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European Journal of Pharmacology Jun 2024Pulmonary hypertension (PH) is a malignant pulmonary vascular disease with a poor prognosis. Although the development of targeted drugs for this disease has made some...
Pulmonary hypertension (PH) is a malignant pulmonary vascular disease with a poor prognosis. Although the development of targeted drugs for this disease has made some breakthroughs in recent decades, PH remains incurable. Therefore, innovative clinical treatment methods and drugs for PH are still urgently needed. DYZY01 is a new drug whose main ingredient is high-purity cannabidiol, a non-psychoactive constituent of cannabinoids that was demonstrated to have anti-inflammatory and anti-pyroptosis properties. Several recent studies have found cannabidiol could improve experimental PH, whereas the mechanistic effect of it warrants further investigation. Thus, this study aimed to investigate whether DYZY01 can treat PH by inhibiting inflammation and pyroptosis and to reveal its underlying mechanism. We established hypoxia and monocrotaline (MCT)-induced PH rat models in vivo and treated them with either DYZY01 (10,50 mg/kg/d) or Riociguat (10 mg/kg/d) by oral administration. The mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVHI), and extent of vascular remodeling were measured. Meanwhile, the effect of DYZY01 on human pulmonary arterial endothelial cells (HPAECs) was assessed in vitro. The results indicated that DYZY01 significantly reduced mPAP and RVHI in PH rats and reversed the extent of pulmonary vascular remodeling. This improvement may have been achieved by reducing endothelial cell pyroptosis via inhibiting the NF-κB/NLRP3/Caspase-1 pathway. Furthermore, DYZY01 could improve endothelial vascular function, possibly by regulating the secretion of vasodilator factors and inhibiting the proliferation and migration of pulmonary endothelial cells.
PubMed: 38942262
DOI: 10.1016/j.ejphar.2024.176785 -
Journal of the American Society of... Jun 2024Though widely used to classify heart failure (HF) patients, the prognostic role of left ventricular ejection fraction (LVEF) is debated. We hypothesized that the...
BACKGROUND AND AIMS
Though widely used to classify heart failure (HF) patients, the prognostic role of left ventricular ejection fraction (LVEF) is debated. We hypothesized that the echocardiographic measures of forward LV output, being more representative of cardiac hemodynamics, may improve risk prediction in a large cohort of HF patients with systolic dysfunction.
METHODS
Consecutive stable HF patients with LVEF <50% on guideline-recommended therapies undergoing an echocardiography including the evaluation of forward LV output (i.e., LV outflow tract velocity-time integral [LVOT-VTI], stroke volume index [SVi], and cardiac index [CI]) over a 6-year period, were selected and followed-up for the endpoint of cardiac and all-cause death.
RESULTS
Among the 1,509 patients analyzed (71±12 years, 75% males, LVEF 35±9%), 328 (22%) died during a median 28-month (14-40) follow-up, 165 (11%) of which for cardiac causes. At multivariable regression analysis, LVOT-VTI (<0.001), SVi (p<0.001), and CI (p<0.001), but not LVEF (p>0.05), predicted cardiac and all-cause death. The optimal prognostic cut-offs for LVOT-VTI, SVi, and CI were 15 cm, 38 mL/m, and 2 L/min/m, respectively. Adding each of these measures to a multivariable risk model (including clinical, biohumoral, and echocardiographic markers) improved risk prediction (p<0.001). Among the different measures of forward LV output, CI was less accurate than LVOT-VTI and SVi.
CONCLUSION
The echocardiographic evaluation of forward LV output improves risk prediction in HF patients across a wide LVEF spectrum over other well-established clinical, biohumoral, and echocardiographic prognostic markers.
PubMed: 38942218
DOI: 10.1016/j.echo.2024.06.008 -
The Journal of Heart and Lung... Jun 2024Right ventricular (RV) imaging has not a definite role in risk stratification of pulmonary arterial hypertension (PAH) patients. We tested the hypothesis that...
