APOE ε4 carriage associates with improved myocardial performance from adolescence to older age.

BACKGROUND: Although APOE ε4 allele carriage confers a risk for coronary artery disease, its persistence in humans might be explained by certain survival advantages (antagonistic pleiotropy). METHODS: Combining data from ~ 37,000 persons from three older age British cohorts (1946 National Survey of Health and Development [NSHD], Southall and Brent Revised [SABRE], and UK Biobank) and one younger age cohort (Avon Longitudinal Study of Parents and Children [ALSPAC]), we explored whether APOE ε4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional metrics by echocardiography and cardiovascular magnetic resonance (CMR). RESULTS: Compared to the non-APOE ε4 group, APOE ε4 carriers had similar cardiac phenotypes in terms of LV ejection fraction, E/e', posterior wall and interventricular septal thickness, and LV mass. However, they had improved myocardial performance resulting in greater LV stroke volume generation per 1 mL of myocardium (higher myocardial contraction fraction). In NSHD (n = 1467) and SABRE (n = 1187), ε4 carriers had a 4% higher MCF (95% CI 1-7%, p = 0.016) using echocardiography. Using CMR data, in UK Biobank (n = 32,972), ε4 carriers had a 1% higher MCF 95% (CI 0-1%, p = 0.020) with a dose-response relationship based on the number of ε4 alleles. In addition, UK Biobank ε4 carriers also had more favorable radial and longitudinal strain rates compared to non APOE ε4 carriers. In ALSPAC (n = 1397), APOE ε4 carriers aged < 24 years had a 2% higher MCF (95% CI 0-5%, p = 0.059). CONCLUSIONS: By triangulating results in four independent cohorts, across imaging modalities (echocardiography and CMR), and in ~ 37,000 individuals, our results point towards an association between ε4 carriage and improved cardiac performance in terms of LV MCF. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed to the pleiotropic effects APOE ε4 carriage that might collectively explain its persistence in human populations.

ZBTB20 Regulates SERCA2a Activity and Myocardial Contractility Through Phospholamban.

BACKGROUND: Intracellular Ca2+ cycling determines myocardial contraction and relaxation in response to physiological demands. SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a) is responsible for the sequestration of cytosolic Ca2+ into intracellular stores during cardiac relaxation, and its activity is reversibly inhibited by PLN (phospholamban). However, the regulatory hierarchy of SERCA2a activity remains unclear. METHODS: Cardiomyocyte-specific ZBTB20 knockout mice were generated by crossing ZBTB20flox mice with Myh6-Cre mice. Echocardiography, blood pressure measurements, Langendorff perfusion, histological analysis and immunohistochemistry, quantitative reverse transcription-PCR, Western blot analysis, electrophysiological measurements, and chromatin immunoprecipitation assay were performed to clarify the phenotype and elucidate the molecular mechanisms. RESULTS: Specific ablation of ZBTB20 in cardiomyocyte led to a significant increase in basal myocardial contractile parameters both in vivo and in vitro, accompanied by an impairment in cardiac reserve and exercise capacity. Moreover, the cardiomyocytes lacking ZBTB20 showed an increase in sarcoplasmic reticular Ca2+ content and exhibited a remarkable enhancement in both SERCA2a activity and electrically stimulated contraction. Mechanistically, PLN expression was dramatically reduced in cardiomyocytes at the mRNA and protein levels by ZBTB20 deletion or silencing, and PLN overexpression could largely restore the basal contractility in ZBTB20-deficient cardiomyocytes. CONCLUSIONS: These data point to ZBTB20 as a fine-tuning modulator of PLN expression and SERCA2a activity, thereby offering new perspective on the regulation of basal contractility in the mammalian heart.

Co-exposure to sodium hypochlorite and cadmium induced locomotor behavior disorder by influencing neurotransmitter secretion and cardiac function in larval zebrafish.

