that the decrease in central THs sensitivity index and the increase in peripheral THs sensitivity index are associated with a higher risk of hypertension in CHD patients.

Cardiac hemodynamics phenotypes and individual responses to training in coronary heart disease patients.

BACKGROUND: In patients with coronary heart disease (CHD), individualized exercise training (ET) programs are strongly recommended to optimize peak oxygen uptake ( V ̇ $$ \dot{\mathrm{V}} $$ O2peak) improvement and prognosis. However, the cardiac hemodynamic factors responsible for a positive response to training remain unclear. The aim of this study was to compare cardiac hemodynamic changes after an ET program in responder (R) versus non-responder (NR) CHD patients. METHODS: A total of 72 CHD patients completed a 3-month ET program and were assessed by cycle ergometer cardiopulmonary exercise test (CPET: V ̇ $$ \dot{\mathrm{V}} $$ O2peak assessment) with impedance cardiography (ICG) for hemodynamic measurements before and after training. Cardiac hemodynamics (e.g., CO, CI, SV, ESV, EDV, and SVR) were measured by ICG during CPET. The R and NR groups were classified using the median change in V ̇ $$ \dot{\mathrm{V}} $$ O2peak (>the median for R and ≤the median for NR). RESULTS: In the R group, V ̇ $$ \dot{\mathrm{V}} $$ O2peak (+17%, p < 0.001), CO, CI, SV, and HR increased by 17%, 17%, 13%, and 5%, respectively (p < 0.05) after the training program. In the NR group, V ̇ $$ \dot{\mathrm{V}} $$ O2peak, CO, CI, and SV increased by 0.5%, 5%, 8%, and 6%, respectively (p < 0.01). The SVR decreased in both groups (-19% in R and -11% in NR, p < 0.001). CONCLUSION: Among CHD patients, the R group showed a better improvement in peak cardiac output via an increase in peak stroke volume and heart rate and a reduced systemic vascular resistance than the NR group. Different cardiac phenotype adaptations and clinical individual responses were identified in CHD patients according to the aerobic fitness responder's status.

Is breathing frequency a potential means for monitoring exercise intensity in people with atrial fibrillation and coronary heart disease when heart rate is mitigated?

PURPOSE: Moderate-intensity aerobic exercise is safe and beneficial in atrial fibrillation (AF) and coronary heart disease (CHD). Irregular or rapid heart rates (HR) in AF and other heart conditions create a challenge to using HR to monitor exercise intensity. The purpose of this study was to assess the potential of breathing frequency (BF) to monitor exercise intensity in people with AF and CHD without AF. METHODS: This observational study included 30 AF participants (19 Male, 70.7 ± 8.7 yrs) and 67 non-AF CHD participants (38 Male, 56.9 ± 11.4 yrs). All performed an incremental maximal exercise test with pulmonary gas exchange. RESULTS: Peak aerobic power in AF ( V ˙ O2peak; 17.8 ± 5.0 ml.kg-1.min-1) was lower than in CHD (26.7 ml.kg-1.min-1) (p < .001). BF responses in AF and CHD were similar (BF peak: AF 34.6 ± 5.4 and CHD 36.5 ± 5.0 breaths.min-1; p = .106); at the 1st ventilatory threshold (BF@VT-1: AF 23.2 ± 4.6; CHD 22.4 ± 4.6 breaths.min-1; p = .240). % V ˙ O2peak at VT-1 were similar in AF and CHD (AF: 59%; CHD: 57%; p = .656). CONCLUSION: With the use of wearable technologies on the rise, that now include BF, this first study provides an encouraging potential for BF to be used in AF and CHD. As the supporting data are based on incremental ramp protocol results, further research is required to assess BF validity to manage exercise intensity during longer bouts of exercise.

Determinants of V̇+O2peak Changes After Aerobic Training in Coronary Heart Disease Patients.

