Durable left ventricular assist device explantation following recovery in paediatric patients: Determinants and outcome after explantation.

OBJECTIVES: Myocardial recovery in children supported by a durable left ventricular assist device is a rare, but highly desirable outcome because it could potentially eliminate the need for a cardiac transplant and the lifelong need for immunosuppressant therapy and the risk of complications. However, experience with this specific outcome is extremely limited. METHODS: All patients < 19 years old supported by a durable left ventricular assist device from the European Registry for Patients with Mechanical Circulatory Support database were included. Participating centres were approached for additional follow-up data after explantation. Associated factors for explantation due to myocardial recovery were explored using Cox proportional hazard models. RESULTS: The incidence of recovery in children supported by a durable left ventricular assist device was 11.7% (52/445; median duration of support, 122.0 days). Multivariable analyses showed body surface area (hazard ratio 0.229; confidence interval 0.093-0.565; P = 0.001) and a primary diagnosis of myocarditis (hazard ratio 4.597; confidence interval 2.545-8.303; P < 0.001) to be associated with recovery. Left ventricular end-diastolic diameter in children with myocarditis was not associated with recovery. Follow-up after recovery was obtained for 46 patients (88.5%). Sustained myocardial recovery was reported in 33/46 (71.7%) at the end of the follow-up period (28/33; >2 year). Transplants were performed in 6/46 (11.4%) (in 5 after a ventricular assist device was reimplanted). Death occurred in 7/46 (15.2%). CONCLUSIONS: Myocardial recovery occurs in a substantial portion of paediatric patients supported with durable left ventricular assist devices, and sustainable recovery is seen in around three-quarters of them. Even children with severely dilated ventricles due to myocarditis can show recovery. Clinicians should be attentive to (developing) myocardial recovery. These results can be used to develop internationally approved paediatric weaning guidelines.

The effects of an IV fluid bolus on mitral annular velocity and the assessment of diastolic function: a prospective non-randomized study.

BACKGROUND: Abnormal diastolic function is an independent predictor of adverse postoperative outcomes. Mitral annular tissue Doppler velocity (e') is a key parameter for assessing diastolic function. The purpose of this study was to confirm that an acute increase in preload did not significantly impact the intraoperative measurement of e' and secondarily evaluate the impact of this acute intravascular volume increase on the clinical assessment of diastolic function using a previously described simplified algorithm. METHODS: This was a prospective, non-randomized study in adult patients undergoing elective cardiac surgeries requiring transesophageal echocardiographic monitoring, arterial pressure and Swan-Ganz catheter placements as part of the surgical procedure. Following baseline echocardiographic and hemodynamic measurements, 500 ml of crystalloid solution was infused over 10 min. Hemodynamic and echocardiographic measurements were repeated 5 min after fluid administration. RESULTS: Complete data sets were available from 84 of the 100 patients who were enrolled in this study. There was no significant change in the values of e'. The average baseline was 7.8 ± 2.0 cm/s (95%CI: 7.4, 8.2) and 8.1 ± 2.4 (95%CI: 7.6, 8.6) following the fluid bolus (p = 0.10). All hemodynamic variables associated with increased intravascular volume (central venous pressure, pulmonary arterial pressures and stroke volume variation) changed significantly. The overall distribution of diastolic function grades did not change following fluid administration (p = 0.69). However, there were many individual patient differences. When using this simplified algorithm, functional grading changed in 35 patients. Thirty of these 35 changes were only a single grade shift. 22 patients had worse functional grading after fluid administration while 13 had improved grading. Nine patients with normal diastolic function at baseline demonstrated diastolic dysfunction after fluid administration while 6 patients with baseline dysfunction normalized following the fluid bolus. CONCLUSION: We confirmed that e' is a robust measurement that is reproducible in the intraoperative setting despite variable vascular volume loading conditions, however, the clinical assessment of diastolic function was still altered in 42% of the patients following an intravenous fluid bolus.

Association of left ventricular diastolic dysfunction with inflammatory activity, renal dysfunction, and liver-related mortality in patients with cirrhosis and ascites.

Left ventricular diastolic dysfunction (LVDD) is the predominant cardiac abnormality in cirrhosis. We investigated the association of LVDD with systemic inflammation and its impact on renal function, occurrence of hepatorenal syndrome (HRS) and survival in patients with cirrhosis and ascites. We prospectively enrolled 215 patients with cirrhosis and ascites. We evaluated the diagnosis and grading of LVDD by Doppler echocardiography, inflammatory markers, systemic hemodynamics, vasoactive factors, radioisotope-assessed renal function and blood flow, HRS development and liver-related mortality. LVDD was diagnosed in 142 (66%) patients [grade 2/3: n  = 61 (43%)]. Serum lipopolysaccharide-binding protein (LBP), plasma renin activity (PRA) and glomerular filtration rate (GFR) were independently associated with the presence of grade 2/3 LVDD and the severity of diastolic dysfunction. Serum tumor necrosis factor-α, cardiac output and plasma noradrenaline were also independently associated with the presence of grade 2/3 LVDD. The diastolic function marker E / e ' was strongly correlated with serum LBP ( r  = 0.731; P  < 0.001), PRA ( r  = 0.714; P  < 0.001) and GFR ( r  = -0.609; P  < 0.001) among patients with LVDD. The 5-year risk of HRS development and death was significantly higher in patients with grade 2/3 LVDD compared to those with grade 1 (35.5 vs. 14.4%; P  = 0.01 and 53.3 vs. 28.2%; P  = 0.03, respectively). The occurrence and severity of LVDD in patients with cirrhosis and ascites is closely related to inflammatory activity. Advanced LVDD is associated with baseline circulatory and renal dysfunction, favoring HRS development, and increased mortality.