Sodium hypochlorite (NaClO) and cadmium (Cd) are widely co-occurring in natural aquatic environment; however, no study has been conducted on effects of their combined exposure on aquatic organisms. To assess effects of exposure to NaClO and Cd in zebrafish larvae, we designed six treatment groups, as follows: control group, NaClO group (300 µg/L), 1/100 Cd group (48 µg/L), 1/30 Cd group (160 µg/L), NaClO+1/100 Cd group, and NaClO+1/30 Cd group analyzed behavior, neurological function and cardiac function. Results revealed that exposure to 1/30 Cd and NaClO+1/30 Cd caused abnormal embryonic development in larvae by altering body morphology and physiological indicators. Combined exposure to NaClO and 1/30 Cd affected the free-swimming activity and behavior of larvae in response to light-dark transition stimuli. Moreover, exposure to 1/30 Cd or NaClO+1/30 Cd resulted in a significant increase in tyrosine hydroxylase and acetylcholinesterase activities, as well as significant changes of various neurotransmitters. Lastly, exposure to 1/30 Cd or NaClO+1/30 Cd influenced the transcription of cardiac myosin-related genes and disturbed the myocardial contractile function. Altogether, our results suggested that combined exposure to NaClO and Cd induced oxidative damage in larvae, resulting in detrimental effects on nervous system and cardiac function, thus altering their swimming behavior.

Outcome prediction by myocardial external efficiency from 11 C-acetate positron emission tomography in cardiac amyloidosis.

AIMS: This study aimed to study the prognostic value of myocardial oxygen consumption (MVO2 ) and myocardial external efficiency (MEE) from 11 C-acetate positron emission tomography (PET) in cardiac amyloidosis (CA) patients. METHODS AND RESULTS: Forty-eight CA patients, both transthyretin (ATTR) and immunoglobulin light chain (AL) amyloidosis, and 20 controls were included. All subjects were examined with 11 C-acetate PET and echocardiography. MVO2 , forward stroke volume (FSV), and left ventricular mass (LVM) were derived from 11 C-acetate PET and used to calculate MEE. CA patients were followed for survival and the prognostic impact of clinical, echocardiographic, and 11 C-acetate PET parameters was analysed. MVO2 and MEE were reduced in CA compared with controls, but without significant difference between deceased and surviving CA patients. The ratio of 11 C-acetate PET-derived FSV and LVM was also reduced in CA and significantly lowered in deceased patients compared with survivors. In univariate analysis, New York Heart Association class, N-terminal pro-brain natriuretic peptide, and the 11 C-acetate PET parameters FSV/LVM and MEE were the strongest prognostic factors. Of the 11 C-acetate PET parameters, FSV/LVM was the strongest survival predictor with hazard ratio of 0.56 per 0.1 mL/g (95% confidence interval 0.39-0.81, P = 0.002) and independently prognostic in a multivariate model. MEE significantly separated deceased from surviving CA patients with the cut-off of 15.7% (P = 0.032). Survival was significantly shorter with FSV/LVM below 0.27 mL/g (P < 0.001), also when separating AL- and ATTR-CA. CONCLUSIONS: Reduced MEE was associated with shorter survival in CA patients, but FSV/LVM was the strongest survival predictor and the only independently prognostic 11 C-acetate PET parameter in multivariate analysis.

Current Targets and Future Directions of Positive Inotropes for Heart Failure.

While a congestive heart failure patient will ultimately need an assist device or even a replacement heart as the disease progresses, not every patient is qualified for such advanced therapy. Such patients awaiting better circulatory support benefit from positive inotropes in the meantime as palliative care. These agents are often prescribed in patients with acute decompensated heart failure, with reduced left ventricular ejection fraction and symptoms of organ dysfunction. Although positive inotropes, for example, digoxin, dobutamine, milrinone, levosimendan, etc., are successfully marketed and in use, a lot of their adverse effects, like arrhythmias, hypotension, and even sudden cardiac death, are rather encouraging further research on the development of novel positive inotropes. This review has investigated the molecular mechanisms of some of these adverse effects in terms of the proteins they target, followed by research on newer targets. Studies from 2013-2023 that have reported new small molecules with positive inotropic effects have been revisited in order to determine the progress made so far in drug discovery.

