Echocardiographic Measures Of Diastolic Function Research Articles

Unmasking early diastolic dysfunction in type 2 diabetes using the peak early-to-late diastolic strain rate ratio by cardiac MRI feature tracking

Abstract Introduction Type 2 diabetes (T2D) is associated with early alterations in left ventricular (LV) diastolic function, which precedes the development of heart failure. These may be quantified by cardiac MRI feature tracking, which permits a direct assessment of myocardial relaxation through calculation of diastolic strain rates. Previous studies have not fully exploited this technique by integrating early and late LV diastolic relaxation in asymptomatic adults with T2D. Purpose To explore whether the peak early-to-late diastolic strain rate ratio (PEDSR:PLDSR), derived from cardiac MRI feature tracking, could: 1) identify diastolic dysfunction in an asymptomatic cohort of adults with T2D, 2) compare this technique with conventional echocardiographic measures of diastolic function. Methods Prospective cross-sectional study. People with T2D (n=253, mean age 63±7 years, 62% male, diabetes duration 11±8 years) without signs, symptoms or history of cardiovascular disease and non-diabetic controls (n=40, mean age 61±8 years, 63% male) underwent comprehensive phenotyping including echocardiography and cardiac MRI. The LV PEDSR:PLDSR was derived from cardiac MRI balanced steady-state free precession cine images using feature tracking. Correlations between circumferential PEDSR:PLDSR and echocardiography-derived E:A and E/e' were explored. Results Compared to controls, people with T2D had evidence of concentric LV remodelling, diastolic dysfunction, and diffuse myocardial fibrosis as demonstrated by increased LV mass/volume, E/e' ratio, and extracellular volume fraction, respectively (Table 1). People with T2D had lower PEDSR (0.87±0.23 vs 0.95±0.24 s–1, p=0.043), higher PLDSR (0.80±0.22 vs 0.67±0.16 s–1, p<0.001), and lower PEDSR:PLDSR ratio (1.18±0.46 vs 1.53±0.61, p<0.001). PEDSR:PLDSR was moderately correlated with E:A (r=0.495, p<0.001) (Figure 1) but not E/e' (r=0.087, p=0.182). Conclusions Compared to people without diabetes, lower PEDSR:PLDSR in asymptomatic subjects with T2D highlights impaired myocardial relaxation in early diastole and greater dependence on atrial contraction for LV filling in this group. This novel MRI measure may be promising tool to assess global diastolic function in people undergoing cardiac MRI and especially useful in those with poor echocardiographic windows. The functional and prognostic significance of PEDSR:PLDSR warrants further assessment in longitudinal studies. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Institute for Health Research (NIHR) United Kingdom through a Research Professorship award (RP-2017-08-ST2-007).British Heart Foundation through a Clinical Research Training Fellowship (FS/16/47/32190).

Is HFpEF Caused by Coronary Microvascular Disease?

Heart failure is responsible for one of eight deaths in the United States. Despite advances in the treatment of heart failure, e.g., beta1‐adrenergic antagonists, angiotensin converting enzyme inhibitors, these therapies are successful only in one type of HF—heart failure with reduced ejection fraction (HFrEF). Another type of heart failure termed HFpEF (heart failure with preserved ejection fraction) presents a far more difficult condition, because there have been no successful clinical trials demonstrating an effective therapy. Moreover, epidemiological data show the prevalence of HFpEF is increasing while that of HFrEF is decreasing. In some studies of patients with non‐obstructive coronary disease, categorized by poor coronary reserve without obstructive coronary artery lesions, HFpEF is observed. Because such patients have coronary microvascular disease, we proposed that a murine model of coronary microvascular disease may also present with HFpEF. In mice null for Kv1.5 channels (KO), a model of inadequate coronary metabolic dilation, we have observed poor exercise tolerance, shortened lifespan, and ventricular fibrosis. We hypothesized that inadequate metabolic dilation in the KO mice leads to chronic coronary insufficiency, i.e., inadequate myocardial blood flow, which would lead to cardiac apoptosis resulting in diffuse fibrosis, stiffening, and culminating in HFpEF. Although many laboratories use standard echocardiographic measurements of diastolic function as verification of HFpEF, such measurements may be spurious in small animals, such as mice, because several indices of diastolic function are heart rate dependent. To overcome this hindrance, we directly evaluated left ventricular diastolic stiffness by measuring LV pressure‐volume (PV) loops, using the slope of the end‐diastolic pressure and volume points (in anesthetized mice using a PV solid‐state transducer). LV PV loops were measured in anesthetized, wild‐type control (WT) and the KO mice during changes in preload induced by slow volume infusion. The series of PV loops were superimposed, and a computer best fit the diastolic PV points to a line, where the slope of the PV line reflects LV diastolic elastance (stiffness). The average slope of the LV end‐diastolic PV lines were roughly doubled in the KO vs WT (P<0.05), indicating increased stiffness. Moreover, LV end‐diastolic pressures were nearly tripled in the KO vs WT, 7.3±1.6 vs 2.8±1.7 mmHg, respectively. (P<0.05). In conclusion, a model of inadequate coronary dilation in mice, which we believe parallels patients with coronary microvascular disease, leads to increased stiffening of the left ventricle and HFpEF.

