Significant Diastolic Dysfunction Research Articles

Early Cardiac Dysfunction in Biopsy-proven Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) encompasses a range of diseases from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and has been linked to cardiovascular disease and sub-clinical cardiac remodeling. This paper presents a retrospective study of biopsy-proven NAFL and NASH to examine the differences in subclinical cardiac remodeling. Patients were recruited from an institutional repository of patients with liver-biopsy-confirmed NAFLD. Patients with a transthoracic echocardiogram (TTE) within 12 months of the liver biopsy were included. The parameters of the diastolic dysfunction were reviewed for the differences between NAFL and NASH as well as between the stages and grades of NASH. Thirty-three patients were included in the study, 17 with NAFL and 16 with NASH. The NASH patients were more likely to have lower platelets, higher AST, higher ALT, and higher rates of type 2 diabetes mellitus, coronary artery disease, and hypertension than the NAFL patients. The E/e' ratio on transthoracic echocardiogram was significantly higher in NASH compared to NAFL, advanced-stage NASH compared to early stage, and high-grade NASH compared to low-grade. The E/e' ratio was also significantly higher in NASH than NAFL in patients without diabetes mellitus. The presence of diastolic dysfunction trended toward significance. The other markers of diastolic dysfunction were similar. Logistic regression revealed a statistical association with E/e' and NASH. NASH patients had evidence of a higher E/e' ratio than NAFL, and there was a trend towards a significant diastolic dysfunction. Patients with NASH compared to NAFL should be closely monitored for signs and symptoms of cardiac dysfunction.

Імунно-запальні предиктори розвитку діастолічної дисфункції лівого шлуночка у хворих на ревматоїдний артрит в поєднанні з артеріальною гіпертензією

Hypertension is the most common concomitant disease in patients with rheumatoid arthritis. Diastolic dysfunction of left ventricle is an important predictor of chronic heart failure, which can be asymptomatic for a long time. Therefore, it is advisable to detect diastolic dysfunction of left ventricle as early as possible, which can slow the progression of chronic heart failure. The purpose of the study was to determine the value of lipid peroxidation, endothelial function and systemic inflammatory response markers for diagnostic of diastolic dysfunction of left ventricle and for diagnostic of pericardial effusion in patients with rheumatoid arthritis combined with hypertension. Materials and methods. 93 patients with rheumatoid arthritis in combination with stage II hypertension were studied. The ultrasound examination of heart was performed. The serum laboratory markers of lipid peroxidation, concentration of pro-inflammatory cytokines, markers of endothelial function were determined. Results and discussion. Signs of diastolic dysfunction of left ventricle were found in 79 patients and no signs of diastolic dysfunction were found in 14 patients. It was detected that there was a significant increase of concentration of asymmetric dimethylarginine by 16.3%, interleukin-1β by 35.3%, interleukin-10 by 24.3%, the ratio of interleukin-1β / interleukin-10 by 62.0%, C-reactive protein by 52.6% and there was a significant decrease of total nitric oxide metabolites by 36.9%, nitrires by 37.5% and nitrates by 37.0% in patients with signs of diastolic dysfunction of left ventricle compared to the patients without diastolic dysfunction of left ventricle (p <0.01). It was found that the levels of isolated double bonds, diene conjugates, diene ketones, schiff bases and malonic aldehyde in patients with diastolic dysfunction of left ventricle were significantly higher by 24.4%, 25.2%, 20.4%, 17.6% and 21.4% respectively compared to the corresponding markers in patients without signs of diastolic dysfunction of left ventricle (p <0.01). The levels of vitamin A, vitamin E and catalase in patients with diastolic dysfunction of left ventricle were significantly lower by 18.2%, 27.4% and 13.4% compared to the corresponding markers of patients with normal left ventricle diastolic function (p <0.01). The highest predictor value for the diagnostic of diastolic dysfunction of left ventricle was detected in interleukin-1β area under the ROC curve 0.882, sensitivity 72.15% and specificity 100%, 95% CI [0.798-0.939] at the optimal distribution point >9.67 pg/ml and in asymmetric dimethylarginine area under the ROC curve 0.879 sensitivity 75.95% and specificity of 100%, 95% CI [0.795-0.937] at the optimal distribution point >0.715 μmol/l. In 17 (18.28%) patients, the effusion in the pericardial cavity was detected. It was detected that there was a significant increase of isolated double bonds by 18.65%, diene conjugates by 19.73%, diene ketones by 25.25%, schiff bases by 20%, malonic aldehyde by 26.76% and there was a significant decrease of vitamin A by 38.4%, vitamin E by 55.4% and catalase by 37.2% in patients with effusion in the pericardial cavity. The significant increase of asymmetric dimethylarginine was detected by 25.25%, interleukin-1β – by 52.24%, interleukin-10 – by 15.76%, the ratio of interleukin-1β / interleukin-10 – by 38.86% and C-reactive protein – by 26.9% in patients with effusion in the pericardial cavity. In addition, patients with cavity effusion have significant decrease of nitric oxide metabolites by 25.0%, nitrires by 30.0% and nitrates by 11.11% compared to the patient without effusion. The highest predictor value for the detection of effusion in the pericardial cavity was found in asymmetric dimethylarginine area under the ROC curve 0.913, 95% CI area under the ROC curve [0.836-0.961] at the optimal distribution point >0.841 μmol/l, sensitivity 94.12% and specificity 85.53%. Conclusion. The markers, which have the highest prognostic value for diagnostic of diastolic dysfunction of left ventricle in patients with rheumatoid arthritis combined with hypertension, are interleukin-1β and asymmetric dimethylarginine. In addition, asymmetric dimethylarginine has the highest predictor value for detecting fluid in the pericardial cavity