This study aimed to highlight the ventilatory and circulatory determinants of changes in ˙VO2peak after exercise-based cardiac rehabilitation (ECR) in patients with coronary heart disease (CHD). Eighty-two CHD patients performed, before and after a 3-month ECR, a cardiopulmonary exercise testing (CPET) on a bike with gas exchanges measurements (˙VO2peak, minute ventilation, i. e., ˙VE), and cardiac output (Q˙c). The arteriovenous difference in O2 (C(a-v¯)O2) and the alveolar capillary gradient in O2 (PAi-aO2) were calculated using Fick's laws. Oxygen uptake efficiency slope (OUES) was calculated. A 5.0% cut off was applied for differentiating non- (NR: ˙VO2<0.0%), low (LR: 0.0≤ ∆˙VO2<5.0%), moderate (MR: 5.0≤∆˙VO2 < 10.0%), and high responders (HR: ∆˙VO2≥10.0%) to ECR. A total of 44% of patients were HR (n=36), 20% MR (n=16), 23% LR (n=19), and 13% NR (n=11). For HR, the ˙VO2peak increase (p<0.01) was associated with increases in ˙VE (+12.8±13.0 L/min, p<0.01), (+1.0±0.9 L/min, p<0.01), and C(a-v¯)O2 (+2.3±2.5 mLO2/100 mL, p<0.01). MR patients were characterized by+6.7±19.7 L/min increase in ˙VE (p=0.04) and+0.7±1.0 L/min of Q˙c (p<0.01). ECR induced decreases in ˙VE (p=0.04) and C(a-v¯)O2 (p<0.01) and a Q˙c increase in LR and NR patients (p<0.01). Peripheral and ventilatory responses more than central adaptations could be responsible for the ˙VO2peak change with ECR in CHD patients.

Respiratory Function of Mitochondria in Patients with Coronary Heart Disease with Implantable Cardioverter-Defibrillator.

We studied the respiratory activity of mitochondria in peripheral blood leukocytes from 36 patients with coronary heart disease (CHD) and a history of ventricular tachyarrhythmias required cardioverter-defibrillator implantation. The measurements were carried out in incubation buffers with different oxidation substrates (succinate and pyruvate-malate mixture). In pyruvate-malate incubation buffer, oxygen consumption rate and respiratory control coefficients in patients with triggered device did not differ significantly from those in patients without cardioverter-defibrillator triggering. At the same time, respiratory control coefficients were below the reference values. In succinate buffer, values of mitochondrial parameters were significantly lower in patients with triggered devices. Our findings indicate that mitochondria of patients with non-triggered cardioverters-defibrillators have better functional and metabolic plasticity. It was concluded that activity of respiratory processes in mitochondria could be an indicator that should be taken into the account when assessing the risk of developing ventricular tachyarrhythmias.

Relationship of Inotropic Effects of Stimulation of ß1- and ß2-Adrenergic Receptors of Isolated Myocardial Fragments with Echocardiography Parameters in Coronary Heart Disease.

We studied the relationship of inotropic responses of the isolated myocardium to stimulation of ß1-and ß2-adrenergic receptors (ß-AR) with echocardiography parameters in 28 patients with coronary heart disease (CHD). Myocardial fragments (trabeculae of the right atrial appendage) were obtained during coronary artery bypass surgery. The inotropic response of the trabeculae was assessed in an isometric mode. Stimulation of ß1-and ß2-AR with agonists was performed against the background of preliminary α-AR blockade. In case of preserved ejection fraction, significant inotropic response of the trabeculae (135 (112; 154)% from the initial contraction amplitude) was observed after ß1-AR stimulation, while in reduced ejection fraction, its significant increase was observed after ß1-AR stimulation (126 (112; 170)% from the initial contraction amplitude). In patients with preserved and reduced ejection fraction, the correlations between the inotropic responses of the trabeculae to ß1-and ß2-AR stimulation and echocardiography parameters were different. The revealed differences reflect the degree of cardiac remodeling under condition of the studied pathology.

[Application of computational fluid dynamics in the evaluation of left ventricular function in cardiomyopathies and coronary disease].

Computational fluid dynamics (CFD) is an emerging technology applied in the field of cardiovascular medicine, which can obtain hemodynamic data by simulating the blood flow in the patient's heart for cardiac function assessment and disease diagnosis. Left ventricular function plays a key role in the occurrence and development of cardiomyopathies and coronary disease. CFD can reconstruct the left ventricular anatomic structures of patients to clarify pathophysiologic mechanisms and analyze hemodynamic parameters to evaluate left ventricular function, verify surgical efficacy, and guide surgical strategy, which has a positive effect on achieving early diagnosis and reducing mortality from cardiomyopathies and coronary disease. At present, there are still technical limitations in the large-scale clinical application of CFD, and various solutions are being developed and tested, and further improvement and refinement are needed.