Proteomic mechanistic profile of patients with diabetes at risk of developing heart failure: insights from the HOMAGE trial

BackgroundPatients with diabetes mellitus (DM) are at increased risk of developing heart failure (HF). The “Heart OMics in AGEing” (HOMAGE) trial suggested that spironolactone had beneficial effect on fibrosis and cardiac remodelling in an at risk population, potentially slowing the progression towards HF. We compared the proteomic profile of patients with and without diabetes among patients at risk for HF in the HOMAGE trial.MethodsProtein biomarkers (n = 276) from the Olink®Proseek-Multiplex cardiovascular and inflammation panels were measured in plasma collected at baseline and 9 months (or last visit) from HOMAGE trial participants including 217 patients with, and 310 without, diabetes.ResultsTwenty-one biomarkers were increased and five decreased in patients with diabetes compared to non-diabetics at baseline. The markers clustered mainly within inflammatory and proteolytic pathways, with granulin as the key-hub, as revealed by knowledge-induced network and subsequent gene enrichment analysis. Treatment with spironolactone in diabetic patients did not lead to large changes in biomarkers. The effects of spironolactone on NTproBNP, fibrosis biomarkers and echocardiographic measures of diastolic function were similar in patients with and without diabetes (all interaction analyses p > 0.05).ConclusionsAmongst patients at risk for HF, those with diabetes have higher plasma concentrations of proteins involved in inflammation and proteolysis. Diabetes does not influence the effects of spironolactone on the proteomic profile, and spironolactone produced anti-fibrotic, anti-remodelling, blood pressure and natriuretic peptide lowering effects regardless of diabetes status. Trial registration NCT02556450.

Racial difference in atrial size and extracellular matrix homeostatic response to hypertension: Is this a potential mechanism of reduced atrial fibrillation in African Americans?

BackgroundAtrial fibrillation (AF) is less common in African Americans (AA) than Caucasians (C) despite a higher prevalence of risk factors such as hypertension (HTN).ObjectiveTest the hypothesis that differences in extracellular matrix (ECM) between AA and C in response to HTN might attenuate atrial enlargement and alter myocardial fibrosis.MethodsECM-related plasma biomarkers and echo data were collected from 326 C and 129 AA subjects with no history of AF, stratified by the presence of HTN, HTN with left ventricular hypertrophy (LVH), or HTN with LVH and heart failure with preserved ejection fraction (HFpEF).ResultsLeft atrial size was significantly smaller and the extent of enlargement in the presence of HTN was less in AA despite similar ventricular relative wall thickness, echocardiographic measures of diastolic function, and 6 minute-walk-test. AA had significantly lower levels of collagen I telopeptide and higher levels of collagen I propeptide among all strata, suggesting unique collagen homeostasis. Matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinase (TIMP) showed a distinctive response to HTN in AA, with significantly lower levels of MMP-2, MMP-3, and MMP-8 in AA with HTN and significantly lower levels of TIMP-1 and TIMP-3 in AA with HTN and AA with LVH. AA had significantly lower levels of NT-pro-BNP in all strata.ConclusionThis cross-sectional study demonstrates a racial disparity in ECM blood biomarkers and atrial remodeling in response to HTN and in the development of LVH and HFpEF that may partly help explain the decreased risk of AF in AA.

Impact of Weight Loss with Laparoscopic Sleeve Gastrectomy on Left Ventricular Diastolic Function: a Prospective Study.

The present study purposed to investigate the effects of weight loss with LSG on echocardiographic parameters of diastolic dysfunction in subjects with morbid obesity. Sixty-one subjects undergoing LSG for standard indications were enrolled. All subjects underwent a physical examination, electrocardiography, and transthoracic echocardiography before and 6months after the LSG. Peak early diastolic velocity (E), deceleration time (DT), and peak late diastolic velocity (A) were measured from the transmitral flow signal. Peak early (e') diastolic mitral annular velocity was measured at the two acquisition sites (basal septal and basal lateral) using the tissue Doppler recordings. A significant improvement was observed in echocardiographic measures of the diastolic function including E/A ratio, E/e' ratio, DT, and isovolumic relaxation time (IVRT) from baseline to the postoperative 6months. Left atrial volume index (LAVI) reduced from 30.3 ± 3.9ml/m2 to 28.0 ± 3.3ml/m2 (p < 0.001). In addition, interventricular septum diameter (IVSD) significantly decreased from 11.3 ± 1.3mm to 10.2 ± 1.1mm (p < 0.001). The change in BMI was significantly correlated with the improvements in DT (r = 0.334, p = 0.012), E/e' (r = 0.440, p = 0.001), E/A (r = - 0.317, p = 0.017), and IVRT (r = 0.348, p = 0.008). LSG leads to a significant improvement in echocardiographic measures of the left ventricular diastolic function in subjects with obesity. Our findings also show that LSG leads to a reverse remodeling indicated by the decrease in interventricular septum thickness and left atrial volume index in this population.