Myocardial Contraction Fraction is not a Predictor of Clinical Outcomes in Acute Systolic Heart Failure: A Brief Report.

Introduction: The utility of myocardial contraction fraction (MCF), a volumetric measure of myocardial shortening, has not been well evaluated in patients with systolic heart failure (SHF). Materials and Methods: A single-center, retrospective cohort study of all adults admitted with acute SHF from 2013 to 2018 at an academic medical center. A chart review was performed to identify key echocardiographic transthoracic echocardiogram (TTE), laboratory, and demographic characteristics. MCF was calculated based on M-mode measurements of estimated stroke volume and myocardial volume based on admission TTE. The primary outcome was 30-day combined all-cause readmission/mortality and 365-day all-cause mortality. Results: A total of 1282 patients were analyzed. The 30-day composite outcome occurred in 310 patients (24.2%), and all-cause death at 365 days occurred in 375 patients (29.3%). There was a weak correlation between the visually estimated ejection fraction (EF) and MCF (r = 0.356, P < 0.001). Neither MCF nor EF was associated with either component of the primary outcome. Other parameters on TTE that were associated with higher risk of primary outcome were higher tricuspid regurgitation (TR) velocity, larger left atrial (LA) diameter, and moderate or greater TR and mitral regurgitation (MR). Conclusion: Echocardiographic predictors of postdischarge adverse events among patients hospitalized with acute SHF include higher TR velocity, larger LA diameter, and at least moderate MR or TR. MCF does not correlate well with visually assessed EF among patients with acute SHF, and neither MCF nor EF provides prognostic information in this population.

Cardiac magnetic resonance for the early prediction of reverse left ventricular remodeling in patients with ST-segment elevation myocardial infarction.

OBJECTIVES: To evaluate the changes in cardiac magnetic resonance (CMR) characteristics and investigate the predictors of reverse left ventricular remodeling (r-LVR) in ST-segment elevation myocardial infarction (STEMI) patients. MATERIALS AND METHODS: Eighty-six STEMI patients (median 56 years) were retrospectively studied. The patients were divided into r-LVR and without r-LVR groups. CMR analysis included LV volume, infarct characteristics, and global and regional myocardial function. The strain and displacement were assessed by CMR-feature tracking. The predictors of r-LVR were analyzed by the logistic regression method. RESULTS: There were 37 patients in the r-LVR group and 49 patients in the without r-LVR group. At initial CMR, there was no difference in LV volume and global cardiac function between the two groups. However, the infarct zone radial and longitudinal displacements were higher in the r-LVR group (p < 0.05, respectively). At the second CMR, the r-LVR group showed higher LVEF, lower LV volume, and total enhanced mass (all p < 0.05). The infarct zone radial and circumferential strains and radial displacement were higher in the r-LVR group (all p < 0.05). The r-LVR group had better recovery of myocardial injury and function. Of note, microvascular obstruction (MVO) mass (odds ratio: 0.779 (0.613-0.989), p = 0.041) and infarct zone peak longitudinal displacement (PLD) (odds ratio: 1.448 (1.044-2.008), p = 0.026) were independent predictors of r-LVR. CONCLUSIONS: At initial CMR, there were no differences in global cardiac function between the two groups, but infarct zone displacements were higher in the r-LVR group. The r-LVR group had better recovery of cardiac function. In addition, MVO mass and infarct zone PLD were independent predictors of r-LVR. CLINICAL RELEVANCE STATEMENT: Our study assessed changes in cardiac structure, function, and tissue characteristics after STEMI by CMR, investigated the best predictors of r-LVR in STEMI patients, and laid the foundation for the development of new parameter-guided treatment strategies for STEMI patients. KEY POINTS: • At initial CMR, the reverse left ventricular remodeling (r-LVR) group had less myocardial damage and higher infarct zone displacement, but there were no differences in global function between the two groups. • Both groups showed recovery of myocardial injury and cardiac function over time, but the r-LVR group had less enhanced mass and better cardiac function compared to the without r-LVR group at the second CMR. • Microvascular obstruction mass and infarct zone peak longitudinal displacement by cardiac magnetic resonance feature-tracking were significant predictors of r-LVR in STEMI patients.

