Progression Of Diastolic Dysfunction Research Articles

Albuminuria is associated with progression of diastolic dysfunction in patients at risk for cardiovascular disease

Abstract Background The number of the patients with heart failure with preserved ejection fraction (HFpEF) is increasing as society ages, which indicates that the number of pre-HFpEF patients is increasing even more. To combat this sociomedical burden, it is critical to establish cost-effective and simple biomarkers to identify the high-risk population at early phase of the disease. Recent studies demonstrated the association between albuminuria and incident heart failure, but the prognostic impact of albuminuria on diastolic dysfunction, an early phenotype of HFpEF, has not been elucidated. Purpose To examine the impact of albuminuria on the diastolic function over time in the patients with cardiovascular risks. Methods One hundred and fifty-eight patients with at least one cardiovascular risk factor without history of heart failure were followed up for 5 years. Echocardiogram was conducted at baseline, year 3, and year 5. Diastolic dysfunction was defined as E/e’ >14. Albuminuria was defined as urine albumin-to-creatinine ratio (UACR) 30 ≧mg/gCre. The patients with ejection fraction <40% and those had diastolic dysfunction at baseline were excluded from the study. The relationship between albuminuria at baseline and diastolic function at year 3 and 5 were investigated. Results Among 158 subjects, 27 showed albuminuria at baseline and the prevalence of hypertension, dyslipidemia, and diabetes was not significantly different between patients with and without albuminuria. The baseline E/e’ tended to be higher in patients with albuminuria, although the difference was not statistically significant (Fig1: E/e’ = 10.0±2.4 vs. 9.4±2.2, p = 0.08) . However, the patients with albuminuria showed a steeper increase in E/e’ than those without albuminuria, and the significant difference was observed at year 3, that was even greater at year 5 (Fig1: E/e’ = 11.1±2.8 vs 10.0±2.6, p = 0.04 in year 3, E/e’ = 12.5±4.1 vs 10.3±2.9, p = 0.002 in year 5, respectively). Furthermore, log UACR at baseline showed significant correlation with E/e’ at year 5 (p = 0.02, r = 0.21) and normo-, micro-, and macroalbuminuria (UACR<30, 30-300, and >300mg/gCre, respectively) at baseline showed elevated E/e’ at year 5 in this order ( p = 0.01 for UACR<30 vs. 30-300mg/gCre, and p = 0.04 for UACR<30 vs. >300mg/gCre, reapectively ). The prevalence of incident diastolic dysfunction increased greater in patients with albuminuria throughout the follow-up period and the difference reached statistical significance at year 5 (Fig2: 18.5% vs. 9.2%, p = 0.28 for year 3, and 25.9% vs. 8.4%, p = 0.009 for year 5, respectively). Conclusion In the patients with cardiovascular risk factors, albuminuria was associated with development and progression of diastolic dysfunction over subsequent 5 years. Future prospective study is warranted to investigate the effectiveness of albuminuria-directed care to prevent development of HFpEF.

Leukocyte Extracellular Vesicles Predict Progression of Systolic Dysfunction in Heart Failure with Mildly Reduced Ejection Fraction (LYCHEE) - A Prospective, Multicentre Cohort Study.

Risk stratification in heart failure with mildly-reduced ejection fraction (HFmrEF) remains challenging. We evaluated the predictive value of advanced glycation end products (AGEs) and plasma concentrations of extracellular vesicles (EVs) for the systolic and diastolic dysfunction progression in HFmrEF patients. Skin AGE accumulation was measured using AGE Reader. Plasma EV concentrations were measured using flow cytometry. Among 74 patients enrolled, 13 (18%) had systolic dysfunction progression and 5 (7%) had diastolic dysfunction progression during 6.5months follow-up. Leukocyte EVs concentrations were higher in patients with systolic dysfunction progression (p = 0.002) and predicted the progression with 75.0% sensitivity and 58.3% specificity, independent of other clinical variables (OR 4.72, 95% CI 0.99-22.31). Skin AGE levels and concentrations of other EV subtypes were not associated with systolic or diastolic dysfunction progression. Increased leukocyte EVs concentrations are associated with 4.7-fold higher odds of systolic dysfunction progression in HFmrEF patients.