Evaluating left atrial strain and left ventricular diastolic strain rate as markers for diastolic dysfunction in patients with mitral annular calcification.

BACKGROUND: Mitral annular calcification (MAC) poses many challenges to the evaluation of diastolic function using standard echocardiography. Left atrial (LA) strain and left ventricular early diastolic strain rate (DSr) measured by speckle-tracking echocardiography (STE) are emerging techniques in the noninvasive evaluation of diastolic function. We aim to evaluate the utility of LA strain and early DSr in predicting elevated left ventricular filling pressures (LVFP) in patients with MAC and compare their effectiveness to ratio of mitral inflow velocity in early and late diastole (E/A). METHODS: We included adult patients with MAC who presented between January 1 and December 31, 2014 and received a transthoracic echocardiogram (TTE) and cardiac catheterization with measurement of LVFP within a 24-h period. We used Spearman's rank correlation coefficient to assess associations of LA reservoir strain and average early DSr with LVFP. Receiver operating characteristic (ROC) curves were computed to assess the effectiveness of LA strain and DSr in discriminating elevated LVFP as a dichotomized variable and to compare their effectiveness with E/A ratio categorized according to grade of diastolic dysfunction. RESULTS: Fifty-five patients were included. LA reservoir strain demonstrated poor correlation with LVFP (Spearman's rho = 0.03, p = 0.81) and poor discriminatory ability for detecting elevated LVFP (AUC = 0.54, 95% CI 0.38-0.69). Categorical E/A ratio alone also demonstrated poor discriminatory ability (AUC = 0.53, 95% CI 0.39-0.67), and addition of LA reservoir strain did not significantly improve effectiveness (AUC = 0.58, 95% CI 0.42-0.74, p = 0.56). Average early DSr also demonstrated poor correlation with LVFP (Spearman's rho = -0.19, p = 0.16) and poor discriminatory ability for detecting elevated LVFP (AUC = 0.59, 95% CI 0.44-0.75). Addition of average early DSr to categorical E/A ratio failed to improve effectiveness (AUC = 0.62, 95% CI 0.46-0.77 vs. AUC = 0.54, 95% CI 0.39-0.69, p = 0.38). CONCLUSIONS: In our sample, LA reservoir strain and DSr do not accurately predict diastolic filling pressure. Further research is required before LA strain and early DSr can be routinely used in clinical practice to assess filling pressure in patients with MAC.

Cardiac monoamine oxidase-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control.

AIMS: A mechanistic link between depression and risk of arrhythmias could be attributed to altered catecholamine metabolism in the heart. Monoamine oxidase-A (MAO-A), a key enzyme involved in catecholamine metabolism and longstanding antidepressant target, is highly expressed in the myocardium. The present study aimed to elucidate the functional significance and underlying mechanisms of cardiac MAO-A in arrhythmogenesis. METHODS AND RESULTS: Analysis of the TriNetX database revealed that depressed patients treated with MAO inhibitors had a lower risk of arrhythmias compared with those treated with selective serotonin reuptake inhibitors. This effect was phenocopied in mice with cardiomyocyte-specific MAO-A deficiency (cMAO-Adef), which showed a significant reduction in both incidence and duration of catecholamine stress-induced ventricular tachycardia compared with wild-type mice. Additionally, cMAO-Adef cardiomyocytes exhibited altered Ca2+ handling under catecholamine stimulation, with increased diastolic Ca2+ reuptake, reduced diastolic Ca2+ leak, and diminished systolic Ca2+ release. Mechanistically, cMAO-Adef hearts had reduced catecholamine levels under sympathetic stress, along with reduced levels of reactive oxygen species and protein carbonylation, leading to decreased oxidation of Type II PKA and CaMKII. These changes potentiated phospholamban (PLB) phosphorylation, thereby enhancing diastolic Ca2+ reuptake, while reducing ryanodine receptor 2 (RyR2) phosphorylation to decrease diastolic Ca2+ leak. Consequently, cMAO-Adef hearts exhibited lower diastolic Ca2+ levels and fewer arrhythmogenic Ca2+ waves during sympathetic overstimulation. CONCLUSION: Cardiac MAO-A inhibition exerts an anti-arrhythmic effect by enhancing diastolic Ca2+ handling under catecholamine stress.