Abstract P364: Liraglutide Protects Against Angiotensin-induced Diastolic Dysfunction And Is Associated With Altered Acetyl-coa Metabolism

Background: The mechanisms underlying diastolic dysfunction remain complicated and poorly understood. Previously implicated mechanisms include increased interstitial fibrosis and oxidative damage, altered calcium handling, and mitochondrial dysfunction. In this study, we investigate changes in the cardiac metabolic profile from mice with Angiotensin-II (Ang)-induced diastolic dysfunction. Because treatment with the GLP-1 agonist liraglutide (Lira) relieves Ang-induced diastolic dysfunction, we examined altered metabolites in Ang and Ang+Lira mice to identify metabolic pathways involved. Methods: 8-wk mice were implanted with Ang pumps (1000 ng/kg/min) +/- Lira (0.2 mg/kg/day) therapy for 4 wks and compared to sham mice. Baseline and 4-wk echocardiography was performed. Hearts were collected for RNA-sequencing, Western blot, histology, radiolabeled palmitate assay, and targeted metabolomics by liquid chromatography-mass spectrometry to assess metabolic changes. Results: After Ang treatment, mice had significant diastolic dysfunction but only mild hypertrophy based on echo and histologic measures and no evidence of systolic change. Compared to sham mice, Ang mice had reduced E/A (Sham, 2.67±0.40; Ang, 1.71±0.11; p<0.05) and peak reverse longitudinal strain rate (rLSR;Sham, 8.48±0.65/s; Ang, 6.081±0.33/s; p<0.05, consistent with diastolic dysfunction. Ang+Lira mice had improved E/A (3.57±0.50, p<0.01 vs. Ang) and rLSR (8.65±0.68/s, p<0.01 vs Ang). Targeted metabolomic analysis of hearts found significantly increased accumulation of Acetyl-CoA in Ang mice (peak area 0.14±0.02) compared to sham (0.04±0.02 ,p<0.05) that is restored by Lira therapy (0.02±0.01 ,p<0.05 vs sham and Ang). A radiolabeled palmitate oxidation assay found decreased palmitate oxidation in both Ang and Ang+Lira mice compared to sham, but interestingly, also demonstrated significantly lower acid soluble metabolite oxidation in the Ang+Lira mice vs. Ang alone. Conclusions: We found that Ang-treated mice accumulate myocardial Acetyl-CoA, suggesting a defect in TCA flux. Lira resolves the increase in Acetyl-CoA and improved measures of diastolic dysfunction. This data may implicate a novel metabolic pathway in the development of diastolic disease.

Pericardial Constriction and Myocardial Restriction in Pediatric Mulibrey Nanism: A Complex Disease With Diastolic Dysfunction

BackgroundMulibrey nanism (MUL) is a rare condition with profound growth delay. Congestive heart failure is a major determinant of prognosis. The aim was to delineate pericardial constriction and myocardial functional abnormalities in a pediatric MUL sample. MethodsA total of 23 MUL patients and 23 individually sex- and age-matched healthy control subjects were prospectively assessed in a cross-sectional study with echocardiography. ResultsClinical signs of heart failure were present in 7 MUL patients, with severe congestive heart failure in 2. Significant diastolic dysfunction, mainly related to constriction, was found in MUL patients without pericardiectomy (N = 18)—septal bounce, pronounced hepatic vein atrial reversal and right heart inflow–outflow variations, and decreased inferior vena cava collapse during respiration. The appearance of the pericardium was not different from that of control subjects. Longitudinal diastolic myocardial velocities were similar to those in control subjects, suggesting an absence of significant myocardial restriction. Right ventricular free wall longitudinal systolic strain and bilateral longitudinal myocardial systolic velocities were decreased in MUL patients, indicating mild biventricular systolic dysfunction. Myocardial motion abnormalities and persistent congestive heart failure were common (in 3 of 6) in MUL patients with a history of pericardiectomy. Cardiac dimensions were similar between MUL patients and control subjects when adjusting for body size, except for smaller biventricular volumes. ConclusionsMUL disease presents with significant constriction-related diastolic dysfunction and mild bilateral systolic dysfunction. Constriction–restriction assessments during follow-up could be of benefit in decision-making regarding pericardiectomy in MUL disease. Myocardial abnormalities were prevalent among MUL patients who had undergone pericardiectomy and are consistent with progression of myocardial disease in a significant proportion of patients.

Metabolic improvement with short-term, glucagon-like peptide-1 receptor agonist treatment does not improve cardiac diastolic dysfunction in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial.