Interrelations Between Glycated Hemoglobin Trajectories and Left Ventricular Diastolic Dysfunction in Patients with CHD and DM-2

IntroductionThe study of the relationship between the glycemic profile and LVDD in patients with coronary artery disease and type 2 diabetes is topical. PurposeTo analyze the relationship between LVDD and glycated hemoglobin trajectories in patients with coronary artery disease and type 2 diabetes. Material and methods130 patients with coronary artery disease and DM-2 aged 63.9±8.8 years, experience of coronary artery disease 9.69±0.49 and DM 7.3±3.89 years, in whom LVDD parameters were determined. For 2 years of observation, the trajectories were evaluated HbA1c. ResultsIn patients with preserved HbA1c <8 (n-47) and >8.1 (n-50), e`average is below 7.42 [7.38-8.20] and 7.65 [7.20-8. 54], respectively, than in which HbA1 changed (p=0.05). In groups HbA1c>8.1(n-5) and HbA1c>8.1 and became <8 (n-28) e`mean no difference. The E/e` ratio in all groups tended to increase (P=0.694). According to LVDD gradations in all HbA1 groups with a normal type, an increase in patients is recorded (groups: C from 32 to 44%; A+B from 34.04 to 40.43%; C-(A+C) from 28.57% to 32 14%, except for group C´ - reduction in patients with normal LVDD from 60 to 40%. ConclusionNegative dynamics of the e`average index was revealed in the HbA1c<8 (n-47) and HbA1c>8.1 (n-50) groups after 2 years of observation with significant differences between the points of determination, in contrast to the subgroups in which HbA1c transitions were observed. The E/e` ratio in all groups showed a tendency to increase throughout the entire observation period, which indirectly indicates the progression of diastolic dysfunction.

Abstract 19062: Prognostic Impact of Coronary Microvascular Dysfunction on Diastolic Dysfunction and Cardiovascular Events in Patients With Acute Coronary Syndrome

Introduction: Coronary microvascular dysfunction (CMD) has prognostic value in coronary artery disease. Hypothesis: CMD could have an influence on progression of diastolic dysfunction and occurrence of cardiovascular events in acute coronary syndrome (ACS). Methods: We prospectively enrolled ACS patients who underwent successful percutaneous coronary intervention (PCI). CMD was defined by index of microcirculatory resistance (IMR &gt;40) after PCI. Cardiac diastolic dysfunction was defined by echocardiographic parameters (early diastolic transmitral flow velocity/early diastolic mitral annular velocity, e’ velocity, tricuspid regurgitation velocity, and left atrial volume index). The primary end point was 1-year diastolic dysfunction and secondary end point was cardiovascular death or admission for heart failure during 5 years of follow-up. Results: Among 163 patients, 39 patients (23.9%) had CMD. Prevalence of 1-year diastolic dysfunction was increased during 1 year (baseline 29.4% vs. 1 year 46.0%). Progression rate of diastolic dysfunction during 1 year was significantly higher in CMD (40.3% vs. 64.1%, OR 2.64, p=0.008) (Figure). After adjustment with clinical variables, presence of CMD was strongly associated with progression of 1-year diastolic dysfunction (HR, 2.95, 95% CI 1.30 - 8.74, p=0.030). Risk of cardiovascular death or admission for heart failure was increased in CMD (37.9% vs. 7.1%; Log-rank test p=0.003) Conclusions: This study showed the association between presence of CMD and progression of diastolic dysfunction during 1 year, they might have synergistic influence on occurrence of cardiovascular events in ACS patients.

Survivors of Pediatric Hematopoietic Stem Cell Transplantation Exhibit Progressive Diastolic Dysfunction Over Years of Follow-Up