Evaluation of Intraoperative Left-Ventricular Diastolic Function by Myocardial Strain in On-Pump Coronary Artery Bypass Surgery.

OBJECTIVES: Left ventricular (LV) diastolic function strongly predicts outcomes after cardiac surgery, but there is no consensus about appropriate intraoperative assessment. Recently, intraoperative diastolic strain-based measurements assessed by transesophageal echocardiography (TEE) have shown a strong correlation with LV relaxation, compliance, and filling, but there are no reports about evaluation through the entire perioperative period. Therefore, the authors describe the intraoperative course of this novel assessment technique in patients who underwent coronary artery bypass grafting, and compare it with conventional echocardiographic measures and common grading algorithms of LV diastolic dysfunction (LVDD). DESIGN: Prospectively obtained data. SETTING: A single university hospital. PARTICIPANTS: Thirty adult patients scheduled for isolated on-pump coronary artery bypass grafting surgery with preoperative preserved left and right ventricular systolic function, without significant heart valve disease and pulmonary hypertension, and an uneventful intraoperative course were included. INTERVENTIONS: Transesophageal echocardiography was performed after induction of anesthesia (T1), after termination of cardiopulmonary bypass (T2), and after sternal closure (T3). Echocardiographic evaluation was performed in stable hemodynamic conditions, in sinus rhythm or atrial pacing, and vasopressor support with norepinephrine ≤0.1 µg/kg/min. MEASUREMENTS AND MAIN RESULTS: Strain-based measurements of peak longitudinal strain rate during isovolumetric relaxation (SR-IVR) and during early (SR-E) and late (SR-A) LV filling were assessed using EchoPAC v204 software (GE Vingmed Ultrasound AS, Norway). Evaluation of conventional echocardiographic parameters included transmitral Doppler measures of early (E) and late (A) LV filling, as well as lateral-tissue Doppler velocity assessed during early (e´) and late (a´) LV filling, tricuspid regurgitation, and left atrial dilatation. Evaluation and grading of LV diastolic function by myocardial strain was feasible in all included patients at all time points of assessment. Using conventional grading algorithms, however, a substantial number of patients could not be sufficiently graded, falling into an indeterminate zone and not reliably estimating LVDD (T1, 40%; T2, 33%; T3, 36%). There was significant impairment of LV diastolic function after bypass, as measured by SR-IVR (T1 v T2, 0.28 s-1 [IQR 0.23; 0.31) v 0.18 s-1 [IQR 0.14; 0.22]; p < 0.001), SR-E (T1 v T2, 0.95 ± 0.34 s-1v 1.28 ± 0.36 s-1; p < 0.001), and E/SR-IVR (T1 v T2, 2.3 ± 1.0 m v 4.5 ± 2.1 m; p < 0.001]. Conventional echocardiographic measures remained unchanged during the same period (E/A T1 v T2, 1.27 [IQR 0.94; 1.59] v 1.21 [IQR 1.03; 1.47] [p = 1] and E/e´ T1 v T2, 7.0 [IQR 5.3; 9.6] v 6.35 [IQR 5.7; 9.9] [p = 0.9]). There were no significant changes in the values of SR-IVR, SR-E, SR-A, E/SR-IVR, E/A, and E/e´ before and after sternal closure (T2 v T3). CONCLUSION: Intraoperative assessment of strain-based measurements of LV diastolic function and strain-based LVDD grading was feasible in this group of selected patients, whereas conventional parameters failed to describe LVDD sufficiently in a substantial number of patients. Diastolic strain-based measurements showed impairment of LV relaxation and compliance after bypass, which was not detected by conventional echocardiographic parameters. Therefore, diastolic myocardial strain analysis might be more sensitive in detecting myocardial diastolic dysfunction by TEE in the perioperative setting, with its dynamic changes of loading conditions, and might provide valuable and additional information on the perioperative changes of LV diastolic function.

The cardiomyocyte origins of diastolic dysfunction: cellular components of myocardial "stiffness".

The impaired ability of the heart to relax and stretch to accommodate venous return is generally understood to represent a state of "diastolic dysfunction" and often described using the all-purpose noun "stiffness." Despite the now common qualitative usage of this term in fields of cardiac patho/physiology, the specific quantitative concept of stiffness as a molecular and biophysical entity with real practical interpretation in healthy and diseased hearts is sometimes obscure. The focus of this review is to characterize the concept of cardiomyocyte stiffness and to develop interpretation of "stiffness" attributes at the cellular and molecular levels. Here, we consider "stiffness"-related terminology interpretation and make links between cardiomyocyte stiffness and aspects of functional and structural cardiac performance. We discuss cross bridge-derived stiffness sources, considering the contributions of diastolic myofilament activation and impaired relaxation. This includes commentary relating to the role of cardiomyocyte Ca2+ flux and Ca2+ levels in diastole, the troponin-tropomyosin complex role as a Ca2+ effector in diastole, the myosin ADP dissociation rate as a modulator of cross bridge attachment and regulation of cross-bridge attachment by myosin binding protein C. We also discuss non-cross bridge-derived stiffness sources, including the titin sarcomeric spring protein, microtubule and intermediate filaments, and cytoskeletal extracellular matrix interactions. As the prevalence of conditions involving diastolic heart failure has escalated, a more sophisticated understanding of the molecular, cellular, and tissue determinants of cardiomyocyte stiffness offers potential to develop imaging and molecular intervention tools.