Clinical significance of myocardial contraction fraction in significant primary mitral regurgitation.

BACKGROUND: The optimal timing for mitral valve (MV) surgery in asymptomatic patients with primary mitral regurgitation (MR) remains a matter of debate. Myocardial contraction fraction (MCF) - the ratio of the left ventricular (LV) stroke volume to that of the myocardial volume - is a volumetric measure of LV myocardial shortening independent of size or geometry. AIM: To assess the relationship between MCF and outcome in patients with significant chronic primary MR due to prolapse managed in contemporary practice. METHODS: Clinical, Doppler-echocardiographic and outcome data prospectively collected in 174 patients (mean age 62 years, 27% women) with significant primary MR and no or mild symptoms were analysed. The impact of MCF< or ≥30% on cardiac events (cardiovascular death, acute heart failure or MV surgery) was studied. RESULTS: During an estimated median follow-up of 49 (22-77) months, cardiac events occurred in 115 (66%) patients. The 4-year estimates of survival free from cardiac events were 21±5% for patients with MCF <30% and 40±6% for those with ≥30% (P<0.001). MCF <30% was associated with a considerable increased risk of cardiac events after adjustment for established clinical risk factors, MR severity and current recommended class I triggers for MV surgery (adjusted hazard ratio: 2.33, 95% confidence interval: 1.51-3.58; P<0.001). Moreover, MCF<30% improved the predictive performance of models, with better global fit, reclassification and discrimination. CONCLUSIONS: MCF<30% is strongly associated with occurrence of cardiac events in patients with significant primary MR due to prolapse. Further studies are needed to assess the direct impact of MCF on patient management and outcomes.

Stroke volume and myocardial contraction fraction in transthyretin amyloidosis cardiomyopathy: A systematic review.

Background: Cardiac amyloidosis (CA) is primarily a restrictive cardiomyopathy in which the impairment of diastolic function is dominant. Despite this, the left ventricular ejection fraction (LVEF) may be depressed in the late stage of the disease, but it poorly predicts prognosis in the earlier phases and does not represent well the pathophysiology of CA. Many echocardiographic parameters resulted important diagnostic and prognostic tools in patients with CA. Stroke volume (SV) and myocardial contraction fraction (MCF) may be obtained both with echocardiography and cardiac magnetic resonance (MRI). They reflect many factors intrinsically related to the pathophysiology of CA and are therefore potentially associated with symptoms and prognosis in CA. Objectives: To collect and summarize the current evidence on SV and MCF and their clinical and prognostic role in transthyretin (TTR-CA). Methods and results: We performed a systematic review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. We searched the literature database for studies focusing on SV and MCF in patients with TTR-CA. We analysed the following databases: PUBMED, Cochrane Library, EMBASE, and Web of Science database. Fourteen studies were included in the review. Both SV and MCF have important prognostic implications and are related to mortality. Furthermore, SV is more related to symptoms than LVEF and predicts tolerability of beta-blocker therapy in TTR-CA. Finally, SV showed to be an excellent measure to suggest the presence of TTR-CA in patients with severe aortic stenosis. Conclusion: Stroke volume and MCF are very informative parameters that should be routinely assessed during the standard echocardiographic examination of all patients with TTR-CA. They carry a prognostic role while being associated with patients' symptoms. Systematic review registration: https://doi.org/10.17605/OSF.IO/ME7DS.

Hesperetin ameliorates ischemia/hypoxia-induced myocardium injury via inhibition of oxidative stress, apoptosis, and regulation of Ca2+ homeostasis.