DIASTOLIC LEFT VENTRICULAR DYSFUNCTION IN SUDDEN CARDIAC ARREST SURVIVORS

The Registry of Unexplained Cardiac Arrest (CASPER) includes patients without demonstrable structural heart disease who have survived cardiac arrest. The majority of these events remain unexplained despite detailed genotypic and phenotypic investigations, follow-up and family screening. The recent identification of genetic variants associated with cardiomyopathy in the CASPER registry implies that some of these patients may have an arrhythmogenic phase prior to a mechanical phase that presents without evident left ventricular systolic dysfunction, although their diastolic function remains unknown. Sudden death has also been shown to account for ∼20% of deaths in patients with heart failure and preserved ejection fraction. Here, we assess the echocardiographic measures of diastolic function among patients from the CASPER registry. We conducted a retrospective study of patients from British Columbia in the CASPER registry who experienced a cardiac arrest between April 1988 and November 2016. Patients with no obstructive coronary artery disease on angiography and preserved left ventricular ejection fraction (defined as ≥50%) were included. Of the 65 patients identified, 44 had echocardiograms suitable for the assessment of diastolic function within 1 year before or after their cardiac arrest. Diastolic dysfunction was graded based on the 2016 American Society of Echocardiography (ASE) Diastolic Function Guidelines. Patients with and without abnormal diastolic function were compared for various clinical characteristics. The study group included 44 patients (36% female) patients with a mean age of 42 + 14 years. The majority (86%) had normal diastolic function. Three patients (7%) showed indeterminate diastolic function, and 3 patients (7%) displayed abnormal diastolic function (1 with mild diastolic dysfunction, 1 with moderate diastolic dysfunction, and 1 with abnormal diastolic function that could not be classified). All 3 patients with abnormal diastolic function had a history of hypertension. Other risk factors for diastolic dysfunction such as obesity, diabetes, and dyslipidemia were absent. To our knowledge, this is the first study to examine diastolic function in a cohort of patients with unexplained cardiac arrest without overt structural heart disease. This preliminary data set suggests that the prevalence of diastolic dysfunction within this population is higher than the general population. Further characterization of these patients is warranted.

Comparison of echocardiographic measurements to invasive measurements of diastolic function in infants with single ventricle physiology: a report from the Pediatric Heart Network Infant Single Ventricle Trial.

While echocardiographic parameters are used to quantify ventricular function in infants with single ventricle physiology, there are few data comparing these to invasive measurements. This study correlates echocardiographic measures of diastolic function with ventricular end-diastolic pressure in infants with single ventricle physiology prior to superior cavopulmonary anastomosis. Data from 173 patients enrolled in the Pediatric Heart Network Infant Single Ventricle enalapril trial were analysed. Those with mixed ventricular types (n = 17) and one outlier (end-diastolic pressure = 32 mmHg) were excluded from the analysis, leaving a total sample size of 155 patients. Echocardiographic measurements were correlated to end-diastolic pressure using Spearman's test. Median age at echocardiogram was 4.6 (range 2.5-7.4) months. Median ventricular end-diastolic pressure was 7 (range 3-19) mmHg. Median time difference between the echocardiogram and catheterisation was 0 days (range -35 to 59 days). Examining the entire cohort of 155 patients, no echocardiographic diastolic function variable correlated with ventricular end-diastolic pressure. When the analysis was limited to the 86 patients who had similar sedation for both studies, the systolic:diastolic duration ratio had a significant but weak negative correlation with end-diastolic pressure (r = -0.3, p = 0.004). The remaining echocardiographic variables did not correlate with ventricular end-diastolic pressure. In this cohort of infants with single ventricle physiology prior to superior cavopulmonary anastomosis, most conventional echocardiographic measures of diastolic function did not correlate with ventricular end-diastolic pressure at cardiac catheterisation. These limitations should be factored into the interpretation of quantitative echo data in this patient population.

Echocardiographic Detection of Occult Diastolic Dysfunction in Pulmonary Hypertension After Fluid Challenge.