Left Ventricular Morphology and Function in Normotensive, Metabolically Healthy Obese Individuals without Fatty Liver Disease.

BACKGROUND: Obesity is one of the major risk factors for the development of heart failure (HF), although the exact underlying mechanism remains unclear. In the clinical setting, assessing the impact of obesity on the cardiovascular system is difficult due to comorbidities. OBJECTIVES: The purpose of this study was to evaluate an independent influence of obesity on the left ventricular (LV) morphology and function. To eliminate hemodynamic and metabolic confounders, we performed an echocardiographic evaluation of severely obese but normotensive and metabolically healthy patients without fatty liver disease. METHODS: The patients were retrospectively selected from the cohort of 180 consecutive obese patients systematically evaluated with transthoracic echocardiography before bariatric surgery. Finally, 25 obese subjects, predominantly females, were evaluated with transthoracic echocardiography. Inclusion criteria were defined as absence of diabetes, hypertension, and hyperlipidemia, no use of medications and no hepatic steatosis on liver biopsy. They were matched with a control group of healthy subjects with normal body mass index. RESULTS: In obese patients, LV hypertrophy (LVH) (expressed as LV mass indexed for height in meters2.7) was significantly more frequent in the obese group (48 vs. 0%, p < 0.001). LV longitudinal systolic function measured by mitral annular systolic velocity was significantly lower in the obese group (S' 8.5 vs. 9.7 cm/s, p = 0.002). All studied indices of the LV diastolic function (E/A, mean E' and E/E' ratio) were impaired in obese subjects, even after adjustment for systolic blood pressure and heart rate (E/A 1.31 vs. 1.64, p < 0.001, E' mean 11 vs. 14.8 cm/s, p < 0.001, E/E' 7.5 vs. 6.4, p = 0.002 for obese vs. controls, respectively). CONCLUSIONS: LVH is significantly more common, and LV diastolic and longitudinal systolic function is significantly impaired in young, metabolically healthy, normotensive, severely obese individuals without fatty liver disease when compared to age and sex-matched lean subjects. These abnormalities may represent the independent effect of the obesity on the heart, which may contribute to the development the obesity-related HF in later life.

Diastolic function assessment with left atrial strain in long-term survivors of childhood acute lymphoblastic leukemia.

INTRODUCTION AND OBJECTIVES: Survivors of childhood cancer might be at increased risk of diastolic dysfunction at follow-up due to exposure to cardiotoxic treatment. Although assessment of diastolic function is challenging in this relatively young population, left atrial strain might provide a novel insight in this evaluation. Our aim was to examine diastolic function in a cohort of long-term survivors of childhood acute lymphoblastic leukemia by using left atrial strain and conventional echocardiographic parameters. METHODS: Long-term survivors who were diagnosed at a single center between 1985 and 2015 and a control group of healthy siblings were recruited. Conventional diastolic function parameters and atrial strain were compared, and the latter was measured during the 3 atrial phases: reservoir (PALS), conduit (LACS) and contraction (PACS). Inverse probability of treatment weighting was used to account for differences between the groups. RESULTS: We analyzed 90 survivors (age, 24.6±9.7 years, time since diagnosis 18 [11-26] years) and 58 controls. PALS and LACS were significantly reduced compared with the control group: 46.4±11.2 vs 52.1±11.7; P=.003 and 32.5±8.8 vs 38.2±9.3; P=.003, respectively. Conventional diastolic parameters and PACS were similar between the groups. The reductions in PALS and LACS were associated with exposure to cardiotoxic treatment in age- and sex-adjusted analysis (≥ moderate risk, low risk, controls): 45.4±10.5, 49.5±12.9, 52.1±11.7; Padj=.003, and 31.7±9.0, 35.2±7.5, 38.2±9.3; Padj=.001, respectively. CONCLUSIONS: Long-term childhood leukemia survivors showed a subtle impairment of diastolic function that was detected with atrial strain but not with conventional measurements. This impairment was more pronounced in those with higher exposure to cardiotoxic treatment.

Renal and cardiovascular prognostic significance of echocardiographic early diastolic mitral annular velocity in IgA nephropathy.