BACKGROUND
Right ventricular (RV) imaging has not a definite role in risk stratification of pulmonary arterial hypertension (PAH) patients. We tested the hypothesis that echocardiography-derived phenotypes, depicting different degrees of RV remodeling and dysfunction, may provide additional prognostic information to current risk stratification tools.
METHODS
Consecutive incident PAH patients aged ≥ 18 years, diagnosed between January 2005 and December 2021, underwent clinical assessment, right heart catheterization, standard echocardiography. Simple echocardiographic variables were combined in order to define a priori four phenotypes representing different degrees of RV dilatation and RV-pulmonary arterial (PA) coupling: Phenotype 1 with mildy dilated right ventricle and preserved RV-PA coupling (n=152 patients); phenotype 2 with mildly dilated right ventricle and poor RV-PA coupling (n=143 patients); phenotype 3 with severely dilated right ventricle and preserved RV-PA coupling (n=201 patients); phenotype 4 with severely dilated right ventricle and poor RV-PA coupling, with or without severe tricuspid regurgitation (n=519 patients). Risk stratification was based on on the ESC/ERS 3-strata model and REVEAL 2.0 score.
RESULTS
These phenotypes were present in all risk groups. Notably, regardless of the ESC/ERS risk stratum assigned to the patient, phenotype 4 was associated with a 2-fold increase of the odds of death (HR 2.1, 95% C.I. 1.6-2.8, p<0.001), while phenotype 1 was associated with a 71% reduction in the odds of dying (HR 0.29, 95% C.I. 0.18-0.47, p<0.001).
CONCLUSIONS
Echocardiography-derived phenotypes describing RV remodeling and dysfunction may provide prognostic information which is independent of and additional to the clinically defined risk in incident PAH patients.
PubMed: 38942159
DOI: 10.1016/j.healun.2024.06.003 -
Journal of Imaging Informatics in... Jun 2024Cardiac amyloidosis (CA) is characterized by the deposition of amyloid fibrils within the myocardium, resulting in a restrictive physiology. Although microvascular...
Cardiac amyloidosis (CA) is characterized by the deposition of amyloid fibrils within the myocardium, resulting in a restrictive physiology. Although microvascular dysfunction is a common feature, it is difficult to assess. This study aimed to explore myocardial transit time (MyoTT) by cardiovascular magnetic resonance (CMR) as a potential novel parameter of microcirculatory dysfunction in CA. This prospective study enrolled 20 CA patients and 20 control subjects. CMR acquisition included cine imaging, pre- and post-contrast T1 mapping, and MyoTT assessment, which was calculated from the time delay in contrast agent arrival between the aortic root and coronary sinus (CS). Compared to the control group, patients with CA exhibited significantly reduced left ventricular (LV) ejection fraction and myocardial strain, an increase in LV global peak wall thickness (LVGPWT), extracellular volume fraction (ECV), and prolonged MyoTT (14.4 ± 3.8 s vs. 7.7 ± 1.5 s, p < 0.001). Moreover, patients at Mayo stage III had a significantly longer MyoTT compared to those at stage I/II. MyoTT showed a positive correlation with the ECV, LVGPWT, and LV global longitudinal strain (LV-GLS) (p < 0.05). The area under the curve (AUC) for MyoTT was 0.962, demonstrating diagnostic performance comparable to that of the ECV (AUC 0.995) and LV-GLS (AUC 0.950) in identifying CA. MyoTT is significantly prolonged in patients with CA, correlating with fibrosis markers, remodeling, and dysfunction. As a novel parameter of coronary microvascular dysfunction (CMD), MyoTT has the potential to be an integral biomarker in multiparametric CMR assessment of CA.
PubMed: 38940890
DOI: 10.1007/s10278-024-01179-7 -
European Heart Journal. Cardiovascular... Jun 2024Left ventricular (LV) diastolic dysfunction, atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) share common risk factors and are...