BackgroundIdentification of occult diastolic dysfunction often requires invasive right heart catheterization with provocative maneuvers such as fluid challenge. Non‐invasive predictors of occult diastolic dysfunction have not been identified. We hypothesized that echocardiographic measures of diastolic function are associated with occult diastolic dysfunction identified at catheterization.Methods and ResultsWe retrospectively examined hemodynamic and echocardiographic data from consecutive patients referred for right heart catheterization with fluid challenge from 2009 to 2017. A replication cohort of 52 patients who prospectively underwent simultaneous echocardiography and right heart catheterization before and after fluid challenge at Monaldi Hospital, Naples, Italy. In the retrospective cohort of 126 patients (83% female, 56+14 years), 27/126 (21%) had occult diastolic dysfunction. After adjusting for tricuspid regurgitant velocity and left atrial volume index, E velocity (odds ratio 1.8, 95% CI 1.1–2.9, P=0.01) and E/e′ (odds ratio 1.9, 95% CI 1.1–3, P=0.005) were associated with occult diastolic dysfunction with an optimal threshold of E/e′ >8.6 for occult diastolic dysfunction (sensitivity 70%, specificity 64%). In the prospective cohort, 5/52 (10%) patients had diastolic dysfunction after fluid challenge. Resting E/e′ (odds ratio 8.75, 95% CI 2.3–33, P=0.001) and E velocity (odds ratio 7.7, 95% CI 2–29, P=0.003) remained associated with occult diastolic dysfunction with optimal threshold of E/e′ >8 (sensitivity 73%, specificity 90%).ConclusionsAmong patients referred for right heart catheterization with fluid challenge, E velocity and E/e′ are associated with occult diastolic dysfunction after fluid challenge. These findings suggest that routine echocardiographic measurements may help identify patients like to have occult diastolic dysfunction non‐invasively.

Echocardiographic assessment of single-ventricle diastolic function and its correlation to short-term outcomes after the Fontan operation.

Postoperative complications after the Fontan operation for single ventricle heart disease are common and include persistent pleural drainage and prolonged length of hospital stay (LOS). Diastolic ventricular dysfunction may increase risk for postoperative complications by raising central venous pressures. We sought to determine the relationship between preoperative echocardiographic measurements of diastolic function, including myocardial deformation imaging, on (a) preoperative invasive catheterization measurements and (b) postoperative outcomes after the Fontan procedure. All patients that underwent Fontan procedure from 2011 to 2017 were included. Echocardiograms performed within 6months prior to Fontan operation were evaluated. Measurements of ventricular global and diastolic strain and strain rate were performed offline with TomTec speckle tracking software. Other diastolic function measurements included atrioventricular valve inflow and annular tissue Doppler imaging. Diastolic function measurements were correlated with pre-Fontan catheterization measurements and postoperative Fontan outcomes using Spearman's rho. Multivariable logistic regression for a prolonged LOS (>75%ile for postoperative LOS) was performed to adjust for preoperative risk factors. A total of 141 patients were included in the study. Majority had single morphologic right ventricle (58.9%). Median age at time of Fontan was 3.4years (IQR 2.9-4). Median hospital LOS was 9days (IQR 7-11). Circumferential diastolic strain rate weakly correlated with LOS (rho=-0.21, P=.01). There was no correlation between any other diastolic strain measurements and pre-Fontan end-diastolic pressure or postoperative LOS. In multivariable analysis, E/E' was the only echo measurement that predicted prolonged hospital LOS (OR 1.4, 95%CI: 1.1-1.8, P=.003). Preoperative diastolic strain measurements did not have a strong association with postoperative Fontan outcomes. Increased E/E' ratio, however, did predict greater LOS after Fontan procedure, and may be useful in preoperative risk stratification. Future studies are needed to further assess the utility of diastolic strain imaging in the single-ventricle population.

Abstract 004: Novel Serum Metabolites Associate With Diastolic Function: Evidence From the Bogalusa Heart Study