Ischemia/hypoxia (I/H)-induced myocardial injury has a large burden worldwide. Hesperetin (HSP) has a cardioprotective effect, but the molecular mechanism underlying this is not clearly established. Here, we focused on the protective mechanisms of HSP against I/H-induced myocardium injury. H9c2 cardiomyocytes were challenged with CoCl2 for 22 h to imitate hypoxia after treatment groups received HSP for 4 h. The viability of H9c2 cardiomyocytes was evaluated, and cardiac function indices, reactive oxygen species, apoptosis, mitochondrial membrane potential (MMP), and intracellular Ca2+ concentration ([Ca2+ ]i ) were measured. L-type Ca2+ current (ICa-L ), myocardial contraction, and Ca2+ transients in isolated ventricular myocytes were also recorded. We found that HSP significantly increased the cell viability, and MMP while significantly decreasing cardiac impairment, oxidative stress, apoptosis, and [Ca2+ ]i caused by CoCl2 . Furthermore, HSP markedly attenuated ICa-L , myocardial contraction, and Ca2+ transients in a concentration-dependent manner. Our findings suggest a protective mechanism of HSP on I/H-induced myocardium injury by restoring oxidative balance, inhibiting apoptosis, improving mitochondrial function, and reducing Ca2+ influx via L-type Ca2+ channels (LTCCs). These data provide a new direction for HSP applied research as a LTCC inhibitor against I/H-induced myocardium injury.

Improved Physical Function After Cardiac Contractility Modulation Therapy in 10 Patients With Chronic Heart Failure.

BACKGROUND: A new generation of therapeutic devices has expanded the options for managing advanced heart failure. We examined the outcomes of cardiac contractility therapy in a series of 10 patients with chronic heart failure. METHODS: Ten patients with chronic heart failure were nonrandomly selected to receive cardiac contractility modulation therapy. Hemodynamics, left ventricular ejection fraction, functional capacity, and clinical outcomes were evaluated at baseline and after 6 months of therapy. RESULTS: Eight male and 2 female patients (mean [SD] age, 63.4 [9.4] years) received cardiac contractility modulation therapy. Between baseline and 6-month follow-up, mean (SD) left ventricular ejection fraction improved from 27.1% (4.18%) to 35.1% (9.89%), New York Heart Association class declined from 3.9 (0.32) to 2.44 (0.52), and 6-minute walk test distance increased from 159.2 (93.79) m to 212.4 (87.24) m. Furthermore, the mean (SD) number of hospital admissions within the 6 months before cardiac contractility modulation therapy was 2.4 (2.27) compared with 1 (1.52) during the 6 months after therapy. CONCLUSION: Cardiac contractility modulation therapy improved physical functioning and reduced hospital admissions in these patients.

Strain Magnitude Assessed at Rest and During Stress Echocardiography in Patients with Normal Coronary Flow Reserve

Abstract Background Coronary flow and myocardial contractile performance assessed by strain magnitude increase during a dobutamine stress echocardiogram (DSE). Normal coronary flow reserve (CFR) can be attained upon completion of a DSE at age-predicted maximum heart rate (HR) (HRmax = 220 - age)] or submaximal HR [(0.85) HRmax] or before completion (early CFR). Objective To ascertain the association between delta strain and HR in patients with early normal CFR. Methods This prospective study included patients whose normal CFR was obtained before the DSE was completed. Percentage of resting HR (%HRrest) = [(HRrest ÷ HRmax) 100]% and %HR CFR = [(HR at the time of CFR attainment) ÷ (HRmax) 100]% were recorded. Strain was assessed in the left ventricular region of interest, and delta strain was calculated as the difference between the measures obtained at HRrest and after the DSE was completed. Strain agreement analysis for HRrest, %HRrest, and %HR CFR was performed using the kappa coefficient. The Shapiro-Wilk test was used to assess data normality, and the Mann-Whitney test was used to compare the groups. A p-value < 0.05 was considered statistically significant. Results Strain measured -23.3% ± 4.3% at baseline and -31.1% ± 4.9% during the DSE. In delta strain > 8 absolute points, the ROC curves showed an area under the curve of 0.874 ± 0.07 for %HRrest (p = 0.001) and an area under the curve of 0.862 ± 0.07 for %HR CFR (p = 0.001). In delta strain > 8 points, %HRrest ≤ 42.6% of HRmax and %HR CFR ≤ 62.5% of HRmax showed an accuracy of 82.9% and 79.8%, respectively. Conclusion In this study, lower HRrest and HR at the time of CFR attainment had a good association with better myocardial contractile performance, according to the change in strain magnitude.