Left ventricular (LV) diastolic dysfunction, atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) share common risk factors and are closely related to each other and to adverse cardiovascular events. Exertional dyspnea in patients with AF should trigger comprehensive LV diastolic function evaluation since AF frequently precedes incident HFpEF. Echocardiographic assessment of LV diastolic function in patients with AF is challenging, mainly because of variability in cycle length, the absence of atrial contraction, and the frequent occurrence of LA enlargement regardless of LV filling pressures (LVFP). The algorithm of the 2016 recommendations for the evaluation of LV diastolic function cannot be directly applied in this setting. This review discusses the modalities available for diastolic function assessment and HFpEF diagnosis in patients with AF. Based on currently available data, a reasonable clinical target of diastolic function evaluation in AF would be to reach a binary conclusion: LVFP elevated or not. Recently, a two-step algorithm that combined several echocardiographic parameters plus inclusion of body mass index, has been proposed to differentiate normal from elevated LVFP in patients with AF. The echocardiographic evaluation must be complemented by a thorough clinical evaluation along with natriuretic peptides and cardiac catheterization in selected cases. If a diagnosis of HFpEF cannot be ascertained, a close follow up for timely identification of diastolic dysfunction markers along with monitoring and correction of modifiable risk factors are recommended.
PubMed: 38940621
DOI: 10.1093/ehjci/jeae160 -
Biomeditsinskaia Khimiia Jun 2024Type 1 diabetes mellitus (T1DM) is the most severe form of diabetes, which is characterized by absolute insulin deficiency induced by the destruction of pancreatic beta...
Type 1 diabetes mellitus (T1DM) is the most severe form of diabetes, which is characterized by absolute insulin deficiency induced by the destruction of pancreatic beta cells. The aim of this study was to evaluate the effect of a structural analogue of apelin-12 ((NαMe)Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Phe-OH, metilin) on hyperglycemia, mitochondrial (MCh) respiration in permeabilized cardiac left ventricular (LV) fibers, the myocardial energy state, and cardiomyocyte membranes damage in a model of streptozotocin (STZ) diabetes in rats. Metilin was prepared by solid-phase synthesis using the Fmoc strategy and purified using HPLC. Four groups of animals were used: initial state (IS); control (C), diabetic control (D) and diabetic animals additionally treated with metilin (DM). The following parameters have been studied: blood glucose, MCh respiration in LV fibers, the content of cardiac ATP, ADP, AMP, phosphocreatine (PCr) and creatine (Cr), the activity of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in blood plasma. Administration of metilin to STZ-treated rats decreased blood glucose, increased state 3 oxygen consumption, the respiratory control ratio in MCh of permeabilized LV fibers, and increased the functional coupling of mitochondrial CK (mt-CK) to oxidative phosphorylation compared with these parameters in group D. In STZ-treated animals metilin administration caused an increase in the PCr content and prevention of the loss of total creatine (ΣCr=PCr+Cr) in the diabetic hearts, as well as restoration of the PCr/ATP ratio in the myocardium and a decrease in the activity of CK-MB and LDH in plasma to initial values. Thus, metilin prevented energy disorders disturbances in cardiomyocytes of animals with experimental T1DM.
Topics: Animals; Diabetes Mellitus, Experimental; Rats; Male; Diabetes Mellitus, Type 1; Energy Metabolism; Intercellular Signaling Peptides and Proteins; Rats, Wistar; Myocytes, Cardiac; Mitochondria, Heart; Blood Glucose; Myocardium; Streptozocin
PubMed: 38940202
DOI: 10.18097/PBMC20247003135 -
Circulation Research Jun 2024Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular...
BACKGROUND
Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular tachycardia and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear, and its use after myocardial infarction is limited by concerns for potential right ventricular dysfunction.