[Relationship between cardiopulmonary exercise testing and the prognosis of cardiovascular disease in coronary heart disease patients].

Objective: To investigate the predictive value of cardiopulmonary exercise test (CPET) indexes for major adverse cardiovascular events (MACE) in patients with coronary heart disease (CHD). Methods: This study was a retrospective cohort study. CHD patients were consecutively enrolled who procedure CPET before discharge from the Department of Cardiology, General Hospital of Northern Theater Command from November 2015 to September 2021 were enrolled. Demographic information, past medical history, CPET indexes and other baseline data were collected and the patients were followed up. Patients were divided into a MACE group and a control group according to the presence or absence of MACE. A multivariate Cox proportional hazard regression model was used to analyze the CPET indexes with predictive value for MACE in CHD patients. Results: A total of 3 800 patients were eligible for the criterion, age (57.2±8.8) years, 2 920 (76.84%) males. During a follow-up of 1 237 (695, 1 596) days, 390 (10.26%) patients were in MACE group, and 3 410 (89.74%) patients were in control group. In adjusted multivariable analysis, higher metabolic equivalent of tasks (MET) at anaerobic threshold (AT) is an independent protective factor for MACE in patients with CHD (HR=0.75, 95%CI 0.62-0.90, P=0.002), higher VE/VCO2 is an independent risk factor for MACE in CHD patients (HR=1.05, 95%CI 1.02-1.07, P=0.001). Conclusion: In CPET, high MET at AT is an independent protective factor for MACE in patients with CHD, and high VE/VCO2 is an independent risk factor for MACE in CHD patients.

Stress Echocardiography by the ABCDE Protocol ln the Assessment of Prognosis of Stable Coronary Heart Disease.

AIM: To assess the role of clinical indicators and parameters of stress echocardiography performed according to an extended protocol as predictors for the occurrence of a composite cardiovascular endpoint (CCVEP) in IHD. MATERIAL AND METHODS: The study included 186 patients (60.2% men, mean age 60.6±9.9 years) with an established (n=73; 39.2%) and suspected (60.8%) diagnosis of IHD. Stress EchoCG with adenosine triphosphate (38.2%), transesophageal pacing (15.1%), dobutamine (2.6%), and bicycle ergometry on a recumbent ergometer (44.1%) was performed. The stress EchoCG protocol included assessment of regional wall motion abnormalities (WMA), B-lines, LV contractile reserve (CTR), coronary reserve (CR), and heart rate reserve. The median follow-up period was 13 [9; 20] months. The composite CCVEP included death from cardiovascular diseases and their complications, acute coronary syndrome, and revascularization and was defined at the first of these events. Statistical analysis was performed with the Statistica 16.0 and SPSS Statistics 23.0 software packages. Differences were considered statistically significant at p<0.05. RESULTS: Invasive or noninvasive coronary angiography was performed in 90.3% of patients; obstructive coronary disease (stenosis ≥50%) was detected in 67.9% of cases. During the follow-up period, 58 (31.2%) patients had cardiovascular complications. The risk of developing CCVEP was associated with the pretest probability (PTP) of ischemic heart disease (odds ratio, OR, 1.05; 95% confidence interval, CI, 1.02-1.08), dyslipidemia (DLP) (OR 0.40; 95% CI 0.20-0.82), carotid atherosclerosis (OR 0.39; 95% CI 0.18-0.86), LV ejection fraction (OR 0.96; 95% CI 0.93-0.99), appearance at peak stress of new significant (2 LV segments or more) regional WMAs (OR 0.32; 95% CI 0.18-6.55), decreased LV CTR (OR 0.46; 95% CI 0.27-0.79) and CR (OR 0.33; 95% CI 0.18-0.61); p<0.05 for all. In a multivariate analysis with Cox regression, the model with clinical indicators included PTP of IHD (OR 1.04; 95% CI 1.01-1.07; p=0.01) and DLP (OR 0.14; 95% CI 0.02-1.01; p=0.05) as predictors. The model with stress EchoCG parameters included the appearance of new significant WMAs (OR 0.33, 95% CI 0.16-0.65; p=0.001) and reduced <2.0 CR (OR 0.44; 95% CI 0.24-0.82; p=0.01). A comparative analysis of Kaplan-Meier curves confirmed statistically significant differences in the dynamics of the CCVEP occurrence depending on the absence or presence of hemodynamically significant WMAs and/or reduced CR during stress EchoCG (p<0.01). CONCLUSION: Reduced LV CR and WMA during stress EchoCG in patients with suspected or confirmed IHD are significant independent predictors for the CCVEP occurrence. Among clinical indicators, PTP of IHD and DLP are of the greatest importance for prognosis.