Patients who have undergone hematopoietic stem cell transplantation (HSCT) in childhood have a higher risk of diastolic heart failure (HF). The rate of progression of diastolic dysfunction in aging pediatric patients is unknown and is more difficult to assess in young patients secondary to changes in diastolic indices as they grow. HSCT recipients at our center were previously found to have decline in diastolic function indices at 1 year after HSCT. This study provides follow-up of this cohort, using age-normalized z-scores to assess whether the decline in diastolic function noted at 1-year post-HSCT persists, worsens, or improves over time. Patients age <21 years who underwent HSCT at Boston Children's Hospital/Dana-Farber Cancer Center between 2005 and 2008 with ≥3 surveillance echocardiograms, including 1 performed pre-HSCT, were included. Diastolic measures included mitral inflow (E/A ratio) and Doppler tissue imaging of left ventricular lateral wall (LV lateral e'), LV septal wall (septal e') and right ventricular free wall (RV e'). Systolic function was measured by LV ejection fraction (LVEF). Normalization by age was done using z-scores, and >±2 SD was defined as abnormal in linear modeling of diastolic dysfunction and systolic dysfunction over time. In a subset of patients with adequate post-HSCT images of the entire left atrium (LA), LA volume and LA strain analyses also were performed. The study cohort comprised 61 patients (41% female; median age at HSCT, 10.7 years; median follow-up, 7.4 years). Diastolic index z-scores declined by -.045/year for LV lateral e', -.06/year for LV septal e', and -.14/year for RV e' (P < .01). The E/A ratio z-score increased by .034/year (P=.028). Linear modeling demonstrated that LV lateral e' and LV septal e' would become abnormal at 25 and 20 years post-HSCT, respectively, whereas RV e' would become abnormal sooner, at 12.6 years. LVEF z-score declined by -.04/year (P < .01) and was estimated to become abnormal at 40 years post-HSCT. Exposure to total body irradiation (TBI) was associated with worsening diastolic indices, lower LVEF (P ≤ .002), and decreased LA reservoir strain (42.0% versus 45.0%; P=.016) and conduit strain (-31.5% versus -35.1%; P=.029), although there was significant overlap between TBI and anthracycline exposure. Treatment with anthracyclines even at low doses (median, 150 mg/m2) was associated with declining LVEF but not with changes in diastolic indices. Long-term survivors of childhood HSCT exhibit declines in both LV and RV diastolic function indices. These results inform the rate of progression of LV and RV diastolic dysfunction indices over time in long-term survivors of pediatric HSCT. A significant association was observed between TBI and diastolic dysfunction and a decline in LVEF. Treatment with anthracyclines even at low doses was associated with a mild decline in LVEF. Our results can inform a lifespan perspective on disease management in this population, encourage clinicians and patients to be vigilant in following guideline-directed surveillance echocardiography, and inform anticipatory responses by clinicians as patients transition from pediatric care to adult care.

Prevalence of Diastolic Dysfunction in Adult Survivors of Childhood Cancer: A Report From SJLIFE Cohort

BackgroundThe prevalence of diastolic dysfunction has not been systematically evaluated in a large population of survivors of childhood cancer using established guidelines and standards. ObjectivesThis study sought to assess the prevalence and progression of diastolic dysfunction in adult survivors of childhood cancer exposed to cardiotoxic therapy. MethodsComprehensive, longitudinal echocardiographic examinations of adult survivors of childhood cancer ≥18 years of age and ≥10 years from diagnosis in SJLIFE (St. Jude Lifetime Cohort Study) were performed. Diastolic dysfunction was defined based on 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. ResultsAmong 3,342 survivors, the median (25th-75th percentiles [quartile (Q)1-Q3]) age at diagnosis was 8.1 years (Q1-Q3: 3.6-13.7 years), 30.1 years (Q1-Q3: 24.4-37.0 years) at the baseline echocardiography evaluation (Echo 1), and 36.6 years (Q1-Q3: 30.8-43.6 years) at the last follow-up echocardiography evaluation (1,435 survivors) (Echo 2). The proportion of diastolic dysfunction was 15.2% (95% CI: 14.0%-16.4%) at Echo 1 and 15.7% (95% CI: 13.9%-17.7%) at Echo 2, largely attributable to concurrent systolic dysfunction. Less than 5% of survivors with preserved ejection fraction had diastolic dysfunction (2.2% at Echo 1, 3.7% at Echo 2). Using global longitudinal strain assessment in adult survivors with preserved ejection fraction (defined with a cutpoint worse than −15.9%), the proportion of diastolic dysfunction increased to 9.2% at baseline and 9.0% at follow-up. ConclusionsThe prevalence of isolated diastolic dysfunction is low among adults who received cardiotoxic therapies for childhood cancer. The inclusion of left ventricular global longitudinal strain significantly increased the identification of diastolic dysfunction.