Introduction: Diastolic dysfunction is one key causal factor for heart failure with preserved ejection fraction (HFpEF). We conducted a metabolome-wide association study to identify novel diastolic function-related metabolites in relatively young and healthy adults. Hypothesis: We hypothesized that serum metabolites could predict diastolic function and thus potentially serve as biomarkers for subclinical disease. Methods: The study cohort consisted of 1,038 participants of the Bogalusa Heart Study (34.9% black, 57.3% females, aged 33.6-57.5 years). Diastolic function was assessed via 2D and tissue doppler echocardiography, and included peak early filling velocity (E), peak velocity caused by atrial contraction (A), medial mitral annular velocity (e’), left ventricular isovolumic relaxation time (IVRT), as well as deceleration time (DT). Untargeted metabolomic analysis of fasting serum samples was conducted. Multivariable-adjusted linear regression models were employed to assess the relationship of metabolites with echocardiographic measures of diastolic function. Results: Following quality control, 1202 metabolites were tested for association with E/A ratio, E/e’ ratio, IVRT, and DT. After Bonferroni correction, 9 novel metabolites, derived from amino acid, cofactor, energy, lipid, and nucleotide pathways, were significantly associated with diastolic function in blacks with nominal significance and consistent effect direction in whites (Table). Of these significant metabolites, 2 and 6 metabolites were associated with the E/A ratio and E/e’ ratio, respectively. No significant associations of metabolites with IVRT or DT were found. Fatty acid metabolism was the biological sub-pathway most represented in significant diastolic function-metabolite associations. Conclusion: The current study identified novel metabolites associated with diastolic function, suggesting that the serum metabolome, and its underlying biological pathways, may be implicated in HFpEF pathogenesis.

3384 Serum Metabolites from the Trimethylamine Pathway Associate with Left Ventricular Diastolic Function: The Bogalusa Heart Study

OBJECTIVES/SPECIFIC AIMS: This population-based study aims to assess the individual and collective relationship between TMA-associated metabolites and echocardiographic parameters of left ventricular diastolic function. METHODS/STUDY POPULATION: The study cohort consisted of 1,039 adult participants of the Bogalusa Heart Study (35.13% black, 57.94% female, aged 33.60 to 57.47 years). Left ventricular diastolic function was assessed via two dimensional and tissue Doppler echocardiography. Echocardiographic parameters of diastolic function included peak early (E, cm/s) and late transmitral flow velocities (A, cm/s), septal mitral annular velocity (e’, cm/s), left ventricular isovolumic relaxation time (IVRT, ms), and peak early diastolic transmitral flow velocity deceleration time (DT, ms). Metabolomic analysis of fasting serum samples was conducted via ultrahigh performance liquid chromatography-tandem mass spectroscopy. Six metabolites in the TMA pathway, carnitine, choline, TMAO, betaine, ergothioneine, dimethylglycine, and two composite variables, the betaine/choline ratio as well as the weighted sum of the six TMA-associated metabolites (TMA score), were selected a priori and tested for association with echocardiographic parameters of diastolic function. Raw metabolite values were divided by their respective standard deviation to create an exposure variable for each individual metabolite. The betaine/choline ratio was calculated utilizing the raw value of each metabolite. The z-score method was used to transform the six metabolites to the same scale and these values were used to calculate the TMA score. Multivariable-adjusted linear regression models were employed to assess the relationship of TMA-associated metabolites with echocardiographic measures of diastolic function. Covariates adjusted for included sex, age, race, education, alcohol drinking, cigarette smoking, heart rate, systolic blood pressure, glomerular filtrate rate, body mass index, low density lipoprotein cholesterol, high density lipoprotein cholesterol, hemoglobin A1c, serum triglycerides, as well as blood pressure-, lipid-, and glucose-lowering medications. RESULTS/ANTICIPATED RESULTS: After stringent Bonferroni correction for multiple testing, four TMA-associated metabolites as well the TMA score were significantly associated with diastolic function. TMAO was inversely associated with IVRT (ß = −0.002 (0.00); p-value = 2.00E-03). Betaine (ß = 0.40 (0.08); p-value = 2.10E-07), carnitine (ß = 0.30 (0.07); p-value = 7.80E-05), dimethylglycine (ß = 0.27 (0.07); p-value = 3.00E-04), and the TMA score (ß = 0.10 (0.02); p-value = 3.40E-05), were positively associated with the septal E/e’ ratio. No significant associations were observed between metabolites or metabolite composite scores from the TMA pathway and the E/A ratio or DT. DISCUSSION/SIGNIFICANCE OF IMPACT: This is the first population-based study to assess the role of TMA-associated metabolites in left ventricular diastolic function. Betaine, carnitine, dimethylglycine, and a metabolite score combining serum metabolites from the TMA pathway were positively associated with the septal E/e’ ratio, suggesting that a higher concentration of TMA-associated metabolites correlates with impaired diastolic function. These results suggest that both individual and grouped metabolites from the TMA pathway may serve as early biomarkers for pre-clinical diastolic dysfunction, an important causal factor for HFpEF. Future longitudinal, multi-omic studies incorporating microbiome, metabolomic and dietary analyses are needed to characterize the risk of ventricular diastolic function and HFpEF in the setting of exposure to TMA-associated metabolites.