In chronic kidney disease (CKD), as in IgA nephropathy (IgAN), cardiovascular (CV) mortality and morbidity are many times higher than in the general population, and diastolic dysfunction (LVDD) has prognostic significance as well. Tissue Doppler Echocardiography (TDI) is another method for measuring myocardial contractility and determining diastolic dysfunction. 79 IgAN patients (age 46 ± 11 years) with CKD stages 1-3 were investigated and followed for 70 ± 28.7 months. Doppler echocardiography was used to measure the E (early) and A (late) waves, as well as the E wave deceleration time (EDT) during mitral inflow. TDI was used to measure early (Ea) and late (Aa) diastolic velocities (lateral and septal basal wall fragment average). From these, we calculated the E/Ea and Ea/Aa ratios. The primary combined endpoints were total mortality, major CV events, and end-stage renal disease, and the secondary endpoints were cardiovascular or renal (eGFR decreased below 15 ml/min/1.73 m2 or renal replacement therapy was started). Patients with decreased Ea (< 13 cm/s) had significantly more endpoints (20/42 vs. 3/37; p = 0.001) than patients with higher Ea (≥ 13 cm/s). The secondary renal endpoints were also significantly higher (p = 0.004). In a multivariate model, the eGFR showed independent correlation with the E/A ratio (r = 0.466; p < 0.01), EDT (r = - 0.270; p < 0.01), Ea/Aa ratio (r = 0.455; p < 0.01), and decreased Ea (r = 0.544; p < 0.01). Independent factors influencing Ea were only EDT by uni- and multivariate regression but age and albuminuria by logistic regression. Decreased Ea measured by TDI seems to be an eligible factor to predict the prognosis of IgA nephropathy. The decreased Ea may be a helpful parameter to identify high-risk CKD patients.

Intrinsic Wave Velocity Propagation: A Novel Parameter for Assessing the Effect of Anthracycline Chemotherapy Agents on Cardiac Diastolic Function in Breast Cancer Patients.

OBJECTIVE: Anthracycline chemotherapeutic agents have significant cardiotoxicity. The present study emphasized the effect of anthracycline chemotherapy drugs on left ventricular (LV) myocardial stiffness in breast cancer patients by measuring the intrinsic wave velocity propagation (IVP), and evaluating the potential clinical value of IVP in detecting early LV diastolic function impairment. METHODS: A total of 68 newly diagnosed breast cancer patients, who were treated with anthracycline-based chemotherapy, were analyzed. Transthoracic echocardiography was performed at baseline (T0), and after 1, 2, 3, 4 and 8 chemotherapeutic cycles (T1, T2, T3, T4 and T5, respectively). Then, the IVP, LV strain parameters [global longitudinal strain (GLS), longitudinal peak strain rate at systole (LSRs), longitudinal peak strain rate at early diastole (LSRe), longitudinal peak strain rate at late diastole (LSRa), and the E/LSRe ratio], and conventional echocardiographic parameters were obtained and further analyzed. A relative reduction of >15% in GLS was considered a marker of early LV subclinical dysfunction. RESULTS: Compared to the T0 stage, IVP significantly increased at the T1 stage. However, there were no significant changes in GLS, LSRs, or LSRe between the T0 and T1 stages. These parameters significantly decreased from the T2 stage. LSRa started to significantly decrease at the T5 stage, and the E/LSRe ratio started to significantly increase at the T3 stage (all P<0.05). At the T0 stage, IVP (AUC=0.752, P<0.001) had a good predictive value for LV subclinical dysfunction after chemotherapy. CONCLUSIONS: IVP is a potentially sensitive parameter for the early clinical assessment of anthracycline-related cardiac diastolic impairment.

Impact of maternal age and body mass index on the structure and function of the heart in newborns: a Copenhagen Baby Heart Study.

BACKGROUND: Maternal obesity and advanced age have been associated with an increased risk of structural congenital heart defects in the offspring. Whether these factors may also cause abnormalities in infant cardiac dimension and function is unknown. This study investigates whether maternal body mass index (BMI) and maternal age are associated with changes in left ventricular (LV) dimensions and function in the newborn. METHODS: Infants enrolled in the Copenhagen Baby Heart Study (CBHS), who were born at term, and contributed with a transthoracic echocardiography (TTE) within 60 days of birth were included. The exposure variables were prepregnancy maternal BMI (kg/m2) < 18.5; 18.5-24.9 (reference); 25-29.9; 30-34.9 and ≥ 35 and maternal age (years) < 25; 25-29; 30-34 (reference); 35-39 and ≥ 40. Outcomes were LV parameters ascertained by 2D-echocardiography. Associations between each maternal factor and infant LV parameters were analysed with either a linear model adjusted for the child's weight and length at birth, gestational age, sex, age at TTE, and maternal smoking, or a linear mixed model, further adjusted for random effects of analyst and month of analysis. Analyses investigating impact of maternal BMI were adjusted for maternal age, and vice versa. RESULTS: The study cohort included 24,294 infants. Compared with infants in the BMI reference group, infants born to women with a BMI ≥ 25 kg/m2 generally had smaller measures of LV internal diameters in end-diastole, reaching statistical significance for BMI 30-34.9 kg/m2 [-0.11 ± 0.04 mm, p = 0.01]. All groups of infants born to women with a BMI ≥ 25 kg/m2 had significantly smaller LV internal diameters in end-systole: BMI 25-29.9 kg/m2 [-0.04 ± 0.02 mm, p = 0.04], BMI 30-34.9 kg/m2 [-0.12 ± 0.03 mm, p = 0.001] and BMI ≥ 35 kg/m2 [-0.11 ± 0.05 mm, p = 0.03]. Compared with infants in the age reference group, infants born to women ≥ 40 years had significantly smaller LV internal diameters in end-diastole [-0.15 ± 0.04 mm, p = 0.001] and end-systole [-0.09 ± 0.04 mm, p = 0.009]. CONCLUSIONS: Systematic population-based echocardiography of infants showed that a maternal prepregnancy BMI ≥ 25 kg/m2 and maternal age ≥ 40 years were associated with smaller systolic and diastolic LV diameters. The long-term effects are unknown. CLINICAL TRIAL REGISTRATION: April 2016, Copenhagen Baby Heart, NCT02753348 .