Diastolic Dysfunction in Asymptomatic Type 2 Diabetic Patients Having Preserved Systolic Function

Objective: To determine frequency of diastolic dysfunction in asymptomatic type 2 diabetic patients by employing twodimensional (2D) echocardiography as a measurement method.&#x0D; Study Design: It was an Analytical Cross sectional study.&#x0D; Place and Duration of Study: Rawalpindi Institute of Cardiology, Rawalpindi Pakistan, from Jul 2021 to Nov 2021&#x0D; Methodology: Patients, already diagnosed as diabetics for more than 5 years and on dietary control or on medications,presenting to the outpatient department of the hospital were enrolled. They were subjected to a 2D echocardiography in left lateral position. We excluded patients with valvular heart disease, ischemia, congestive heart failure, cardiomyopathy of any aetiology, renal failure, pulmonary illness, anemia, hemoglobinopathies, prior myocardial infarctions in any region, smokers,and hypertension. Diastolic dysfunction was evaluated as per the guidelines of American society of Echocardiography.&#x0D; Results: Overall (n=150) patients were calculated with reference to 11% prevalence of LVDD by sample size calculator, being the part of study who were fulfilling the inclusion criteria. There were 102(68.0%) male and 48(32.0%) female patients; mean age was 45.02±6.07 years. Mean duration of diabetes mellitus in years was 6.93±2.53 with ranges from 5 to 16 years. Patients on oral hypoglycemic were 121(80.7%), on insulin were 5(3.3%), on dietary control were 12(8%) and on mixed treatment were 12(8%). There were 58 (38.7%) patients who had diastolic dysfunction present on echocardiogram. Effect modifiers of durationof diabetes (p=0.2) did not show significant association; however, Age (p=0.001) and Gender (p=0.038) significantly associated with Diastolic Dysfunction.&#x0D; Conclusions: One of the simple and noninvasive approaches to diagnose diastolic dysfunction is doing 2D echocardiography which can identify large percentage of diabetic subjects having pre-clinical diastolic dysfunction. Thus, by on time detection we can initiate treatment and retard the progression of diastolic dysfunction.

NADPH Oxidases in Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases regulate production of reactive oxygen species (ROS) that cause oxidative damage to cellular components but also regulate redox signaling in many cell types with essential functions in the cardiovascular system. Research over the past couple of decades has uncovered mechanisms by which NADPH oxidase (NOX) enzymes regulate oxidative stress and compartmentalize intracellular signaling in endothelial cells, smooth muscle cells, macrophages, cardiomyocytes, fibroblasts, and other cell types. NOX2 and NOX4, for example, regulate distinct redox signaling mechanisms in cardiac myocytes pertinent to the onset and progression of cardiac hypertrophy and heart failure. Heart failure with preserved ejection fraction (HFpEF), which accounts for at least half of all heart failure cases and has few effective treatments to date, is classically associated with ventricular diastolic dysfunction, i.e., defects in ventricular relaxation and/or filling. However, HFpEF afflicts multiple organ systems and is associated with systemic pathologies including inflammation, oxidative stress, arterial stiffening, cardiac fibrosis, and renal, adipose tissue, and skeletal muscle dysfunction. Basic science studies and clinical data suggest a role for systemic and myocardial oxidative stress in HFpEF, and evidence from animal models demonstrates the critical functions of NOX enzymes in diastolic function and several HFpEF-associated comorbidities. Here, we discuss the roles of NOX enzymes in cardiovascular cells that are pertinent to the development and progression of diastolic dysfunction and HFpEF and outline potential clinical implications.

Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction In Patients With Resistant Hypertension and Type 2 Diabetes Mellitus.

Aim To study the incidence and clinical and pathophysiological features of diastolic dysfunction (DD) and chronic heart failure with preserved ejection fraction (HFpEF) in patients with resistant arterial hypertension (RAH) associated with type 2 diabetes mellitus (DM).Material and methods A cross-sectional study that included 36 patients with RAH associated with type 2 DM (mean age, 61.4±6.4 years; 14 men) was performed. Measurement of office and 24-h blood pressure (BP), standard echocardiography with assessment of diastolic function (DF) and ventricular-arterial coupling, doppler ultrasound imaging of renal blood flow, and laboratory tests (blood glucose, glycated hemoglobin, blood creatinine, tumor necrosis factor α (TNF-α), brain natriuretic peptide (BNP), type 2 and type 9 matrix metalloproteinases (MMP-2 and MMP-9), tissue inhibitor of MMP 1 (TIMP-1), 24-h urine protein test, and 24-h urine volume test were performed for all patients. HFpEF was diagnosed according to criteria of the American Society of Echocardiography and the European Society of Cardiology 2019, and the Russian Clinical Guidelines on Diagnosis and Treatment of CHF 2017 and 2020.Results All patients had DD. Incidence of HFpEF detection according to the Russian Guidelines 2017 was 100%; according to the Russian Guidelines 2020, that included a required increase in BNP, and according to the criteria of the European Guidelines 2019, this incidence was 89 %. In 55.6 % of patients, DD corresponded to grade 2 (pseudonormal type). According to the correlation analysis, the DF impairment was associated with increases in pulse BP, myocardial mass, arterial and left ventricular elastance (arterial wall and left ventricular elasticity), basal glycemia and DM duration, MMP-2 level, proteinuria, blood creatinine, renal vascular resistance, and also with decreases in 24-h urine volume, MMP-9, TIMP-1, and TIMP-1/MMP-2. Significance of the relations of mean E / e' ratio with nighttime pulse BP, MMP-9, and 24-h urine volume were confirmed by results of multiple linear regression analysis. Increased myocardial and vascular wall stiffness, concentrations of MMP-2 and TNF-α and reduced 24-h urine volume were associated with progressive impairment of DF.Conclusion The combination of RAH and DM-2 is characterized by an extremely high incidence of DD that determines a great prevalence of HFpEF. The development and progression of DD in such patients are closely related with a complex of metabolic, proinflammatory and profibrotic biomarkers, increased vascular wall stiffness, pronounced left ventricular hypertrophy, and with structural and functional alterations in kidneys.