Abstract 17067: MAVERICK-HCM: Phase 2 Randomized, Multi-Center, Double-Blind, Placebo-Controlled Concentration-Guided Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) carries substantial lifelong morbidity. Mutations in sarcomeric proteins that lead to HCM cause excess contractility, poor relaxation, and inefficient energy utilization. Although obstructive physiology is a prominent feature of disease, approximately 30% of HCM patients experience symptoms in the context of non-obstructive HCM (nHCM). Management options are extremely limited with little other than cardiac transplantation to offer severely affected patients. Mavacamten (MAVA), a first-in-class small molecule, is a selective modulator of cardiac myosin that inhibits the cardiac myosin ATPase to reversibly attenuate cardiac contractility. In addition to its effects on contractility, MAVA has been shown to improve LV compliance in preclinical and clinical studies. The Phase 2 MAVERICK-HCM study is designed to evaluate safety and tolerability, and to provide pilot data on the effects of MAVA on biomarkers, cardiac function, and exercise capacity in nHCM. Methods: This double-blind study will enroll 60 individuals with nHCM (Left ventricular outflow tract gradient &lt;30 mmHg; resting or provoked), NYHA Class II or III, and LVEF ≥55%. Subjects will be randomized 1:1:1 to one of two target plasma drug concentrations (Group 1: ~200 ng/mL and Group 2: ~500 ng/mL) or placebo for 16 weeks. The starting dose of MAVA is 5 mg, with one-step dose titration at Week 6 based on plasma drug concentration. Predefined criteria, including LVEF, will guide study drug discontinuation if indicated. Cardiopulmonary exercise testing will be performed at baseline and Week 16 to assess the impact on exercise capacity. The primary endpoint is the frequency and severity of treatment-emergent adverse events. The study design also includes multiple secondary endpoints including echocardiographic measures of diastolic function, NT-proBNP levels, patient reported outcomes, and physical activity by wearable accelerometer. An independent data monitoring committee will oversee safety. Conclusions: MAVERICK-HCM is testing a novel therapy to improve symptom burden in nHCM; a patient cohort currently lacking effective treatment. By targeting a core molecular mechanism of disease, MAVA has the potential to alter natural history.

Correlation between Invasive Hemodynamic Measurements and Echocardiographic Markers of LV Diastolic Function in Heart Transplant Recipients

Introduction Left ventricular diastolic dysfunction in orthotopic heart transplant patients has been thought to be a marker of rejection and predictive of increased mortality. However, standard echocardiographic measurements of diastolic function have not been validated in this population. Factors unique to transplant recipients including larger atria, younger donor hearts, and electrical dissociation between donor and recipient hearts may affect echo measurements. We evaluated the correlation between echo parameters and left-ventricular end diastolic pressure in transplant recipients. Hypothesis At one year post-transplant, standard echocardiographic markers of diastolic function do not correlate well with invasive hemodynamic measurements of diastolic function given the unique characteristics of cardiac transplantation. Methods A series of 115 consecutive heart transplant recipients at our institution between January 2010 and December 2015 who were assessed at the time of their one-year post-transplant follow-up visit with same-day echocardiograms and cardiac catheterizations were studied. Left ventricular end-diastolic pressure (LVEDP) was measured at cardiac catheterization. Echocardiographic parameters of diastolic function included E/A, septal E/e', lateral E/e', average E/e', and left atrial volume. Chart abstraction was performed for clinical data evaluation. Linear association among catheterization and echo parameters was determined by the Pearson product moment correlation coefficient. Results None of the standard echocardiographic parameters of diastolic function were well correlated with LVEDP ( Table 1 ). Only E/A had a statistically significant correlation with LVEDP, with a correlation coefficient of 0.27 (p = 0.007). Septal, lateral, and average E/e’ were predictors of death and re-hospitalization for rejection (p ≤ 0.001 for all). Conclusions Standard echocardiographic markers of diastolic function were not well-correlated with LVEDP, suggesting they are not reliable surrogates of LVEDP. However, elevated E/e’ ratio was associated with subsequent death and hospitalization for allograft rejection, implying that early mitral filling and tissue velocity may describe important allograft functional properties independent of resting LVEDP.