Trends in Recurrent Coronary Heart Disease After Myocardial Infarction Among US Women and Men Between 2008 and 2017.

BACKGROUND: Rates for recurrent coronary heart disease (CHD) events have declined in the United States. However, few studies have assessed whether this decline has been similar among women and men. METHODS: Data were used from 770 408 US women and 700 477 US men <65 years of age with commercial health insurance through MarketScan and ≥66 years of age with government health insurance through Medicare who had a myocardial infarction (MI) hospitalization between 2008 and 2017. Women and men were followed up for recurrent MI, recurrent CHD events (ie, recurrent MI or coronary revascularization), heart failure hospitalization, and all-cause mortality (Medicare only) in the 365 days after MI. RESULTS: From 2008 to 2017, age-standardized recurrent MI rates per 1000 person-years decreased from 89.2 to 72.3 in women and from 94.2 to 81.3 in men (multivariable-adjusted P interaction by sex <0.001). Recurrent CHD event rates decreased from 166.3 to 133.3 in women and from 198.1 to 176.8 in men (P interaction <0.001). Heart failure hospitalization rates decreased from 177.4 to 158.1 in women and from 162.9 to 156.1 in men (P interaction=0.001). All-cause mortality rates decreased from 403.2 to 389.5 in women and from 436.1 to 417.9 in men (P interaction=0.82). In 2017, the multivariable-adjusted rate ratios comparing women with men were 0.90 (95% CI, 0.86-0.93) for recurrent MI, 0.80 (95% CI, 0.78-0.82) for recurrent CHD events, 0.99 (95% CI, 0.96-1.01) for heart failure hospitalization, and 0.82 (95% CI, 0.80-0.83) for all-cause mortality. CONCLUSIONS: Rates of recurrent MI, recurrent CHD events, heart failure hospitalization, and mortality in the first year after an MI declined considerably between 2008 and 2017 in both men and women, with proportionally greater reductions for women than men. However, rates remain very high, and rates of recurrent MI, recurrent CHD events, and death continue to be higher among men than women.

Usefulness of estimated pulse wave velocity for identifying prevalent coronary heart disease: findings from a general Chinese population.

BACKGROUND: Aortic stiffness and coronary heart disease (CHD) share a similar spectrum of risk factors; previous studies have identified the association between aortic stiffness and CHD. Recent studies have demonstrated estimated pulse wave velocity (ePWV) as a simple and easy-acquired indicator of aortic stiffness. Our work aims to evaluate the association between ePWV and the prevalence of CHD and assess the value of ePWV for the identification of prevalent CHD. METHODS: The current cross-sectional work included 7012 subjects from rural areas of southeastern China between September 2020 and February 2021. ePWV was calculated from age and mean blood pressure by specific algorithm. RESULTS: The prevalence of CHD in our population was 3.58% (251 patients among 7012 subjects). After adjusting for age, sex, education, income and exercise level, current smoking and drinking status, body mass index, waist circumference, fasting plasma glucose, total cholesterol, high density lipoprotein, estimated glomerular filtration rate and cerebrovascular diseases, each standard deviation increment of ePWV would produce an additional 37.8% risk of prevalent CHD. Moreover, after dividing ePWV into quartiles, the 4th quartile of ePWV showed a significant risk of prevalent CHD (OR (95% CI): 3.567 (1.963-6.479)) when compared with the 1st quartile. Additionally, the subgroup analysis showed the association between ePWV and prevalent CHD was robust to several common risk factors of CHD, including age, sex, body mass index, hypertension, diabetes and reduced estimated glomerular filtration rate. Finally, the area under curve (AUC) displayed an improvement when adding ePWV into common CHD risk factors (0.705 vs. 0.718. P = 0.044). Consistently, net reclassification index (0.436, 95% CI: 0.301-0.571, P < 0.001) and integrated discrimination index (0.004, 95% CI: 0.001-0.006, P = 0.002) demonstrated the value of ePWV to optimize the identification of prevalent CHD in the general population. CONCLUSION: The present analysis implicates the robust association between ePWV, a simple, rapid, and practical marker of aortic stiffness, and prevalent CHD in the general Chinese population. More importantly, the results suggest the value of ePWV as a potential marker to improve the identification of prevalent CHD.