Study of left ventricular diastolic dysfunction as an early predictor of cardiovascular disease in patients with type 2 diabetes mellitus

Diabetes Mellitus (DM) is a disease with multi-system complications. Left ventricular diastolic dysfunction (LVDD) is an early stage of diabetic cardiomyopathy that can develop to heart failure. It has no clinical symptoms and can be easily diagnosed with echocardiography. The study aims to evaluate the LVDD in Type-2 DM with no symptoms of cardiovascular disease and its association with glycaemic control (HbA1c), DM duration, and microangiopathy. The cross-sectional hospital-based study included 100 asymptomatic patients with type 2 DM without evidence of cardiovascular involvement were studied. LVDD was evaluated by doppler echocardiography, which included E/A ratio, assessed in relation with age, sex, duration of diabetes and HbA1c level. LVDD was present in 57 % of the type 2 DM patients with males accounting for the majority of cases (63.2%). Diastolic dysfunction was more common in patients on oral hypoglycaemic agents (78%), insulin (2%) and/or both (19%). There was a linear progression of diastolic dysfunction with the increase age group (P = 0.001). LVDD was significantly associated with uncontrolled diabetes as measured by HbA1c levels with higher number patients among HbA1c &gt;8.5 (71.9%; P = 0.001) and a longer duration of DM with highest among 6 -10 years (38.6%; P = 0.001).

AN OBSERVATIONAL STUDY ON DIASTOLIC FUNCTION IN POST MYOCARDIAL INFARCTION PATIENTS IN A TERTIARY CARE CENTRE IN KANCHEEPURAM DISTRICT

Background: Diastolic dysfunction may be the earliest marker which leads to progressive cardiac failure. Thus the importance of detecting diastolic dysfunction using tissue doppler echocardiography helps in preventing the progression of patients to symptomatic congestive cardiac failure Objectives: 1. To find the prevalence of diastolic dysfunction in post myocardial infarction patients 2. To study the association between left ventricular diastolic dysfunction and variables such as smoking, Diabetes, Hypertension, Killip class,Type of Myocardial Infarction Methodology: Study design: Cross sectional study Study population : Post Myocardial infarction patients between 30 to 60 years of age Study period :18 months Sample size :144 Sampling technique :Convenient sampling Results:Prevalence of left ventricular diastolic dysfunction is 56%.There is statistically significant association between risk factors like smoking ,hypertension ,diabetes and occurrence of left ventricular diastolic dysfunction(P&lt;0.05).There is no association between type of Myocardial infarction and left ventricular diastolic dysfunction . Conclusion: Worsening diastolic function can be detected even in apparently healthy persons. Although confirmation in other studies would be helpful, our data suggest that persistence or progression of diastolic dysfunction is a risk factor for heart failure in post myocardial infarction patients.

A G-protein-biased S1P1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome.