Bromuconazole exposure induces cardiotoxicity and lipid transport disorder in larval zebrafish.

Bromuconazole (BRO), as one of the typical triazole fungicides, has not been reported on its effects on aquatic organisms. In this study, zebrafish embryos were used as experimental objects to evaluate the toxicity of BRO. In the acute embryo toxicity test, it was observed that the heart rate and growing development were affected by BRO in a concentration-dependent manner, and the half-lethal concentration (LC50) of BRO at 96 h post-fertilization (hpf) was about 11.83 mg/L. Then, low concentrations of BRO (50 ng/L, 0.075 mg/L, 0.3 mg/L, 1.2 mg/L), which were set according to the LC50 and environmental related concentrations, were used to analyze the toxic effects on the different endpoints in larval zebrafish. Interestingly, the transcriptomic analysis found that most different expressed genes (DEGs) could be focused on the pathways of lipid metabolism, myocardial function, glycometabolism, indicating that heart function and lipid metabolism in larval zebrafish were disrupted by BRO. For supporting this idea, we re-exposed the transgenic zebrafish and WT zebrafish embryos, proved that BRO caused damage to heart development and lipid transport on morphological and genetic level, which was consistent with transcriptomic results. In addition, BRO exposure caused oxidative damage in the larvae. Taken together, BRO exposure could affect the myocardial contraction function and lipid transport in larval zebrafish, accompanied by disturbances in the level of oxidative stress, which was of great significance for improving the biotoxicological information of BRO.

Reserva contráctil por fracción de eyección sola, o con elastancia. ¿Cuál es el mejor predictor de eventos luego de un Eco Estrés sin isquemia? / Contractile Reserve by Left Ventricular Ejection Fraction Alone, o Considering Elastance. ¿Which is the Best Predictor of Events After a Stress Echo Without Ischemia?

RESUMEN Introducción: El comportamiento de la fracción de eyección del ventrículo izquierdo (FEVI) durante el ejercicio se utiliza para medir la reserva contráctil (RC). La RC medida por elastancia podría tener mayor valor pronóstico. Objetivo: Establecer si la medición de la RC por elastancia añade valor pronóstico a largo plazo en relación al comportamiento aislado de la FEVI en pacientes con un Eco Estrés sin isquemia miocárdica. Material y métodos: Estudio retrospectivo, realizado en 904 pacientes con Eco Estrés con ejercicio sin isquemia. Se valoró la RC por FEVI y por elastancia. Se dividieron en 2 grupos: Grupo 1: RC por FEVI presente (a su vez este grupo se dividió en 2 subgrupos: Grupo 1 A, RC con elastancia presente y Grupo 1B: ausencia de RC por elastancia), y Grupo 2: pacientes con ausencia de RC por FEVI. El seguimiento fue de 17,7 ± 5,4 meses. Se consideraron como eventos: muerte, infarto agudo de miocardio (IAM), accidente cerebrovascular (ACV) y/o internación de causa cardiovascular. Resultados: Del total del Grupo 1 (536 pacientes), 200 (37,3%) se incluyeron en el Grupo 1A y 336 (62,7%) en el Grupo 1B. En el Grupo 2, se incluyeron 368 pacientes. En el seguimiento, los pacientes del Grupo 2 tuvieron más eventos, 30 (8,1%) vs. 22 (2,6%) (HR 3,14, IC95% 1,95-5,9, log rank test p<0,001). Dentro del G1, los pacientes del Grupo 1B presentaron más eventos: 18 (5,3%) vs 4 eventos (2%) (HR 2,46 IC95% 1,06-7,3, log rank test p<0,05). En el modelo de regresión, la elastancia fue la única variable predictora de eventos (HR 3,2, IC95% 1,83-5,6, p<0,001). Conclusiones: En el Eco Estrés ejercicio negativo para isquemia, el comportamiento de la RC evaluada por elastancia permitió identificar un subgrupo de peor pronóstico a largo plazo en pacientes con comportamiento normal de la FEVI.