Evaluation of the relationship between ventricular end-diastolic pressure and echocardiographic measures of diastolic function in adults with a Fontan circulation

BackgroundEchocardiographic assessment of diastolic function in the setting of Fontan physiology is not well validated. We recently demonstrated that atrioventricular systolic to diastolic duration ratio (AVV S/D ratio) independently predicts mortality in Fontan-adults and that a value >1.1 was associated with poor prognosis. PurposeTo correlate echocardiographic measures of diastolic function with direct measurement of ventricular end-diastolic pressure (VEDP). MethodsA retrospective analysis was undertaken of Fontan-adults who had transthoracic echocardiography (TTE) within 12 months of direct measurement of VEDP during cardiac catheterisation. ResultsFifteen Fontan adults (3 males, mean age 29 ± 9 years) were evaluated. Thirteen patients had dominant morphologic left ventricle and 2 had morphologic right ventricle. Four had atriopulmonary connection and 11 had total cavopulmonary connection. Twelve patients were NYHA Class I/II and 3 were Class III. Time between TTE and cardiac catheter was 46 ± 113 days; VEDP was 8 ± 5 mmHg. Ten patients had preserved ventricular function, 3 had mild and 2 had moderate systolic impairment by subjective TTE assessment. AVV S/D ratio had the strongest correlation with VEDP (r = 0.8, p = 0.001). AVV S/D ratio ≥ 1.1 had 100% positive predictive value and 92% negative predictive value for detecting VEDP >10 mmHg. The only conventional echocardiographic measure of diastolic function that correlated with VEDP was pulmonary vein A wave - atrioventricular A wave duration difference (r = 0.8, p = 0.02). ConclusionsTTE measures reflect VEDP in adults with a Fontan circulation. AVV S/D ratio is a simple parameter yet to enter standard practice that can be used to identify elevated VEDP.

Echocardiographic Detection of Increased Ventricular Diastolic Stiffness in Pediatric Heart Transplant Recipients: A Pilot Study

Pediatric heart transplant recipients are at risk for increased left ventricular (LV) diastolic stiffness. However, the noninvasive evaluation of LV stiffness has remained elusive in this population. The objective of this study was to compare novel echocardiographic measures of LV diastolic stiffness versus gold-standard measures derived from pressure-volume loop (PVL) analysis in pediatric heart transplant recipients. Patients undergoing left heart catheterization were prospectively enrolled. PVLs were obtained via conductance. The end-diastolic pressure-volume relationship was obtained via balloon occlusion. The stiffness constant, β, was calculated. Echocardiographic measures of diastolic function were derived from spectral and tissue Doppler and two-dimensional speckle-tracking. Ventricular volumes were measured using three-dimensional echocardiography. The novel echocardiographic estimates of ventricular stiffness included E:e'/end-diastolic volume (EDV) and E:early diastolic strain rate/EDV. Of 24 children, 18 were heart transplant recipients. Six control patients had hemodynamically insignificant patent ductus arteriosus or coronary fistula. The mean age was 9.1±5.6years. Median end-diastolic pressure was 9mm Hg (interquartile range, 8-13mm Hg). Lateral E:e'/EDV (r=0.59, P<.01), septal E:e'/EDV (r=0.57, P<.01), and (E:circumferential early diastolic strain rate)/EDV (r=0.54, P<.01) correlated with β. Lateral E:e'/EDV displayed a C statistic of 0.93 in detecting patients with abnormal LV stiffness (β>0.015mL-1). A lateral E:e'/EDV of >0.15mL-1 had 89% sensitivity and 93% specificity in detecting an abnormal β. Echocardiographic estimates of ventricular stiffness may be accurate compared with the gold standard in pediatric heart transplant recipients. The clinical usefulness of these noninvasive measures in assessing LV stiffness merits further study in children.

Reduced Myocardial Flow Reserve Is Associated With Diastolic Dysfunction and Decreased Left Atrial Strain in Patients With Normal Ejection Fraction and Epicardial Perfusion

IntroductionCoronary microvascular dysfunction (MVD) may contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Using myocardial flow reserve (MFR) measured by positron emission tomography (PET) as an assessment of microvascular function, we hypothesized that abnormal MFR is associated with LV diastolic dysfunction (DD) and reduced LV and LA strain in patients with risk factors for HFpEF and normal epicardial perfusion on cardiac PET. Methods and ResultsRetrospective study of patients without heart failure who underwent cardiac rubidium-82 PET and echocardiography. Global MFR was calculated as the ratio of global stress to rest myocardial blood flow. Echocardiographic measures of diastolic function were recorded. Global longitudinal LA and LV strain were measured with a 2-dimensional speckle-tracking technique. Relationships among MFR and echocardiographic measures were assessed with linear regression, analysis of variance, and test for trend. Seventy-three patients (age 64 ± 11 years, 52% male) were identified with no epicardial perfusion defect on cardiac PET and an ejection fraction ≥50%. Decreased MFR was associated with LV DD (P = .02) and increased E/e', an estimation of LV filling pressure (low E/e' [<8] vs. high E/e' [>15], P < .001). MFR was associated with LA strain independent of age, gender, and common comorbidities (adjusted β = 2.6% per unit MFR, P = 0.046); however, MFR was only marginally related to LV strain. ConclusionsIn patients with risk factors for HFpEF, MVD assessed with MFR was associated with DD, increased estimated LV filling pressure, and abnormal LA strain.