AimHeart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively. Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P1) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function.Methods31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing adult and aged animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799.ResultsEchocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in adult and aged animals: in adult animals E/e’ was evaluated at 21.8 ± 1.4 for Ob-ZSF1-CTRL, 19.5 ± 1.2 for Ob-ZSF1-SAR247799 p<0.01, and 19.5 ± 2.3 for Le-ZSF1-CTRL (median ± IQR). In aged animals E/e’ was evaluated at 23.15 ± 4.45 for Ob-ZSF1-CTRL, 19.5 ± 5 for Ob-ZSF1-SAR247799 p<0.01, and 16.69 ± 1.7 for Le-ZSF1-CTRL, p<0.01 (median ± IQR). In aged animals, SAR247799 reduced cardiac hypertrophy (g/mm mean ± SEM of heart weight/tibia length 0.053 ± 0.001 for Ob-ZSF1-CTRL vs 0.046 ± 0.002 for Ob-ZSF1-SAR247799 p<0.01, Le-ZSF1-CTRL 0.035 ± 0.001) and myocardial perivascular collagen content (p<0.001), independently of any changes in microvascular density. In adult animals, SAR247799 improved endothelial function as assessed by the very low frequency bands of systolic blood pressure variability (mean ± SEM 67.8 ± 3.41 for Ob-ZSF1-CTRL 55.8 ± 4.27 or Ob-ZSF1-SAR247799, p<0.05 and 57.3 ± 1.82 Le-ZSF1-CTRL), independently of any modification of arterial blood pressure. In aged animals, SAR247799 reduced urinary protein/creatinine ratio, an index of glomerular injury, (10.3 ± 0.621 vs 8.17 ± 0.231 for Ob-ZSF1-CTRL vs Ob-ZSF1-SAR247799, respectively, p<0.05 and 0.294 ± 0.029 for Le-ZSF1-CTRL, mean ± SEM) and the fractional excretion of electrolytes. Circulating lymphocytes were not decreased by SAR247799, confirming lack of S1P1 desensitization.ConclusionsThese experimental findings suggest that S1P1 activation with SAR247799 may be considered as a new therapeutic approach for LVH and diastolic dysfunction, major components of HFpEF.

Loss of Mitochondrial Ca2+ Uniporter Limits Inotropic Reserve and Provides Trigger and Substrate for Arrhythmias in Barth Syndrome Cardiomyopathy.

Barth syndrome (BTHS) is caused by mutations of the gene encoding tafazzin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Beyond the first months of life, BTHS cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, blunted contractile reserve during exercise, and arrhythmic vulnerability. Previous studies traced BTHS cardiomyopathy to mitochondrial formation of reactive oxygen species (ROS). Because mitochondrial function and ROS formation are regulated by excitation-contraction coupling, integrated analysis of mechano-energetic coupling is required to delineate the pathomechanisms of BTHS cardiomyopathy. We analyzed cardiac function and structure in a mouse model with global knockdown of tafazzin (Taz-KD) compared with wild-type littermates. Respiratory chain assembly and function, ROS emission, and Ca2+ uptake were determined in isolated mitochondria. Excitation-contraction coupling was integrated with mitochondrial redox state, ROS, and Ca2+ uptake in isolated, unloaded or preloaded cardiac myocytes, and cardiac hemodynamics analyzed in vivo. Taz-KD mice develop heart failure with preserved ejection fraction (>50%) and age-dependent progression of diastolic dysfunction in the absence of fibrosis. Increased myofilament Ca2+ affinity and slowed cross-bridge cycling caused diastolic dysfunction, in part, compensated by accelerated diastolic Ca2+ decay through preactivated sarcoplasmic reticulum Ca2+-ATPase. Taz deficiency provoked heart-specific loss of mitochondrial Ca2+ uniporter protein that prevented Ca2+-induced activation of the Krebs cycle during β-adrenergic stimulation, oxidizing pyridine nucleotides and triggering arrhythmias in cardiac myocytes. In vivo, Taz-KD mice displayed prolonged QRS duration as a substrate for arrhythmias, and a lack of inotropic response to β-adrenergic stimulation. Cellular arrhythmias and QRS prolongation, but not the defective inotropic reserve, were restored by inhibiting Ca2+ export through the mitochondrial Na+/Ca2+ exchanger. All alterations occurred in the absence of excess mitochondrial ROS in vitro or in vivo. Downregulation of mitochondrial Ca2+ uniporter, increased myofilament Ca2+ affinity, and preactivated sarcoplasmic reticulum Ca2+-ATPase provoke mechano-energetic uncoupling that explains diastolic dysfunction and the lack of inotropic reserve in BTHS cardiomyopathy. Furthermore, defective mitochondrial Ca2+ uptake provides a trigger and a substrate for ventricular arrhythmias. These insights can guide the ongoing search for a cure of this orphaned disease.

NR3C2 genotype is associated with response to spironolactone in diastolic heart failure patients from the Aldo-DHF trial.