To investigate if short-term treatment with liraglutide, a glucagon-like peptide-1 receptor agonist, improves left ventricular diastolic function. An investigator-initiated, double-blind, randomized, placebo-controlled trial on the effect of 18 weeks of treatment with liraglutide on diastolic function was assessed in patients with type 2 diabetes with signs of diastolic dysfunction (echo-Doppler determined E/e' ≥ 9 and/or lateral e' ≤ 10cm/s). Primary outcomes were improved left ventricle filling (the early peak filling rate [ePFR]) and left atrium ease of emptying (the passive emptying fraction [LAPEF ]), assessed by cardiac magnetic resonance imaging at rest and during chronotropic stress. Secondary outcomes included left ventricular and left atrial volumes and systolic function, measures of aortic stiffness and echocardiographic diastolic variables. Forty patients were randomized to liraglutide subcutaneously 1.8 mg/day (n=20) or placebo (n=20). Liraglutide reduced HbA1c (-0.47%, 95% CI [-0.88% to -0.06%] [-5.1, 95% CI {-9.7 to -0.62} mmol/mol]) and weight (-2.9, 95% CI [-4.6 to -1.2] kg); both P < .03. Liraglutide did not change ePFR at rest (-24 ± 60 vs. -6 ± 46 mL/s), during stress (2 ± 58 vs. -2 ± 38 mL/s), or the changes from rest to stress (12.9 ± 72.5 vs. 4.7 ± 104.0; all P > .05). LAPEF decreased with liraglutide during stress (-3.1% [-9.0%, 1.1%] vs. 1.0% [-2.9%, 6.1%]; P=.049), but no changes were evident at rest (-4.3% [-7.9%, 1.9%] vs. -0.6% [-3.1%, 2.2%]; P=.19), or for the changes from rest to stress (-1.7 ± 8.4 vs. 0.8 ± 8.2; P=.4). Secondary outcomes were unchanged by liraglutide. Short-term treatment with liraglutide did not improve left ventricular diastolic function, suggesting the cardioprotective effect is not exerted through the improvement in diastolic dysfunction.

Fibrosis biomarkers and global myocardial strain in the diagnosis and prediction of diastolic dysfunction in patients with myocardial infarction and preserved ejection fraction

Aim. To assess the correlation of fibrosis biomarkers with parameters of diastolic function (DF) in assessing global longitudinal strain in patients with ST-segment elevation myocardial infarction (STEMI) and preserved left ventricular ejection fraction (EF).Material and methods. We examined 50 patients (100%) with primary STEMI and preserved LVEF at the end of hospitalization. On the 1st day of MI, standard diagnostic investigations were carried out. On the 12th day, the serum concentration of procollagen type I carboxy-terminal propeptide (PICP), N-terminal propeptide of procollagen type III (PIIINP), and galectin-3 was determined, as well as echocardiography was performed to assess left ventricular DF. After 1 year, all participants underwent reassessment of PICP, PIIINP, and galectin-3 serum levels. Echocardiography was also performed with an assessment of DF and LV global longitudinal strain.Results. According to speckle-tracking echocardiography, LV global longitudinal strain was visualized in 30 patients (60%), who were included in the final analysis. In the rest of the patients (40%), the limitations did not allow the technique to be performed. During the hospitalization, signs of diastolic dysfunction (DD) were detected in 5 (16,6%) patients; after 1 year, their number increased by 7 (23,3%). During the 1-year follow-up, the total number of patients with echocardiographic signs of DD was 20 (67%). At the same time, global strain parameters indicated the presence of DD in 23 (77%) patients. However, comparison of the incidence of DD according to echocardiography and using the speckle-tracking technology did not show significant differences (p=0,283). Throughout the entire follow-up period, the concentration of the studied fibrosis markers significantly exceeded the control group values. We recorded associations of global strain parameters with biochemical markers of fibrosis and LV DF indicators.Conclusion. Fibrosis biomarkers (PICP, PIIINP, galectin-3), assessed in the subacute period of MI in patients with preserved EF, correlated with indicators of global myocardial strain, which indicates the potential value of their determination for predicting and detecting DD in the postinfarction period.

Signs of diastolic dysfunction are graded by serum testosterone levels in aging C57BL/6 male mice

We investigated whether maladaptive, age-associated changes in heart structure and function were linked to circulating testosterone levels. Male C57BL/6 mice had a gonadectomy (GDX) or sham surgery at 4 weeks and effects of GDX on the heart were examined with echocardiography. Serum testosterone was measured with ELISA. Left ventricular (LV) mass increased with age but was smaller in GDX mice than sham at 18 months (144.0 ± 8.7 vs 118.2 ± 11.9 mg; p = 0.009). The isovolumic relaxation time (IVRT) declined with age but was prolonged in GDX mice at 18 months (10.5 ± 0.8 vs 12.5 ± 0.5 msec, p = 0.008). Ejection fraction did not change with age or GDX, but E/A ratios were lower in GDX mice than controls at 18 months (1.6 ± 0.2 vs 1.3 ± 0.1, p = 0.021). When links between serum testosterone and cardiac parameters were examined longitudinally in 18−24-month-old mice, LV mass declined with decreasing testosterone (β = 37.70, p = 0.016), however IVRT increased as testosterone decreased (β=−2.69, p = 0.036). Since longer IVRT and lower E/A ratios are signs of diastolic dysfunction, low circulating testosterone may promote or exacerbate diastolic dysfunction in older males. These findings suggest that lower testosterone directly modifies heart structure and function to promote maladaptive remodeling and diastolic dysfunction in the aging heart.