ABSTRACT Background: The behavior of left ventricular ejection fraction (LVEF) during exercise is used to measure contractile reserve (CR). CR measured by elastance could have greater prognostic value. Objective: To establish whether the measurement of CR by elastance adds long-term prognostic value to CR measured by LVEF in patients with a Stress Echo without myocardial ischemia. Material and methods: Retrospective study, carried out in 904 patients with an exercise Stress Echo without ischemia. CR was assessed by LVEF and by elastance. Patients were divided into 2 groups: Group 1: presence of CR by LVEF (in turn this group was divided into 2 subgroups: Group 1A, CR with elastance present, and Group 1B: absence of CR by elastance), and Group 2: patients with absence of CR by LVEF. The follow-up was 17,7 ± 5,4 months. Outcomes considered were death, acute myocardial infarction (AMI), stroke, and cardiovascular hospitalization. Results: 536 patients were included in Group 1, 200 (37,3 %) in Group 1A and 336 (62,7%) in Group 1B. In Group 2, 368 patients were included. At follow-up, patients in Group 2 had more events, 30 (8.1%) vs. 22 (2.6%) (HR 3.14, 95% CI 1.95-5.9, log rank test p <0.001). Within G1, patients in Group 1B presented more events: 18(5.3%) vs 4 (2%) (HR 2.46 CI 95% 1.06-7.3, log rank test p <0.05). In the regression model, CR assessed by LVEF and additionally by elastance was the only significant outcome predictor (HR 3.2, 95% CI 1.83-5.6, p <0.001). Conclusions: In an exercise Stress Echo negative for ischemia, CR behavior evaluated by elastance allowed us to identify a subgroup with a worse long-term prognosis in patients with normal LVEF response.

Echocardiographic assessment of cardiovascular function and clinical outcomes in liver transplant recipients.

BACKGROUND & AIMS: Cardiovascular disease contributes to a high rate of morbidity and mortality after liver transplantation (LT). However, the progression of cardiac function and cardiac remodeling in LT recipients remains poorly understood. This study sought to evaluate the progression of cardiac function and structure in LT recipients and identify independent predictors of prognosis using echocardiography. METHODS: From 2009 to 2019, 178 adult LT recipients at a tertiary academic transplant center were retrospectively studied. Transthoracic echocardiograms 1-year pre- and post-LT were assessed. Primary outcomes were progression of systolic and diastolic function. Secondary outcomes included left ventricular remodeling, all-cause mortality, and heart failure readmission post-LT. Subgroup analyzes were performed for etiology of native liver disease. A multivariable model was constructed to examine independent predictors of outcomes. RESULTS: Systolic function significantly worsened, with reduction in stroke volume (45-37 ml/m2 , p < .001), left ventricular ejection fraction (LVEF) (65%-62%, p < .001) and cardiac index (3.00-2.60 L/min/m2 , p < .001). Conversely, there were significant improvements in diastolic indices, including tricuspid regurgitation Vmax (228-215 cm/s, p = .017), left atrial volume index (LAVI) (32-26 ml/m2 , p < .001) and right ventricular systolic pressure (RVSP) (31-28 mmHg, p = .001). Additionally, patients had increased relative wall thickness (RWT) (p < .001) and decreased left ventricular end-diastolic dimension/body surface area (p < .001) post-LT. The independent predictors for all-cause mortality and heart failure were increased pre-LT mitral annular early diastolic velocity (HR 1.11, CI 1.02-1.22, p = .018), LAVI (HR 1.06, CI 1.02-1.11, p = .007) and decreased LVEF (HR .89, CI .82-.97, p = .006). The effect of non-alcoholic steatohepatitis on cardiovascular outcomes post-LT was largely comparable to that of Hepatitis B. CONCLUSION: This study showed reduced systolic and improved diastolic function in LT recipients and highlighted the utility of pre-LT echocardiogram in the prognostication and risk stratification of LT candidates.