Compensatory role of neuregulin-1 in diabetic cardiomyopathy.

Diabetes mellitus is a prevalent risk factor for congestive heart failure. Diabetic cardiomyopathy patients present with left ventricular (LV) diastolic dysfunction at an early stage, then systolic dysfunction as the disease progresses. The mechanism underlying the development of diabetic cardiomyopathy has not yet been fully understood. This study aimed to elucidate the mechanisms by which diastolic dysfunction precedes systolic dysfunction at the early stage of diabetic cardiomyopathy. We hypothesized that the downregulation of cardioprotective factors is involved in the pathogenesis of diabetic cardiomyopathy. LV diastolic dysfunction, but not systolic dysfunction, was observed in type-1 diabetes mellitus model mice 4 weeks after STZ administration (STZ-4W), mimicking the early stage of diabetic cardiomyopathy. Counter to expectations, neuregulin-1 (NRG1) was markedly upregulated in the vascular endothelial cell in the ventricles of STZ-4W mice. To clarify the functional significance of the upregulated NRG1, we blocked its receptor ErbB2 with trastuzumab (TRZ). In STZ-4W mice, TRZ significantly reduced the systolic function without affecting diastolic function and caused a more prominent reduction in Akt phosphorylation levels. These results indicate that the compensatory upregulated NRG1 contributes to maintaining the LV systolic function, which explains why diastolic dysfunction precedes systolic dysfunction at the early stage of diabetic cardiomyopathy.

Decreased diastolic hydraulic forces incrementally associate with survival beyond conventional measures of diastolic dysfunction.

Decreased hydraulic forces during diastole contribute to reduced left ventricular (LV) filling and heart failure with preserved ejection fraction. However, their association with diastolic function and patient outcomes are unknown. The aim of this retrospective, cross-sectional study was to determine the mechanistic association between diastolic hydraulic forces, estimated by echocardiography as the atrioventricular area difference (AVAD), and both diastolic function and survival. Patients (n = 5176, median [interquartile range] 5.5 [5.0-6.1] years follow-up, 1213 events) were selected from the National Echo Database Australia (NEDA) based on the presence of relevant transthoracic echocardiographic measures, LV ejection fraction (LVEF) ≥ 50%, heart rate 50-100 beats/minute, the absence of moderate or severe valvular disease, and no prior prosthetic valve surgery. NEDA contains echocardiographic and linked national death index mortality outcome data from 1985 to 2019. AVAD was calculated as the cross-sectional area difference between the LV and left atrium. LV diastolic dysfunction was graded according to 2016 guidelines. AVAD was weakly associated with E/e', left atrial volume index, and LVEF (multivariable global R2 = 0.15, p < 0.001), and not associated with e' and peak tricuspid regurgitation velocity. Decreased AVAD was independently associated with poorer survival, and demonstrated improved model discrimination after adjustment for diastolic function grading (C-statistic [95% confidence interval] 0.644 [0.629-0.660] vs 0.606 [0.592-0.621], p < 0.001) and E/e' (0.649 [0.635-0.664] vs 0.634 [0.618-0.649], p < 0.001), respectively. Therefore, decreased hydraulic forces, estimated by AVAD, are weakly associated with diastolic dysfunction and demonstrate an incremental prognostic association with survival beyond conventional measures used to grade diastolic dysfunction.

Plasma cystine/methionine ratio is associated with left ventricular diastolic function in patients with heart disease.