Clinical relevance of spectral tissue Doppler-derived E/e′ in older patients with preserved ejection fraction

BackgroundThe E/e′ index measured in spectral tissue Doppler is included in the recommendations for the diagnosis by transthoracic Doppler echocardiography of left ventricular diastolic dysfunction and heart failure with preserved ejection fraction. While E/e′ is influenced by age in healthy individuals, no studies have evaluated this index in elderly patients. This study addressed the clinical relevance of E/e′ in assessment of left ventricular diastolic function in elderly patients with preserved ejection fraction and its relevance from both a diagnostic and prognostic perspective based on the existing literature. MethodsA total of 76 patients≥70years of age were prospectively included. The analysis of left ventricular diastolic function was adapted from the 2016 ASE/EACVI recommendations without consideration of E/e′. ResultsThe mean age was 85years. In all, 42 patients had moderate-to-severe diastolic dysfunction (elevated left atrial pressure). Mean E/e′ was significantly correlated with diastolic function (r=0.58, P<0.001). Mean E/e′>13.3 had a sensitivity of 86% and a specificity of 91% in the diagnosis of moderate-to-severe diastolic dysfunction (AUC: 0.92). E/(e′xs′) (AUC: 0.89) and NT pro-BNP (AUC: 0.80) did not perform better than E/e′. The existing literature offers large body of evidence that E/e′ provides essential diagnostic and prognostic information in older patients with cardiovascular disease. ConclusionE/e′ is accurate in the diagnosis of significant diastolic dysfunction, in the diagnosis of heart failure with preserved ejection fraction and in risk stratification in older patients with cardiovascular disease.

Cardiac abnormalities determined by tissue Doppler imaging and arrhythmias in adolescents with anorexia nervosa.

Anorexia nervosa has a prevalence of 0.5-3% in adolescents, placing this population at increased risk of cardiac anomalies including arrhythmias, pericardial effusion, and myocardial dysfunction. Our objective is to describe cardiovascular anomalies observed by tissue Doppler imaging in patients with anorexia nervosa. We retrospectively reviewed electrocardiogram, Holter, and echocardiography findings in 28 patients diagnosed with anorexia nervosa. Electrocardiogram was abnormal in 71% of patients with sinus bradycardia observed in 57%. Holter confirmed sinus bradycardia without significant pauses. Prolonged QTc, low voltage, and ectopic beats were each seen in 14% of patients. Wenckebach atrioventricular block was observed in one patient. Supraventricular or ventricular tachycardia was not observed. Echocardiography showed structurally normal heart in all patients. Pericardial effusion was seen in 7.1% of patients and left ventricular mass was decreased in 10.7%. Mean ejection fraction was 0.73 and mean fractional shortening was 38.4%. Tissue Doppler imaging revealed systolic or diastolic dysfunction in four patients with e', a', and s' velocities in the lateral and septal basal segments more than two standard deviations below the mean. Two patients had decreased left ventricular mass but no significant difference in disease duration from the group. Basal segment velocities below one standard deviation were also observed in an additional seven patients. A trend for decreased tissue Doppler imaging velocities was seen in 25.0% of patients, while significant systolic and diastolic dysfunction was seen in 14.3% of patients, associated with a significant reduction in left ventricular mass and independent of disease duration.

Soluble ST2 and renal function in ischemic heart failure with atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Soluble ST2 (sST2) is a novel cardiac biomarker whose concentration rises in response to myocardial strain. The aim of this study was to analyse the relationship between soluble ST2 (sST2) level and renal function in heart failure (HF) patients with atrial fibrillation (AF). Methods The study involved 113 (83.2% men) patients with mean age 60.0 [54.0-67.0] years with II-IV functional class (recommendations of the New York Heart Association) is due to ischemic heart disease. Serum levels of N-terminal proBNP (NT-proBNP), sST2, TIMP-1 and Cystatine C (CysC) were quantified by ELISA of 33 patients with HF and AF and 80 patients with HF without AF. Echocardiography was performed according to the American Society of Echocardiography/European Association of Echocardiography recommendations. Estimated glomerular filtration rate (eGFR) was calculated by MDRD formula. Nonparametric Mann-Whitney U-test for independent data, Spearman’s rank correlation and multiple linear regression coefficients were calculated. Results Patients with HF and AF characterized significantly higher concentration of sST2 (1453.2 [1184.3-1945.7] vs 1279.7 [1110.9-1616.6] pg/ml, p = 0.05), as well as the marker of kidney dysfunction CysC (1375 [1111.7-1867.4] vs 1136.4 [955-1386.4] ng/ml, p = 0.02) and was significantly lower eGFR (67.7 [60.6-77.2] vs 79.3 [70.9-88.0] ml/min/1.73m2; p = 0.0002). sST2 correlated with TIMP-1 (r = 0.56; p = 0.004) E/e’ (r = 0.87; p = 0.002), as well as CysC with NT-proBNP (r = 0.56; p = 0.002), with age (r = 0.49; p = 0.009) in patients with HF and AF. At multivariate linear regression analysis, only TIMP-1 (β=0.63) and left atrial volume index (β=0.22) were independently associated with sST2 (R2 = 0.58; p = 0.002). Conclusions In patients with ischemic HF and atrial fibrillation elevation sST2, associated with high level cystatine C and correlated with TIMP-1, E/e’, markers which showed abnormal collagen homeostasis and significant diastolic dysfunction LV. Multivariate analysis shows, that sST2 independently associated with TIMP-1 and LAVi. Further studies are needed to clarify the prognostic role of marker renal function (CysC) and cardiovascular stress (sST2) in ischemic HF patients with atrial fibrillation.