Effects of Hyperthyroidism on Contractility and Na+/Ca2+ Exchanger Activity in the Isolated Papillary Muscle of Rats

Abstract Background: Hyperthyroidism (Hy) is an endocrine disorder, in which the thyroid hormones markedly alter the cardiac function. Increased myocardial contractility and cardiac output, improvement in diastolic relaxation, changes in electrical activity, increments in ventricular mass, and arrhythmias have been reported. However, the influences of thyroid hormones upon molecular mechanisms of cardiac functions have not yet been fully understood. Objectives: To evaluate changes in cardiac contractile parameters and the Na+/Ca2+ exchanger (NCX) function in induced hyperthyroid rats. Methods: Hy was induced by intraperitoneal injections of T3 (15 μg/100 g) for 10 days. Contractile parameters and NCX function were evaluated in the isolated papillary muscle. Data normality was confirmed by the Shapiro-Wilk test. The comparison between groups was performed through an unpaired Student's t-test. Results are expressed as mean ± SD. The accepted significance level was p < 0.05. Results: Our data revealed, in the Hy group, an increase of 30.98% in the maximum speed of diastolic relaxation (-284.64 ± 70.70 vs. -217.31 ± 40.30 mN/mm2/sec (p = 0.027)) and a boost of 149% in the NCX function in late phase of relaxation (20.17 ± 7.90 vs. 50.22 ± 11.94 minutes (p = 0.002)), with no changes in the maximum twitch force (p = 0.605) or maximum speed of systolic contraction (p = 0.208) when compared to the control. Conclusion: The improvement in relaxation parameters is hypothetically attributed to an increase in Sarco-Endoplasmic Reticulum Ca2+ATPase isoform 2 (SERCA2) expression and an increased calcium flow through L-type channels that boosted the NCX function.

Effects of Short Term Adiponectin Receptor Agonism on Cardiac Function and Energetics in Diabetic db/db Mice.

Objective: Impaired cardiac efficiency is a hallmark of diabetic cardiomyopathy in models of type 2 diabetes. Adiponectin receptor 1 (AdipoR1) deficiency impairs cardiac efficiency in non-diabetic mice, suggesting that hypoadiponectinemia in type 2 diabetes may contribute to impaired cardiac efficiency due to compromised AdipoR1 signaling. Thus, we investigated whether targeting cardiac adiponectin receptors may improve cardiac function and energetics, and attenuate diabetic cardiomyopathy in type 2 diabetic mice. Methods: A non-selective adiponectin receptor agonist, AdipoRon, and vehicle were injected intraperitoneally into Eight-week-old db/db or C57BLKS/J mice for 10 days. Cardiac morphology and function were evaluated by echocardiography and working heart perfusions. Results: Based on echocardiography, AdipoRon treatment did not alter ejection fraction, left ventricular diameters or left ventricular wall thickness in db/db mice compared to vehicle-treated mice. In isolated working hearts, an impairment in cardiac output and efficiency in db/db mice was not improved by AdipoRon. Mitochondrial respiratory capacity, respiration in the presence of oligomycin, and 4-hydroxynonenal levels were similar among all groups. However, AdipoRon induced a marked shift in the substrate oxidation pattern in db/db mice towards increased reliance on glucose utilization. In parallel, the diabetes-associated increase in serum triglyceride levels in vehicle-treated db/db mice was blunted by AdipoRon treatment, while an increase in myocardial triglycerides in vehicle-treated db/db mice was not altered by AdipoRon treatment. Conclusion: AdipoRon treatment shifts myocardial substrate preference towards increased glucose utilization, likely by decreasing fatty acid delivery to the heart, but was not sufficient to improve cardiac output and efficiency in db/db mice.