This study aimed to determine if variants in NR3C2, which codes the target protein of spironolactone, or CYP11B2, which is involved in aldosterone synthesis, were associated with spironolactone response, focused on the primary end point of diastolic function (E/e'), in Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) participants. Post-hoc genetic analysis. Data and samples were derived from the multi-center, randomized, double-blind, placebo-controlled Aldo-DHF trial. Aldo-DHF participants treated with spironolactone (n=184) or placebo (n=178) were included. Participants were genotyped for NR3C2 rs5522, NR3C2 rs2070951 and CYP11B2 rs1799998 via pyrosequencing. In the placebo and spironolactone arms, separate multivariable linear regression analyses were performed for change in E/e' with each single nucleotide polymorphism (SNP), adjusted for age, sex, and baseline E/e'. To discern potential mechanisms of a genotype effect, associated SNPs were further examined for their association with change in blood pressure, circulating procollagen type III N-terminal peptide (PIIINP), and left atrial area. Carriers of the rs5522 G allele in the placebo arm had a greater increase in E/e' over the 12-month course of the trial compared to noncarriers (β=1.10; 95% confidence interval [CI]: 0.05-2.16; p=0.04). No corresponding E/e' worsening by rs5522 genotype was observed in the spironolactone arm. None of the other genotypes were associated with change in E/e'. Compared to noncarriers, rs5522 G carriers also had a greater increase in left atrial area with placebo (β=0.83; 95% CI: 0.17-1.48; p=0.01) and a greater reduction in diastolic blood pressure with spironolactone (β=-3.56; 95% CI: -6.73 to -0.39; p=0.03). Serum PIIINP levels were similar across rs5522 genotypes. Our results suggest that spironolactone attenuates progression of diastolic dysfunction associated with the NR3C2 rs5522 G allele. Validation of our findings is needed.

Potential of valsartan+sacubitril therapy in hypertensive heart disease

The course of hypertension is often complicated by left ventricular hypertrophy (or hypertensive heart disease, HHD). The main “corridor” of natural HHD is development of heart failure with preserved ejection fraction (HFpEF). With HFpEF, the bioavailability of natriuretic peptides (NP) is significantly reduced, as a result of which the activity of cGMP-PKG signaling pathway, which plays a key role in maintaining normal diastolic function, weakens. It is possible to increase the activity of this pathway using the neprilysin inhibitor sacubitril. In case of HFpEF, the greatest efficacy from valsartan+sacubitril therapy should be expected in patients with severe concentric LVH, who have the most pronounced natriuretic peptide deficiency. Valsartan+sacubitril therapy has a clear hypotensive effect, causes a reversal of left ventricular hypertrophy and fibrosis. Since no effective treatment has yet been found for HFpEF, the main way for HHD treatment should be to prevent the diastolic dysfunction progression, which justifies valsartan+sacubitril therapy starting from the early/ asymptomatic stages.

Non-alcoholic fatty liver disease and left ventricular diastolic dysfunction in patients with metabolic syndrome

The purpose of the study was to determine the frequency and nature of manifestations of left ventricular diastolic dysfunction in patients with non-alcoholic fatty liver disease with the background of metabolic syndrome (MS).Characteristics of patients and research methods: To solve this problem, 227 patients with MS (130 men and 97 women) were examined. The study was conducted in two phases. At the first stage, all patients with MS are divided into two groups: patients with NAFLD — 205 people and 22 — without liver damage. At the next stage, a group of NAFLD patients with left ventricular DD (n=136) (66.34%) (the main group) and patients with no DD (n=69) (33.66%) (the comparison group) were identified.Results of the study: the results of diagnostics, clinical and laboratory manifestations of left ventricular diastolic dysfunction in 136 patients with NAFLD on the background of metabolic syndrome are Presented. Significant factors of development and progression of diastolic dysfunction were identified, which include increased body weight and adipose tissue, insulin resistance, dyslipidemia, hyperuricemia, activity and stage of liver damage. According to the data of structural and functional changes in the myocardium, the role of diastolic dysfunction in the development of chronic heart failure in patients with NAFLD with manifestations of metabolic syndrome has been established.Conclusion: it was Found that the development of left ventricular diastolic dysfunction in patients with NAFLD is due to the morphofunctional state of the liver.