Elevated circulating homocysteine (Hcy) is a well-known risk factor for cardiovascular diseases (CVDs), including coronary artery disease (CAD) and heart failure (HF). It remains unclear how Hcy and its derivatives relate to left ventricular (LV) diastolic function. The aim of the present study was to investigate the relationship between plasma Hcy-related metabolites and diastolic dysfunction (DD) in patients with heart disease (HD). A total of 62 HD patients with preserved LV ejection fraction (LVEF ≥ 50%) were enrolled. Plasma Hcy and its derivatives were measured by liquid chromatography‒mass spectrometry (LC-MS/MS). Spearman's correlation test and multiple linear regression models were used to analyze the associations between metabolite levels and LV diastolic function. The cystine/methionine (CySS/Met) ratio was positively correlated with LV diastolic function, which was defined from the ratio of mitral inflow E and mitral e' annular velocities (E/e') (Spearman's r = 0.43, p < 0.001). When the subjects were categorized into two groups by E/e', the high-E/e' group had a significantly higher CySS/Met ratio than the low-E/e' group (p = 0.002). Multiple linear regression models revealed that the CySS/Met ratio was independently associated with E/e' after adjustment for age, sex, body mass index (BMI), diabetes mellitus, hypertension, chronic kidney disease (CKD),　hemoglobin, and lipid peroxide (LPO) {standardized ß (95% CI); 0.14 (0.04-0.23); p = 0.005}. Hcy, CySS, and Met did not show a significant association with E/e' in the same models. A high plasma CySS/Met ratio reflected DD in patients with HD.

Associations Between Coronary Artery Calcification and Left Ventricular Global Longitudinal Strain and Diastolic Parameters: the ELSA-Brasil Study.

Atherosclerosis burden can be evaluated in asymptomatic patients by measuring coronary artery calcification (CAC), whereas the global longitudinal strain (GLS) and diastolic function parameters (mitral E/e' ratio, septal e', and lateral e') are used to evaluate subclinical left ventricular (LV) dysfunction. We investigated whether subjects with CAC (CAC >0 Agatston units) would present with an impairment in LV functional parameters. Among the participants of the ELSA-Brasil cohort free of clinically prevalent cardiovascular disease who performed cardiac computed tomography and echocardiography within the study protocol, we tested whether those with CAC >0 presented with worse GLS and diastolic function parameters. CAC >0 was present in 203 of the 612 included participants (33.17%; age 51.4 ± 8.6 years, 52.1% women). Absolute CAC values did not correlate with GLS (ro = 0.07, p = 0.105) but did so with E/e' (ro = 0.19, p <0.001), septal e' (ro = 0.28, p <0.001), and lateral e' (ro = 0.30, p <0.001), with stronger correlations in men. Those with CAC >0 had worse mitral E/e' ratios (7.75 ± 0.13 vs 7.01 ± 0.09; p ≤0.001), septal e' (8.25 ± 0.15 vs 9.59 ± 0.11 cm/s; p <0.001), and lateral e' (10.13 ± 0.20 vs 11.99 ± 0.14 cm/s; p ≤0.001), respectively. However, these associations were not independent of diabetes, obesity, hypertension, smoking, and low-density lipoprotein cholesterol, persisting only as significant associations of CAC >0 with mitral E/e' ratio and septal e' in men. There is an association between subclinical coronary atherosclerosis and impaired LV functional parameters. These associations are more likely attributed to the presence of common cardiovascular risk factors in the general population. However, in men, it seems to exist as an independent association.

[Analysis of PKP2 gene variants in a child with Arrhythmogenic right ventricular cardiomyopathy].

OBJECTIVE: To explore the clinical and genetic characteristics of a child with Arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS: A 6-year-old boy with ARVC who had visited Fujian Provincial Children's Hospital on August 23, 2022 was selected as the study subject. Relevant clinical data were collected, and peripheral venous blood samples were collected from the child and his parents for genetic testing through whole exome sequencing (WES). Sanger sequencing was carried out for family verification, and pathogenicity analysis was conducted for the candidate variants. RESULTS: The child had exhibited clinical symptoms including systemic edema, generalized heart enlargement, universal reduction of interventricular septum and ventricular wall movement, reduced left ventricular diastolic and systolic function, and reduced right ventricular systolic function. WES revealed that the child has harbored compound heterozygous variants of the PKP2 gene, namely c.119_122del (p.Leu40ArgfsTer71) and c.1978G>A (p.Gly660Arg), which were verified by Sanger sequencing to be respectively inherited from his father and mother. The c.119_122del variant has not been recorded in the 1000 Genomes, gnomAD and ExAC databases, and was predicted to lead to truncation of the PKP2 protein by SWISS-MODEL and PyMOL online software and classified as likely pathogenic based on the guidelines jointly developed by the American College of Medical Genetics and Genomics (ACMG) and ClinGen. The c.1978G>A variant has also not been recorded in the 1000 Genomes, gnomAD and ExAC databases, and was predicted to be deleterious by online software including REVEL, SIFT, CADD, Mutation Taster, and PolyPhen-2. The amino acid encoded by the variant site was highly conserved among various species by analysis using T-coffee and ESPript v3.0 online servers. The variant may affect the protein function by SWISS-MODEL and PyMOL online server analysis, and was classified as likely pathogenic based on the guidelines jointly developed by the ACMG and ClinGen. CONCLUSION: The compound heterozygous variants of c.119_122del (p.Leu40ArgfsTer71) and c.1978G>A (p.Gly660Arg) of the PKP2 gene probably underlay the ARVC in this child. Above finding has broadened the spectrum of PKP2 gene variants and provided a reference for the diagnosis and genetic counseling.