Participation of the C-terminal propeptide procollagen type I in the formation of cardiofibrosis in patients with myocardial infarction with preserved left ventricular ejection fraction

Aim. To study the dynamics of procollagen type I carboxy-terminal propeptide (PICP) with an assessment of potential associations with cardiac fibrosis (CF) and diastolic dysfunction (DD) of the left ventricle (LV) during the hospitalization and one year after ST segment elevation myocardial infarction (STEMI).Material and methods. The study included 120 patients with STEMI. There were following inclusion criteria: diagnosis of STEMI (2015 European Society of Cardiology guidelines); Killip £III acute heart failure (AHF); signed informed consent; patient age &gt;18 years old. There were following exclusion criteria: STEMI due to percutaneous coronary intervention or coronary artery bypass grafting; Killip IV AHF; patient age &gt;80 years; clinically significant comorbidities; death of the patient during the first day of hospitalization. On the 1st, 12th day of the disease and after a year all patients underwent echocardiography and the PICP concentration was determined. One year after myocardial infarction, contrast-enhanced cardiac magnetic resonance imaging was performed to assess CF. In the analyzed group of patients, on day 1 of STEMI, mean values of LV ejection fraction (EF) in the range of 40-49% were observed in 3 (2,5%) patients, LVEF &lt;40% — in 31 (26%), LVEF ≥50% — in 86 (71,7%). The final analysis was performed on a sample of patients with preserved LVEF (n=86) (71,7%).Results. On the first day of myocardial infarction, signs of DD were noted in 25 (29,1%) patients, while after 1 year, their number increased by 9 (10%) and amounted to 34 (39,5%) patients. In 15 (17,6%) people, worsening of myocardial systolic dysfunction was noted. Patients with a CF ³16% had the highest PICP expression on the first day of the disease. CF ≥16% one year after STEMI with preserved EF is associated with PICP concentration on day 1 of the disease. In addition, multidirectional correlations were revealed between the CF ≥16% and parameters of LV diastolic function (e’, mean pulmonary artery pressure, E/e’).Conclusion. Determination of the PICP concentration on the 1st day of myocardial infarction will allow early identification of patients at risk of CF one year after STEMI with preserved EF.

High Rate of Systolic Heart Failure in Patients with Hereditary Transthyretin Cardiac Amyloid

Purpose Hereditary Transthyretin Cardiac Amyloidosis (hATTR- CM) is an infiltrative cardiomyopathy that is usually associated with significant ventricular hypertrophy and restrictive diastolic dysfunction. Recent studies have demonstrated that patients with the V122Ile hATTR-CM variant present with worse functional status at diagnosis compared to wild-type and other hereditary variants. Therefore, we sought to assess the prevalence of systolic heart failure and associated clinical characteristics at the time of diagnosis of V122Ile hATTR-CM patients in our single, tertiary care center. Methods 69 patients were diagnosed with V122Ile hATTR-CM between 2013 - 2020 by genetic testing in combination with technetium pyrophosphate scanning or endomyocardial biopsy. Demographic and diagnostic data were collected by retrospective chart review and patients with systolic heart failure, defined as EF ≤ 40%, were identified. All data is reported as mean ± standard error or percentage of whole. Results Among our cohort of 69 patients with V122Ile hATTR-CM, 46 (67%) were found to have systolic heart failure with a LVEF of 26% ± 10.1, IVS thickness of 17.4 mm ± 4.1, and LV Mass Index was 166.2 g/m2 ± 61.2. Troponin I and BNP biomarkers averaged 0.26 ± 0.61 and 885 ± 561, respectively. The most prominent extra-cardiac manifestations among the systolic heart failure group were bilateral carpal tunnel syndrome in 25 (54%) patients, lumbar stenosis in 11 (24%), and polyneuropathy in 9 (20%). A significant delay in diagnosis was seen with an average time of 19 months from time of presentation to ATTR diagnosis. Average survival time after diagnosis was 2.5 ± 1.8 years and 6 (16%) patients underwent successful orthotopic heart transplant. 33% of patients with systolic heart failure were found to have primary prevention ICDs. Conclusion In a cohort of 69 V122Ile hATTR-CM patients, 67% were found to have systolic heart failure at the time of initial diagnosis. A significant delay was noted in time to diagnosis, which is consistent with the existing literature. Despite the delay in diagnosis and depressed LVEF at presentation, average survival remained > 2 years. Delayed diagnosis remains a critical problem for hATTR-CM patients.

N-terminal propeptide of type III procollagen for predicting diastolic dysfunction in patients with myocardial infarction and preserved ejection fraction

Aim. To study changes in the level of fibrotic scarring marker — the N-terminal propeptide type III procollagen (PIIINP) and structural and functional parameters with the assessment of diastolic function in patients a year after ST segment elevation myocardial infarction (STEMI) and preserved left ventricle (LV) contractility.Material and methods. At first, the study included 120 (100%) STEMI patients. Next, patients with an LV ejection fraction (EF) ≥50% were selected. The final analysis included 86 STEMI patients. Upon hospitalization, the patients underwent routine diagnostic tests, coronary angiography with stenting of culprit artery. Echocardiography and determination of venous blood PIIINP and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels was on the 1st (time point 1) and 12th day (time point 2) of disease and after a year (time point 3). To compare the obtained values of fibrotic scarring markers, a control group was formed, including 20 (100%) healthy volunteers, identical in age and sex with the studied sample.Results. On the first day of MI, 25 (29,1%) patients with signs of diastolic dysfunction (DD) were identified among those with preserved LVEF. After 1 year, the number of such patients increased by 10% (n=9). Initially increased (relative to the control group) concentration of PIIINP on the first day (311,2 [220,1; 376,3] ng/ml) decreased by the 12th day (223,3 [195,3; 312,1] ng/ml) and returned to the initial values a year after the MI (312,6 [228,0; 383,8] ng/ml). The NT-proBNP concentration during the hospitalization period did not exceed the reference values and did not differ between 1 and 2 time points (p=0,127). One year later, the NT-proBNP concentration significantly exceeded the values of the previous determinations and amounted to 124,4 pg/ml (p=0,043). According to the ROC analysis, with a PIIINP ≥387,8 ng/ml on the first day, the risk of DD increases (p=0,050, sensitivity, 84,62%, specificity, 55,56%) within a year after STEMI with preserved LVEF.Conclusion. The threshold of PIIINP (≥387,8 ng/ml) was established for the first day of MI, at which the risk of DD increases one year after the index event. An increase in NT-proBNP concentration one year after STEMI indicates the progression of heart failure.