The Molecular and Cellular Mechanisms Associated with a Microvascular Inflammation in the Pathogenesis of Heart Failure with Preserved Ejection Fraction

Heart failure withpreserved ejection fraction (HFpEF) is a severe disease with an often unfavorable outcome. The prevalence of HFpEF continues to increase, while effective treatment options remain elusive. All the medical strategies used toimprove the outcome in a heart failure with reduced ejection fraction proved ineffective in HFpEF, which was probably due to the different mechanisms ofdevelopment of these two types of heart failure and the diversity of the HFpEF phenotypes. According to the current paradigm of HFpEF development, a chronic mild pro-inflammatory statecauses a coronary microvascular endothelial inflammation, with further myocardial fibrosis and diastolic dysfunction progression. This inflammatory paradigm of HFpEF has been confirmed with someevidence, and suppressing the inflammation may become a novel strategy for treating and managing HFpEF. This review summarizes current concepts about a microvascular inflammation in hypertrophied myocardium and provides a translational perspective of the anti-inflammatory and immunomodulatory approaches in HFpEF.

Abstract 383: Cavβ2a Transgenic Mouse as a Hfpef Model With Hypercontractile Cardiomyocytes

Objective: Heart failure (HF) with preserved ejection fraction (HFpEF) is characterized by a preserved cardiac EF, the presence of HF symptoms and diastolic dysfunction. There is a lack of animal models for exploring the mechanisms and treatments of HFpEF. This study aimed to test if cardiomyocyte (CMs) specific, inducible Cavβ2a transgenic (Cavβ2a TG) mice, having hypercontractile CMs, could be a model for HFpEF. Methods: High (HE) and low (LE) expression Cavβ2a TG mice were studied since transgene expression at the age of 2m till the age of 8m monthly to evaluate the systolic and diastolic function. At 8m, animals were euthanized for intra-left ventricular hemodynamic measurement, myocyte function and histological analyses, and Western blotting measurements. Results: LE and HE TG ventricular myocytes (VMs) had greater Ca2+ currents at the age of 2m (LE increased by 95.5%; HE increased by 171.9% ) and maintained at a similar level at the age of 8m. VM contraction and calcium transients had greater amplitudes in TG than in control VMs while the time from the peak contraction to 90% relaxation and the tau of Ca2+ transient decay of VMs were not different between groups probably due to enhanced NCX expression and increased SERCA activity because of increased phospholamban phosphorylation at the Thr17 site. Till 8m, LE and HE mice had a higher level of mortalities than control mice (LE: 32%, HE: 15%, control:5%), but more HE (87.5%) mice showed pleural effusion. The EF was highest in LE mice at the age of 2m but decreased to the same (&gt;60%) as in HE and control mice at 8m. The ratio of mitral E to mitral inflow A wave velocities (E/A) was increased significantly at 3 and 4m then decreased to the lowest in HE at 5m followed by a rise at 6-8m, while LE mice had the lowest E/A at 5m and 6m and increased at 8m. E wave to mitral annulus e’ velocity (e’ wave) was higher in LE and HE groups than control mice. More fibrosis of the LV tissue, cardiomyocyte necrosis was observed in HE than in LE hearts. LE and HE mice had greater left ventricular wall relaxation rates, as indicated by larger reversed radial and longitudinal strain rates. Conclusion: LE and HE mice showed progression of diastolic dysfunction, from impaired relaxation to restrictive filling pattern. Cavβ2a TG mouse is a model for HFpEF for exploring HF pathobiology and mechanisms.

The Molecular and Cellular Mechanisms Associated with a Microvascular Inflammation in the Pathogenesis of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a severe disease with an often unfavorable outcome. The prevalence of HFpEF continues to increase, while effective treatment options remain elusive. All the medical strategies used to improve the outcome in a heart failure with reduced ejection fraction proved ineffective in HFpEF, which was probably due to the different mechanisms of development of these two types of heart failure and the diversity of the HFpEF phenotypes. According to the current paradigm of HFpEF development, a chronic mild pro-inflammatory state causes a coronary microvascular endothelial inflammation, with further myocardial fibrosis and diastolic dysfunction progression. This inflammatory paradigm of HFpEF has been confirmed with some evidence, and suppressing the inflammation may become a novel strategy for treating and managing HFpEF. This review summarizes current concepts about a microvascular inflammation in hypertrophied myocardium and provides a translational perspective of the anti-inflammatory and immunomodulatory approaches in HFpEF.

Longitudinal Effect of Hydroxyurea Therapy on Left Ventricular Diastolic Function in Sickle Cell Anemia

Longitudinal Effect of Hydroxyurea Therapy on Left Ventricular Diastolic Function in Sickle Cell Anemia