A new assessment method for right ventricular diastolic function using right heart catheterization by pressure-volume loop.

Diastolic stiffness coefficient (ß) and end-diastolic elastance (Eed) are ventricular-specific diastolic parameters. However, the diastolic function of right ventricle had not been investigated sufficiently due to the lack of established evaluation method. We evaluated the validity of these parameters calculated using only data of right heart catheterization (RHC) and assessed it in patients with restrictive cardiomyopathy (RCM) and cardiac amyloidosis. We retrospectively analyzed 46 patients with heart failure who underwent RHC within 10 days of cardiac magnetic resonance (CMR). Right ventricular end-diastolic volume and end-systolic volume were calculated using only RHC data, which were found to be finely correlated with those obtained from CMR. ß and Eed calculated by this method were also significantly correlated with those derived from conventional method using CMR. By this method, ß and Eed were significantly higher in RCM with amyloidosis group than dilated cardiomyopathy group. In addition, the ß and Eed calculated by our method were finely correlated with E/A ratio on echocardiography. We established an easy method to estimate ß and Eed of right ventricle from only RHC. The method finely demonstrated right ventricular diastolic dysfunction in patients with RCM and amyloidosis.

A new indicator of contrast-induced nephropathy in patients undergoing elective coronary angiography: tissue doppler-derived E/(EA × SA) index.

OBJECTIVE: Hemodynamic instability plays an important role in the development of contrast-induced nephropathy (CIN), which is an important complication of coronary angiography. Left ventricular (LV) end-diastolic pressure (LVEDP) accurately reflects hemodynamic changes. In clinical practice, measuring LVEDP invasively presents some challenges and is not always accessible. This study aimed to investigate the relationship between tissue Doppler-derived early diastolic conduction velocity (E)/[early mitral annular diastolic velocity (Ea), × peak systolic annular velocity (Sa)] index, an important surrogate for LVEDP, and CIN in patients undergoing elective coronary angiography (ECA). PATIENTS AND METHODS: This retrospective study included 388 consecutive patients undergoing ECA. CIN was defined as a 25% or 0.5 mg/dL increase in serum creatinine compared to baseline values within 72 hours after ECA. Mehran score was calculated in all patients and systolic and diastolic functions were evaluated with Doppler echocardiography. RESULTS: The incidence of CIN was 9.7%. There was a positive correlation between LV EDP levels and LV E/(Ea × Sa) index (r = 0.691, p < 0.001). Higher LV E/(Ea × Sa) index (OR = 1.03, p < 0.001) and Mehran score (OR = 1.41, p < 0.001) were independent predictors of CIN. The threshold value of LV E/(Ea × Sa) index in predicting CIN was > 1.71 with 75.7% sensitivity and 84.3% specificity (AUC = 0.825). CONCLUSIONS: In patients undergoing ECA, the non-invasively measured E/(Ea × Sa) index can be used as a risk indicator for CIN.

Transcatheter tricuspid valve edge-to-edge repair after a heart transplant: a single-centre experience with a novel therapy†.

OBJECTIVES: Tricuspid regurgitation (TR) in patients who had heart transplants is associated with poor outcome. The increased risk for surgical and postoperative complications might be reduced in these vulnerable patients by transcatheter therapies. METHODS: All patients with a prior heart transplant (HTX) undergoing transcatheter edge-to-edge repair in the tricuspid position (T-TEER) were prospectively enrolled in an institutional registry. RESULTS: Seven patients who had heart transplants (5/7 female) at a mean age of 53 [48; 64] and median TRI-SCORE of 14 [7; 22] underwent T-TEER to treat symptomatic TR ≥ IV in an elective (n = 6) and urgent (n = 1) setting, respectively. The median time from HTX to T-TEER was 13 years. A total of 2 (n = 4) and 3 (n = 3) clips were implanted with a technical success in 6/7 (one single- device detachment). TR reduction was effective and durable within a median echocardiographic follow-up time of 10 months (TR baseline vs last follow-up: P = 0.03). Further, significant right ventricular remodelling (right ventricular end-diastolic diameter: 50 mm-36 mm, P = 0.02), decrease in the inferior vena cava diameter (24 mm-18 mm, P = 0.04) and in the gamma-glutamyl-transferase (255 U/l-159 U/l, P = 0.04) was found. Four of 7 patients were free of cardiovascular death (n = 1, 267 days after T-TEER), cardiac redo surgery (n = 1) and heart failure hospitalization (n = 2) and had no further clinical signs of right heart failure. CONCLUSIONS: T-TEER after HTX is feasible and effective regarding TR reduction in a short-term follow-up. The initial results may pave the way for a novel approach in TR management in patients having HTX.