South Asian-Specific MYBPC3Δ25bp Deletion Carriers Display Hypercontraction and Impaired Diastolic Function Under Exercise Stress

Background: A 25-base pair (25bp) intronic deletion in the MYBPC3 gene enriched in South Asians (SAs) is a risk allele for late-onset left ventricular (LV) dysfunction, hypertrophy, and heart failure (HF) with several forms of cardiomyopathy. However, the effect of this variant on exercise parameters has not been evaluated.Methods: As a pilot study, 10 asymptomatic SA carriers of the MYBPC3Δ25bp variant (52.9 ± 2.14 years) and 10 age- and gender-matched non-carriers (NCs) (50.1 ± 2.7 years) were evaluated at baseline and under exercise stress conditions using bicycle exercise echocardiography and continuous cardiac monitoring.Results: Baseline echocardiography parameters were not different between the two groups. However, in response to exercise stress, the carriers of Δ25bp had significantly higher LV ejection fraction (%) (CI: 4.57 ± 1.93; p < 0.0001), LV outflow tract peak velocity (m/s) (CI: 0.19 ± 0.07; p < 0.0001), and higher aortic valve (AV) peak velocity (m/s) (CI: 0.103 ± 0.08; p = 0.01) in comparison to NCs, and E/A ratio, a marker of diastolic compliance, was significantly lower in Δ25bp carriers (CI: 0.107 ± 0.102; p = 0.038). Interestingly, LV end-diastolic diameter (LVIDdia) was augmented in NCs in response to stress, while it did not increase in Δ25bp carriers (CI: 0.239 ± 0.125; p = 0.0002). Further, stress-induced right ventricular systolic excursion velocity s' (m/s), as a marker of right ventricle function, increased similarly in both groups, but tricuspid annular plane systolic excursion increased more in carriers (slope: 0.008; p = 0.0001), suggesting right ventricle functional differences between the two groups.Conclusions: These data support that MYBPC3Δ25bp is associated with LV hypercontraction under stress conditions with evidence of diastolic impairment.

Combination of Static Echocardiographic Indices for the Prediction of Fluid Responsiveness in Patients Undergoing Coronary Surgery: A Pilot Study

We investigated the role of echocardiographic indices consisting of left ventricular end-diastolic area (LVEDA) in combination with Doppler-derived surrogates of diastolic compliance and filling (E/E′, E′/S′, E′/A′; early transmitral flow velocity (E), tissue Doppler-derived early (E′) diastolic, late (A′) diastolic, or peak systolic (S′) velocity of the mitral annulus) in predicting fluid responsiveness in off-pump coronary surgery. Hemodynamic and echocardiographic variables were prospectively assessed under general anesthesia before and after a fluid challenge of 6 mL/kg during apnea at atmospheric pressure in 64 patients with LV ejection fraction ≥40%. Forty patients (63%) were fluid responders (≥15% increase in stroke volume index). E/E′ and E′/S′ could predict fluid responsiveness with area under the receiver operating characteristic curve (AUROC) of 0.71 (95% confidence interval [CI], 0.56–0.85; p = 0.006) and 0.68 (95% CI, 0.54–0.82; p = 0.017), respectively. The combination of LVEDA and E/E′ showed incremental predictive ability for fluid responsiveness compared with LVEDA (AUROC, 0.60; p = 0.170) or pulse pressure variation (AUROC, 0.70; p = 0.002), yielding the highest AUROC of 0.78 (95% CI, 0.66–0.90; p < 0.001). The combined index of echocardiographic variables reflecting LV dimension (LVEDA) and diastolic compliance and filling (E/E′) is a potentially useful predictor of fluid responsiveness.

Abstract 13402: FHL-1 Contributes to and Colocalizes With Titin in Cardiac Hypertrophy

Increased myocardial stiffness is a hallmark of impaired diastole in heart failure (HF). Hypo-phosphorylation of the N2B unique sequence (N2Bus) of titin (TTN), a giant myofilament protein, increases passive tension leading to diastolic dysfunction in HF. Enhancing the altered N2Bus phosphorylation improves cardiac stiffness and function. FHL-1, an interacting protein potentially modulating N2Bus phosphorylation is increased in HF. FHL-1 knockout mice display blunted cardiac hypertrophy and improved diastolic compliance in response to pressure-overload by transverse aortic constriction, TAC. FHL-1 also regulates skeletal muscle hypertrophy. We hypothesize that FHL-1 contributes to cardiac hypertrophy and colocalizes/interacts with TTN in heart failure. In house IHC data showed site-specific N2Bus hypo-phosphorylation at S4099, S4010 and S4185 in human HCM and/or DCM tissue samples. Longitudinal in-vivo studies showed that FHL-1 and cardiac hypertrophy markers genes were increased in left ventricles (LV) of TAC mice using RNA-seq. A persistently enhanced FHL-1 protein expression by immunoblotting and mass spectrometry strongly correlated with LV hypertrophy at 1, 4, and 6 weeks post-TAC. In addition, LV hypertrophy correlated negatively with function (fractional shortening). Increases in FHL-1 and hypertrophy markers mRNA levels were confirmed by RT-qPCR in neonatal rat ventricular myocytes (NRVM) under phenylephrine (PE) and endothelin-1 (ET-1) induced hypertrophy. Under similar conditions, FHL-1 protein levels were increased by immunofluorescence (IF) in cytoplasmic, perinuclear and nuclear regions of NRVM. Colocalization of phospho-TTN and FHL-1 was observed in NRVM and was enhanced under PE- and ET-1 induced hypertrophy. IF studies in human skeletal myotubes showed that FHL-1 expression was increased during myoblast differentiation and IGF1-E3R induced hypertrophy. Preliminary data using Microscale Thermophoresis showed binding affinity between N2Bus and FHL-1 proteins. Our studies show that FHL-1 contributes to hypertrophy in addition to N2B hypo-phosphorylation status contributing to diastolic dysfunction in HF. Targeting FHL-1 and TTN can be a potential strategy to improve diastolic compliance in HF.