Coronary Microvascular Dysfunction, Left Ventricular Remodeling, and Clinical Outcomes in Patients With Chronic Kidney Impairment.

BACKGROUND: Cardiac dysfunction and cardiovascular events are prevalent among patients with chronic kidney disease without overt obstructive coronary artery disease, but the mechanisms remain poorly understood. Coronary microvascular dysfunction has been proposed as a link between abnormal renal function and impairment of cardiac function and cardiovascular events. We aimed to investigate the relations between chronic kidney disease, coronary microvascular dysfunction, cardiac dysfunction, and adverse cardiovascular outcomes. METHODS: Patients undergoing cardiac stress positron emission tomography, echocardiogram, and renal function ascertainment at Brigham and Women's Hospital were studied longitudinally. Patients free of overt coronary (summed stress score <3 and without a history of ischemic heart disease), valvular, and end-organ disease were followed up for the adverse composite outcome of death or hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was determined from positron emission tomography. Echocardiograms were used to measure cardiac mechanics: diastolic (lateral and septal E/e') and systolic (global longitudinal, radial, and circumferential strain). Image analyses and event adjudication were blinded. The associations between estimated glomerular filtration rate (eGFR), CFR, diastolic and systolic indices, and adverse cardiovascular outcomes were assessed in adjusted models and mediation analyses. RESULTS: Of the 352 patients (median age, 65 years; 63% female; 22% black) studied, 35% had an eGFR <60 mL·min-1·1.73 m-2, a median left ventricular ejection fraction of 62%, and a median CFR of 1.8. eGFR and CFR were associated with diastolic and systolic indices, as well as future cardiovascular events (all P<0.05). In multivariable models, CFR, but not eGFR, was independently associated with cardiac mechanics and cardiovascular events. The associations between eGFR, cardiac mechanics, and cardiovascular events were partly mediated via CFR. CONCLUSIONS: Coronary microvascular dysfunction, but not eGFR, was independently associated with abnormal cardiac mechanics and an increased risk of cardiovascular events. Coronary microvascular dysfunction may mediate the effect of chronic kidney disease on abnormal cardiac function and cardiovascular events in those without overt coronary artery disease.

Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study.

BACKGROUND: Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD. METHODS AND FINDINGS: The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events. CONCLUSIONS: Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD. TRIAL REGISTRATION: ClinicalTrials.gov NCT00799903.

Coronary remodeling and biomechanics: Are we going with the flow in 2020?

Under normal conditions, coronary blood flow (CBF) provides critical blood supply to the myocardium so that it can appropriately meet the metabolic demands of the body. Dogmatically, there exist several known regulators and modulators of CBF that include local metabolites and neurohormonal factors that can influence the function of the coronary circulation. In disease states such as diabetes and myocardial ischemia, these regulators are impaired or shifted such that CBF is reduced. Although functional considerations have been and continued to be well studied, more recent evidence builds upon established studies that collectively suggest that the relative roles of coronary structure, biomechanics, and the influence of cardiac biomechanics via extravascular compression may also play a significant role in dictating CBF. In this mini review, we discuss these regulators of CBF under normal and pathophysiological conditions and their potential influence on the control of CBF.

Coronary heart disease and atrial fibrillation: a vicious cycle.