METHODS
Myocardial infarction was created in Yorkshire pigs (N=22) by left anterior descending coronary artery occlusion. Six weeks after myocardial infarction, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. Right and left ventricular hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity and intrinsic cardiac neural activity, and ventricular effective refractory periods and slope of restitution (S) were assessed before and after TEA. Ventricular tachyarrhythmia inducibility was assessed by programmed electrical stimulation.
RESULTS
TEA reduced inducibility of ventricular tachyarrhythmias by 70%. TEA did not affect right ventricular-systolic pressure or contractility although left ventricular-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular effective refractory periods prolonged significantly at critical sites of arrhythmogenesis, and S was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both baroreflex sensitivity and intrinsic cardiac neural activity.
CONCLUSIONS
TEA does not compromise right ventricular function in infarcted hearts. Its antiarrhythmic mechanisms are mediated by increases in ventricular effective refractory period and ARIs, decreases in S, and reductions in border zone electrophysiological heterogeneities. TEA improves parasympathetic function, which may independently underlie some of its observed antiarrhythmic mechanisms. This study provides novel insights into the antiarrhythmic mechanisms of TEA while highlighting its applicability to the clinical setting.
PubMed: 38939925
DOI: 10.1161/CIRCRESAHA.123.324058 -
Journal of Arrhythmia Jun 2024Patients with atrial fibrillation (AF) and heart failure (HF) have high stroke risk owing to left atrial dysfunction. However, anticoagulation is a concern in patients...
BACKGROUND
Patients with atrial fibrillation (AF) and heart failure (HF) have high stroke risk owing to left atrial dysfunction. However, anticoagulation is a concern in patients with high bleeding risk. We aimed to identify independent predictors of stroke in HF patients with AF.
METHODS
We retrospectively examined 320 patients (mean age 79 ± 12 years, 163 women) hospitalized with acute HF complicated by AF between January 2014 and December 2018. Patients were followed from admission until ischemic stroke or systemic embolism (SSE) onset or death or were censored at the last contact date or September 2023.
RESULTS
SSE occurred in 40 patients (median follow-up of 528 days). Multivariate Cox regression analysis identified age (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.00-1.07, = .034), direct oral anticoagulant (DOAC) use (HR 0.26, 95% CI 0.11-0.60, = .002), and early diastolic peak flow velocity to early diastolic peak annular velocity (E/e'; HR 1.05, 95% CI 1.02-1.08, < .001) to be independent predictors of SSE, whereas left atrial reservoir strain was not. After determining an appropriate E/e' cutoff by receiver-operating characteristic curve analysis and adjusting the multivariate Cox model, E/e' ≥17.5 (HR 3.30, 95% CI 1.56-6.83, = .001) independently predicted SSE. The results were consistent with no interaction in the subanalysis except for gender.
CONCLUSION
Elderly patients not on DOACs with elevated E/e' may be at higher risk of stroke, suggesting that DOACs should be the first choice for patients with elevated E/e' and aggressive additional prophylaxis and careful follow-up are needed.
PubMed: 38939759
DOI: 10.1002/joa3.13031 -
JACC. Advances May 2024It is not known whether the transition from obesity and severe obesity, as 2 different metabolic disease entities, affect flow-mediated and, thus, endothelium-dependent...
BACKGROUND
It is not known whether the transition from obesity and severe obesity, as 2 different metabolic disease entities, affect flow-mediated and, thus, endothelium-dependent epicardial vasodilation.
OBJECTIVES
The purpose of this study was to investigate the effect of obesity and severe obesity on flow-mediated epicardial vasomotion with positron emission tomography/computed tomography-determined longitudinal decrease in myocardial blood flow (MBF) from the base-to-apex direction of the left ventricle or gradient.