Invited Commentary: Searching for the Perfect Measure of Diastolic Dysfunction-A Futile Exercise?

Heart failure with preserved ejection fraction (HFpEF) is common, recalcitrant to treatment, and associated with poor outcomes. Diastolic dysfunction (DD) is an independent predictor of HFpEF risk, associated clinical manifestations, and long-term outcomes. However, the usefulness of diastolic function assessment is limited by the heterogeneity in the existing definitions of DD. In this issue of the Journal, Rasmussen-Torvik et al. (Am J Epidemiol. 2017;185(12):1221-1227) have highlighted this problem by evaluating the prevalence and concordance of 4 established definitions of DD in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. The authors demonstrate significant variability in prevalence of DD and its association with established risk factors across the different definitions. These findings suggest that the current 1-dimensional approach to HFpEF risk prediction based on noninvasive measures of diastolic function may not be optimal. Perhaps the future of HFpEF risk assessment lies in a multimodality approach that combines the relevant echocardiographic measures of diastolic function with blood-based biomarkers (such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP)) and a measure of functional status (such as exercise capacity).

Utility of Echocardiography in the Assessment of Left Ventricular Diastolic Function and Restrictive Physiology in Children and Young Adults with Restrictive Cardiomyopathy: A Comparative Echocardiography-Catheterization Study.

The aim of the study is to determine the utility of echocardiography in the assessment of diastolic function in children and young adults with restrictive cardiomyopathy (RCM). RCM is a rare disease with high mortality requiring frequent surveillance. Accurate, noninvasive echocardiographic measures of diastolic function may reduce the need for invasive catheterization. Single-center, prospective, observational study of pediatric and young adult RCM patients undergoing assessment of diastolic parameters by simultaneous transthoracic echocardiogram (TTE) and invasive catheterization. Twenty-one studies in 15 subjects [median (IQR)=13.8years (7.0-19.2), 60% female] were acquired with median left ventricular end-diastolic pressure (LVEDP) 21 (IQR 18-25) mmHg. TTE parameters of diastolic function, including pulmonary vein A wave duration (r s =0.79) and indexed left atrial volume (r s =0.49), demonstrated significant positive correlation, while mitral valve A (r s =-0.44), lateral e' (r s =-0.61) and lateral a' (r s =-0.61) velocities showed significant negative correlation with LVEDP. Lateral a' velocity (≤0.042m/s) and pulmonary vein A wave duration (≥156m/s) both had sensitivity and specificity ≥80% for LVEDP≥20mmHg. In pediatric and young adult patients with RCM, lateral a' velocity and pulmonary vein A wave duration predicted elevated LVEDP with high sensitivity and specificity; however, due to technical limitations the latter was reliably measured in 12/21 patients. These noninvasive parameters may have utility in identifying patients that require further assessment with invasive testing. These findings require validation in a multicenter prospective cohort prior to widespread clinical implementation.

Speckle-Tracking Echocardiographic Measures of Right Ventricular Diastolic Function Correlate with Reference Standard Measures Before and After Preload Alteration in Children.

The accuracy of echocardiographic measures of right ventricular (RV) diastolic function has been sparsely studied. Our objective was to evaluate the correlation between echocardiographic and reference standard measures of RV diastolic function derived from micromanometer pressure analysis before and after preload alteration in children. Echocardiograms and micromanometer pressure analyses were prospectively performed before and after fluid bolus in children undergoing right heart catheterization. The isovolumic relaxation time constant (τ) and end-diastolic pressure (EDP) were measured. Conventional and speckle-tracking echocardiographic (STE) parameters of RV systolic and diastolic function were assessed. Normal saline bolus was given to increase RV EDP by 20%. Twenty-eight studies were performed in 22 patients with congenital heart disease or postheart transplantation. Mean age was 8.7±6.1years. RV longitudinal early diastolic strain rate (EDSR) correlated with τ before (r=0.57, p=0.001) and after fluid bolus (r=0.48, p=0.008). No conventional echocardiographic measures correlated with τ both before and after fluid bolus. Multiple regression analysis revealed RV EDSR and LV circumferential EDSR as independent predictors of RV τ. There were no independent predictors of EDP. RV EDSR appears to correlate with the reference standard measure of early active ventricular relaxation in children at baseline and after changes in preload. Conventional echocardiographic measures of diastolic function were not predictive of diastolic function after preload alteration. Future studies should assess the prognostic significance of STE measures of diastolic function in this population.

Midlife blood pressure predicts future diastolic dysfunction independently of blood pressure

ObjectivesHigh blood pressure (BP) is associated with diastolic dysfunction, but the consequence of elevated BP over the adult life course on diastolic function is unknown. We hypothesised that high BP...