Pre- and postoperative left atrial and ventricular volumetric and deformation analyses in severe aortic regurgitation

BackgroundThe impact of volume overload due to aortic regurgitation (AR) on systolic and diastolic left ventricular (LV) indices and left atrial remodeling is unclear. We assessed the structural and functional effects of severe AR on LV and left atrium before and after aortic valve replacement.MethodsPatients with severe AR scheduled for aortic valve replacement (n = 65) underwent two- and three-dimensional echocardiography, including left atrial strain imaging, before and 1 year after surgery. A control group was selected, and comprised patients undergoing surgery for thoracic aortic aneurysm without aortic valve replacement (n = 20). Logistic regression analysis was used to assess predictors of impaired left ventricular functional and structural recovery, defined as a composite variable of diastolic dysfunction grade ≥ 2, EF < 50%, or left ventricular end-diastolic volume index above the gender-specific normal range.ResultsDiastolic dysfunction was present in 32% of patients with AR at baseline. Diastolic LV function indices and left atrial strain improved, and both left atrial and LV volumes decreased in the AR group following aortic valve replacement. Preoperative left atrial strain during the conduit phase added to left ventricular end-systolic volume index for the prediction of impaired LV functional and structural recovery after aortic valve replacement (model p < 0.001, accuracy 70%; addition of left atrial strain during the conduit phase to end-systolic volume index p = 0.006).ConclusionsOne-third of patients with severe AR had signs of diastolic dysfunction. Aortic valve surgery reduced LV and left atrial volumes and improved diastolic indices. Left atrial strain during the conduit phase added to the well-established left ventricular end-diastolic dimension for the prediction of impaired left ventricular functional and structural recovery at follow-up. However, long-term follow-up studies with hard endpoints are needed to assess the value of left atrial strain as predictor of myocardial recovery in aortic regurgitation.

ПРОГНОСТИЧЕСКИЕ ФАКТОРЫ СИНДРОМА ВОЛЬФА-ПАРКИНСОНА-УАЙТА В ДЕТСКОМ ВОЗРАСТЕ

Objective: to determine the prognostic factors determining the severity of Wolff-Parkinson-White syndrome (WPW) in children. Methods: a retrospective analysis of the course of the disease was performed in 108 children with WPW syndrome aged 13.6 (12-16) years. Depending on the number of attacks of paroxysmal tachycardia (PT), all children were divided into 2 groups: group A consisted of 47 children (43.5%) with a history of no more than three attacks of PT and they were rare; group B included 61 children (56.5%) with frequent (more than once a month) attacks of PT, more than four in the history. We studied: the family history, the clinical picture of the disease, the nature of paroxysmal tachycardia, the effectiveness of treatment, and the results of instrumental studies. Using the method of mathematical modeling, the informative value of each feature was determined, and the diagnostic value was determined. Results: age and gender differences in the development of WPW syndrome in children were established. The presence of a family history of ECG signs of ventricular preexcitation is a reliable sign (p=0.02), contributing to more frequent PT attacks. More frequent development of PT attacks was noted in patients with mitral valve prolapse (p=0.03) and additional chords in the left ventricular cavity (p=0.001). In the group with frequent PT attacks, signs of sinus node dysfunction were detected more often (&lt;0.001). According to the echocardiographic study, children with frequent PT attacks were more likely to have disorders in the form of thickening of the interventricular septum in the diastole (p=0.010) and signs of diastolic dysfunction of the right ventricle (p = 0.010). Conclusion: The factors of prognostic value include: male gender, the presence of the expressed symptoms of the attack of PT and PT frequency more than once per month, low vagal efficiency on relieving the attack, a history of frequent attacks, a family history of ECG characteristics of premature ventricular excitation, the presence of signs of sinus node dysfunction during 24 hours without the attack and the signs of arrhythmogenic myocardial dysfunction by echocardiography.

Prevalence and determinants of systolic and diastolic cardiac dysfunction and heart failure in acute ischemic stroke patients: The SICFAIL study.