METHODS
N-ammonia positron emission tomography/computed tomography evaluated global MBF during pharmacologically induced hyperemia and at rest for assessment of coronary microvascular function. In addition, the Δ longitudinal MBF gradient (hyperemia minus rest) was determined. Patients were then grouped according to the body mass index (BMI) into normal weight (NW) (BMI 20.0-24.9 kg/m, n = 27), overweight (OW) (BMI 25.0-29.9 kg/m, n = 29), obesity (OB) (BMI 30.0-39.9 kg/m, n = 53), and severe obesity (morbid obesity: BMI ≥40 kg/m, n = 43).
RESULTS
Compared to NW, left ventricular Δ longitudinal MBF gradient progressively declined in OW and OB (0.04 ± 0.09 mL/g/min vs -0.11 ± 0.14 mL/g/min and -0.15 ± 0.11 mL/g/min; ≤ 0.001, respectively) but not significantly in SOB (-0.01 ± 0.11 mL/g/min, = 0.066). Regadenoson-induced global hyperemic MBF was lower in OB than in NW (1.88 ± 0.40 mL/g/min vs 2.35 ± 0.32 mL/g/min; ≤ 0.001), while comparable between NW and SOB (2.35 ± 0.32 mL/g/min vs 2.26 ± 0.40 mL/g/min; = 0.302). The BMI of the study population was associated with the Δ longitudinal MBF gradient in a U-turn fashion (r = 0.362, standard error of the estimate = 0.124; < 0.001).
CONCLUSIONS
Increased body weight associates with abnormalities in coronary circulatory function that advances from an impairment flow-mediated, epicardial vasodilation in overweight and obesity to coronary microvascular dysfunction in obesity, not observed in severe obesity. The U-turn of flow-mediated epicardial vasomotion outlines obesity and severe obesity to affect epicardial endothelial function differently.
PubMed: 38939628
DOI: 10.1016/j.jacadv.2024.100936 -
JACC. Advances Feb 2024Previous studies have linked cardiovascular risk factors during midlife to cognitive function in later life. However, few studies have looked at the association between...
BACKGROUND
Previous studies have linked cardiovascular risk factors during midlife to cognitive function in later life. However, few studies have looked at the association between cardiac function, brain structure, and cognitive function and even less have included diverse middle-aged populations.
OBJECTIVES
The objective of this study was to determine associations between cardiac and brain structure and function in a multiethnic cohort of middle-aged adults.
METHODS
A cross-sectional study was conducted in participants of the Dallas Heart Study phase 2 (N = 1,919; 46% Black participants). Left ventricular (LV) mass, LV ejection fraction, LV concentricity, and peak systolic strain (LV E) were assessed by cardiac magnetic resonance imaging. White matter hyperintensities (WMH) volume was measured by fluid attenuated inversion recovery magnetic resonance imaging. The Montreal Cognitive Assessment was used to measure cognitive functioning. Associations between cardiac and brain measures were determined using multivariable linear regression after adjusting for cardiovascular risk factors, education level, and physical activity.
RESULTS
LV ejection fraction was associated with total Montreal Cognitive Assessment score (β = 0.06 [95% CI: 0.003-0.12], = 0.042) and LV E was associated with WMH volume (β = 0.08 [95% CI: 0.01-0.14], = 0.025) in the overall cohort without significant interaction by race/ethnicity. Higher LV mass and concentricity were associated with larger WMH volume in the overall cohort (β = 0.13 [95% CI: 0.03-0.23], = 0.008 and 0.10 [95% CI: 0.03-0.17], = 0.005). These associations were more predominant in Black than White participants (β = 0.17 [95% CI: 0.04-0.30] vs β = -0.009 [95% CI: -0.16 to 0.14], = 0.036 and β = 0.22 [95% CI: 0.13-0.32] vs β = -0.11 [95% CI: -0.21 to -0.01], < 0.0001, for LV mass and concentricity, respectively).
CONCLUSIONS
Subclinical cardiac dysfunction indicated by LVEF was associated with lower cognitive function. Moreover, LV mass and concentric remodeling were associated with higher WMH burden, particularly among Black individuals.
PubMed: 38939405
DOI: 10.1016/j.jacadv.2023.100777