The population suffering from coronary heart disease (CHD) complicated by atrial fibrillation (AF) is rising rapidly. A strong correlation between the two diseases has been reported, and the many common risk factors they share may play prominent roles in their development. In addition, CHD can directly promote the progression of AF by affecting reentry formation, focal ectopic activity, and neural remodeling. At the same time, AF also affects CHD through three aspects: 1) atherosclerosis, 2) the mismatch of blood supply and oxygen consumption, and 3) thrombosis. In conclusion, CHD and AF can aggravate each other and seem to form a vicious cycle. For patients with CHD complicated by AF, principal studies and guidelines have focused on antithrombotic treatment and rhythm control, which are paramount for these patients. Of note, our review sheds light on the strategies to break the cycle of the two diseases, which may be fundamental to treat these patients and optimize the benefit.

Delineating phenotypes of Kawasaki disease and SARS-CoV-2-related inflammatory multisystem syndrome: a French study and literature review.

OBJECTIVE: To better define the clinical distinctions between the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related paediatric inflammatory multisystem syndrome (PIMS) and Kawasaki disease (KD). METHODS: We compared three groups of patients: group 1, cases from our national historic KD database (KD-HIS), before the SARS-CoV-2 pandemic; group 2, patients with KD admitted to an intensive care unit (KD-ICU) from both our original cohort and the literature, before the SARS-CoV-2 pandemic; and group 3, patients with PIMS from the literature. RESULTS: KD-HIS included 425 patients [male:female ratio 1.3, mean age 2.8 years (s.d. 2.4)], KD-ICU 176 patients [male:female ratio 1.3, mean age 3.5 years (s.d. 3.1)] and PIMS 404 patients [male:female ratio 1.4, mean age 8.8 years (s.d. 3.7)]. As compared with KD-HIS patients, KD-ICU and PIMS patients had a higher proportion of cardiac failure, digestive and neurological signs. KD-ICU and PIMS patients also had a lower frequency of typical KD-mucocutaneous signs, lower platelet count, higher CRP and lower sodium level. As compared with KD-HIS and KD-ICU patients, PIMS patients were older and more frequently had myocarditis; they also had fewer coronary abnormalities and lower sodium levels. Unresponsiveness to IVIG was more frequent in KD-ICU than KD-HIS and PIMS patients. CONCLUSION: On clinical grounds, KD-HIS, KD-ICU and PIMS might belong to a common spectrum of non-specific pathogen-triggered hyperinflammatory states. The causes of increasing inflammation severity within the three entities and the different effects on the heart remain to be determined.

Use of peripheral arterial tonometry in detection of abnormal coronary flow reserve.

BACKGROUND: We assessed the utility of EndoPAT, a device that measures reactive hyperemia index (RHI) as a clinical screening tool for identifying low coronary flow reserve (CFR). Distinguishing normal from low CFR aids assessment for coronary microvascular dysfunction (CMD) or large vessel coronary artery disease (CAD). METHODS: From June 2014-May 2019, in a convenience sample, we measured RHI in adults undergoing clinically indicated cardiac Rubidium-82 positron emission tomography/computed tomography (PET/CT) at a single center. Exclusion criteria were inability to consent, lack of English proficiency, and physical limitation. We defined low RHI as <1.67 and low CFR as <2.5. Distribution of RHI was skewed so we used its natural logarithm (LnRHI) to calculate Pearson correlation and area under the curve (AUC). RESULTS: Of 265 patients with PET/CT, we enrolled 131, and 100 had adequate data. Patients had a mean age of 61 years (SD = 12), 46% were female, 29% non-white. Thirty-six patients had low RHI, and 60 had depressed CFR. LnRHI did not distinguish patients with low from normal CFR (AUC = 0.53; 95% Cl, 0.41-0.64) and did not correlate with CFR (r = -0.021, p = 0.83). Low RHI did not distinguish patients with traditional CAD risk factors, presence of calcification, or perfusion defect (p > 0.05). Conversely, mean augmentation index, a measure of arterial stiffness, was higher with low RHI (p = 0.005) but not CFR (p = 0.625). RHI was lower in patients we identified as CMD (low CFR, no perfusion defect and calcium score of 0) (1.88 versus 2.21, p = 0.35) although we were underpowered (n = 12) to meet statistical significance. CONCLUSIONS: Peripheral RHI is insufficient as a clinical screening tool for low CFR as measured by cardiac PET/CT. Differences in vascular pathology assessed by each method may explain this finding.