AimsIschaemic stroke (IS) might induce alterations of cardiac function. Prospective data on frequency of cardiac dysfunction and heart failure (HF) after IS are lacking. We assessed prevalence and determinants of diastolic dysfunction (DD), systolic dysfunction (SD), and HF in patients with acute IS.Methods and resultsThe Stroke‐Induced Cardiac FAILure in mice and men (SICFAIL) study is a prospective, hospital‐based cohort study. Patients with IS underwent a comprehensive assessment of cardiac function in the acute phase (median 4 days after IS) including clinical examination, standardized transthoracic echocardiography by expert sonographers, and determination of blood‐based biomarkers. Information on demographics, lifestyle, risk factors, symptoms suggestive of HF, and medical history was collected by a standardized personal interview. Applying current guidelines, cardiac dysfunction was classified based on echocardiographic criteria into SD (left ventricular ejection fraction < 52% in men or <54% in women) and DD (≥3 signs of DD in patients without SD). Clinically overt HF was classified into HF with reduced, mid‐range, or preserved ejection fraction. Between January 2014 and February 2017, 696 IS patients were enrolled. Of them, patients with sufficient echocardiographic data on SD were included in the analyses {n = 644 patients [median age 71 years (interquartile range 60–78), 61.5% male]}. In these patients, full assessment of DD was feasible in 549 patients without SD (94%). Prevalence of cardiac dysfunction and HF was as follows: SD 9.6% [95% confidence interval (CI) 7.6–12.2%]; DD in patients without SD 23.3% (95% CI 20.0–27.0%); and clinically overt HF 5.4% (95% CI 3.9–7.5%) with subcategories of HF with preserved ejection fraction 4.35%, HF with mid‐range ejection fraction 0.31%, and HF with reduced ejection fraction 0.78%. In multivariable analysis, SD and fulfilment of HF criteria were associated with history of coronary heart disease [SD: odds ratio (OR) 3.87, 95% CI 1.93–7.75, P = 0.0001; HF: OR 2.29, 95% CI 1.04–5.05, P = 0.0406] and high‐sensitive troponin T at baseline (SD: OR 1.78, 95% CI 1.31–2.42, P = 0.0003; HF: OR 1.66, 95% CI 1.17–2.33, P = 0.004); DD was associated with older age (OR 1.08, 95% CI 1.05–1.11, P < 0.0001) and treated hypertension vs. no hypertension (OR 2.84, 95% CI 1.23–6.54, P = 0.0405).ConclusionsA substantial proportion of the study population exhibited subclinical and clinical cardiac dysfunction. SICFAIL provides reliable data on prevalence and determinants of SD, DD, and clinically overt HF in patients with acute IS according to current guidelines, enabling further clarification of its aetiological and prognostic role.

Non-invasive estimation of relative pressure for intracardiac flows using virtual work-energy.

Intracardiac blood flow is driven by differences in relative pressure, and assessing these is critical in understanding cardiac disease. Non-invasive image-based methods exist to assess relative pressure, however, the complex flow and dynamically moving fluid domain of the intracardiac space limits assessment. Recently, we proposed a method, νWERP, utilizing an auxiliary virtual field to probe relative pressure through complex, and previously inaccessible flow domains. Here we present an extension of νWERP for intracardiac flow assessments, solving the virtual field over sub-domains to effectively handle the dynamically shifting flow domain. The extended νWERP is validated in an in-silico benchmark problem, as well as in a patient-specific simulation model of the left heart, proving accurate over ranges of realistic image resolutions and noise levels, as well as superior to alternative approaches. Lastly, the extended νWERP is applied on clinically acquired 4D Flow MRI data, exhibiting realistic ventricular relative pressure patterns, as well as indicating signs of diastolic dysfunction in an exemplifying patient case. Summarized, the extended νWERP approach represents a directly applicable implementation for intracardiac flow assessments.

Abstract 14864: Parental Obesity Leads to Mild Diastolic Dysfunction and Impaired Exercise Tolerance, but Not Hypertension, in Female Offspring

We found that parental obesity leads to high blood pressure (BP) and diastolic dysfunction in male offspring. Here, we examined the impact of parental obesity on BP regulation, systolic and diastolic function, and exercise tolerance in female offspring. The following groups were studied: 1) offspring fed normal diet (N) born from N lean parents (N-F1-N, n=5); 2) offspring fed high fat diet (H) born from N parents (N-F1-H, n=6); 3) offspring fed N born from H obese parents (H-F1-N, n=7); and 4) offspring fed H born from H obese parents (H-F1-H, n=7). Parents were fed H or N from weaning until the end of lactation, while offspring were placed on N or H diet from weaning until 22 weeks of age. Body weight, fat and lean mass were measured weekly (EchoMRI4-in-1 System). Cardiac function including ejection fraction (EF), isovolumetric relaxation time (IVRT), early (E’) and late (A’) mitral annular diastolic velocities were measured by echocardiography (VisualSonics VEVO-3100) using left ventricle long and short axes, pulse wave and tissue Doppler. BP, measured by telemetry, was similar among all groups. Compared to lean N-F1-N control mice, H-F1-N mice had similar body weight (23.7±0.1 vs. 25.2±1.8 g), fat mass (3.4±0.1 vs. 4.4±1.6 g) and lean mass (22.9±0.4 vs. 24.6±0.3 g). Both offspring groups fed H after weaning were heavier than offspring fed normal diet, however, H-F1-H mice were significantly heavier than N-F1-H mice (41.2±1.6 vs. 37.4±1.0 g) due to greater fat mass (16.2±1.1 vs. 13.2±1.0 g) and lean mass (25.1±1.7 vs. 22.9 vs. 0.3 g). Despite no major differences in EF among all 4 groups, mice born from obese H parents exhibited signs of diastolic dysfunction, irrespective of their own diet, as indicated by reduced E’/A’ ratio (0.8±0.1 and 1.2±0.2 vs. 1.6±0.1 and 1.5±0.2, for H-F1-H and H-F1-N vs. N-F1-N and H-F1-H, respectively), reduced exercise capacity (4.2±0.7 and 4.7±0.5 vs. 5.9±0.7 and 7.4±0.3 m.kg), and increased IVRT in obese H-F1-H compared to obese N-F1-H (28.4±2.3 vs. 22.2±0.8 ms). These results indicate that despite no alterations in BP diet-induced parental obesity is associated with signs of diastolic dysfunction and impaired fitness in female offspring, which is exacerbated by continuing to feed the offspring with H diet.

Abstract 16060: Cardiac Magnetic Resonance Imaging Diastolic Indices Correlate With Cardiac Catheterization Filling Pressures in Pediatric Heart Transplant Recipients

Background: Atrial and ventricular filling pressures are routinely used in pediatric heart transplant (HTx) recipients to assess graft function. Cardiac magnetic resonance (CMR) can provide a non-invasive assessment of diastolic function, but data are lacking in pediatric HTx. We hypothesized that CMR indices of diastolic function correlate with filling pressures, providing a non-invasive approach to assessment of ventricular dysfunction. Method: Pediatric HTx recipients were prospectively enrolled at the time of cardiac catheterization. Pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) were measured. CMR included standard volumetric analysis and T1 and extracellular volume (ECV) mapping in the short axis at the mid-left ventricle (LV) to evaluate extracellular matrix expansion. Filling curves were calculated by contouring every phase in the short axis stack and global longitudinal and circumferential strain (GLS, GCS) were calculated using feature tracking. Correlations were analyzed using Spearman’s correlation. Results: A total of 31 patients with a mean age of 16.2 y/o were included, 9 with biopsy-proven acute rejection. The median time from transplant was 6.9 years and the mean LVEF was 58%. Peak LV ejection rate/end-diastolic volume (PER/EDV) correlated with PCWP (rho=-0.43, p=0.02, Fig 1) and RAP (rho=-0.40, p=0.03). GLS and GCS correlated with RAP (rho=0.51 p=0.007, and rho=0.38 p=0.05, respectively); GLS also correlated with PCWP (rho=0.46, p=0.02). Native T1 time-correlated with PCWP (rho=0.54, p=0.003), while the correlation between ECV and PCWP did not reach statistical significance (rho=0.37, p=0.06). Conclusion: CMR can be a useful non-invasive modality to assess for early signs of diastolic dysfunction in patients after pediatric HTx. Further research is needed to describe the clinical significance of these associations.

Abstract MP113: Protein Hyperacetylation Mediates Bradyarrhythmia in Mice With Mitochondrial Disease

Background: Mice with germline mutation of the mitochondrial respiratory complex I subunit Ndufs4 exhibit progressive neurodegenerative phenotypes resembling Leigh syndrome (LS). Cardiomyocyte-specific Ndufs4 -/- mice demonstrate protein hyperacetylation and accelerated heart failure in response to pressure overload. Methods and Results: LS mice developed bradyarrhythmia with heart rate &lt;400 bpm. EKG showed sick sinus syndrome (SSS) and high degree AV block. Supplementation of Nicotinamide Riboside (NR), which increased cellular NAD + , significantly reduced arrhythmia events and restored normal sinus rhythm, as shown by confocal scanning of sinoatrial nodal tissue dissected from LS mouse hearts. Immunoprecipitation and immunohistochemistry using antibody specific for K1479 of Nav 1.5 showed hyperacetylation of LS SA nodal tissue, which was attenuated by NR. HEK293-cells deficient in mitochondrial complex I subunit Ndufs2 had higher DCFDA (ROS) and lower TMRM intensity (mitochondrial membrane potential) compared with Ndufs4 knock-out cells. Ndufs2-knock-out HEK293 cells transfected with wild-type Nav 1.5 showed hyperacetylation of K1479 of Nav 1.5 . Patch clamp showed significantly reduced sodium current (I Na ) in Ndufs2 deficient HEK293 cells. NR prevented the decrease of I Na in Ndufs2 KO cells. HEK293 cells expressing mutant Nav 1.5 constructs mimicking deacetylation (K1479R) had increased I Na compared with HEK293 expressing WT Nav 1.5, suggesting that acetylation status affect Nav1.5 function. Arrythmia was noted in conduction tissue specific HCN4-Ndufs4 -/- mice, suggested a cell autonomous effect leading to arrhythmia. These findings indicate that mitochondrial complex I deficiency lead to hyperacetylation of Nav 1.5 , reduction of I Na , which subsequently cause bradyarrhythmia and this can be reversed by NR. Using echocardiography, we demonstrated significant diastolic dysfunction (decreased E’/A’, prolonged isovolemic relaxation time) in LS mice, which was ameliorated by NR. The calcium transient amplitude and decay rate, an indicator of ryanodine receptor and SERCA2 functions, was significantly decreased by ~15% in LS hearts and this was mitigated by NR, concomitant with reversal of SERCA2 hyperacetylation. Conclusions: Despite normal cardiac structure and systolic function, LS mice showed SSS, high degree AV block and diastolic dysfunction, which is mediated by hyperacetylation of Nav 1.5 and SERCA2, respectively. NR significantly reversed both arrhythmia and diastolic dysfunction. Our study demonstrates novel mechanistic link between mitochondrial complex I deficiency and the function of Nav 1.5 and SERCA2.