Trabecular cutting: a novel surgical therapy to increase diastolic compliance

Heart failure with preserved ejection fraction (HFpEF) is a common cause of hospital admission in patients over 65 yr old and has high mortality. HFpEF is characterized by left ventricular (LV) hypertrophy that reduces compliance. Current HFpEF therapies control symptoms, but no existing medications or therapies can sustainably increase LV compliance. LV trabeculae develop hypertrophy and fibrosis that contribute to reduced LV compliance. This study expands our previous results in ex vivo human hearts to show that severing LV trabeculae increases diastolic compliance in an ex vivo working rabbit heart model. Trabecular cutting was performed in ex vivo rabbit hearts set up in a working heart perfusion system perfused with oxygenated Krebs-Henseleit buffer. A hook was inserted in the LV to cut trabeculae. End-systolic and end-diastolic pressure-volume relationships during transient preload reduction were recorded using an admittance catheter in the following three groups: control (no cutting; n = 9), mild cutting (15 cuts; n = 5), and aggressive cutting (30 cuts; n = 5). In a second experiment, each heart served as its own control. Hemodynamic data were recorded before and after trabecular cutting ( n = 10) or sham cutting ( n = 5) within the same heart. In the first experiments, trabecular cutting did not affect systolic function ( P > 0.05) but significantly increased overall diastolic compliance ( P = 0.009). Greater compliance was seen as trabecular cutting increased ( P = 0.002, r2 = 0.435). In the second experiment, significant increases in systolic function ( P = 0.048) and diastolic compliance ( P = 0.002) were seen after trabecular cutting compared with baseline. In conclusion, trabecular cutting significantly increases diastolic compliance without reducing systolic function. NEW & NOTEWORTHY We postulate that, in mammalian hearts, free-running trabeculae carneae exist to provide tensile support to the left ventricle and minimize diastolic wall stress. Because of hypertrophy and fibrosis of trabeculae in patients with left ventricular hypertrophy, this supportive role can become pathologic, worsening diastolic compliance. We demonstrate a novel operation involving cutting trabeculae as a method to acutely increase diastolic compliance in patients presenting with heart failure and diastolic dysfunction to improve their left ventricle compliance.

The Effect of Trabeculae Carneae on Left Ventricular Diastolic Compliance: Improvement in Compliance With Trabecular Cutting

The role of trabeculae carneae in modulating left ventricular (LV) diastolic compliance remains unclear. The objective of this study was to determine the contribution of trabeculae carneae to the LV diastolic compliance. LV pressure–volume compliance curves were measured in six human heart explants from patients with LV hypertrophy at baseline and following trabecular cutting. The effect of trabecular cutting was also analyzed with finite-element model (FEM) simulations. Our results demonstrated that LV compliance improved after trabecular cutting (p < 0.001). Finite-element simulations further demonstrated that stiffer trabeculae reduce LV compliance further, and that the presence of trabeculae reduced the wall stress in the apex. In conclusion, we demonstrate that integrity of the LV and trabeculae is important to maintain LV stiffness and loss in trabeculae leads to more LV compliance.

Relationship between obesity and left ventricular hypertrophy in children

Background Obesity is a chronic metabolic disorder associated with cardiovascular disease (CVD) increasing morbidity-mortality rates. It is apparent that a variety of adaptations/alterations in cardiac structure and function occurs as excessive adipose tissue accumulates. This leads to a decrease in diastolic compliance, eventually resulting in an increase in left ventricular filling pressure and left ventricular enlargement.Objective To evaluate left ventricular hypertrophy (LVH) among obese using electrocardiographic (ECG) criteria.Methods A cross-sectional study was conducted on 74 children aged 10-15 years from February 2009 to October 2009. The subjects were divided into obese and control groups. Physical examination and standard 12 lead electrocardiography (ECG) were done in both groups.Results Of 37 obese children, LVH were featured in 3 subjects, while in control group, only 1 child had LVH (P= 0.304). We found that mean RV6 in obese and control group were 9.8446 (SD 3.5854) and 11.9662 (SD 3.2857), respectively (P=0.005). As an additional findings, we found that birth weight was related to obesity in children.Conclusion There is no relation between obesity and left ventricular using ECG criteria in obese children aged 10-15 years.

Abstract 11217: A New Treatment for Diastolic Heart Failure: Trabecular Cutting

Background: Heart failure with preserved ejection fraction remains a leading cause of hospitalization, without development of new medications and operative procedures to treat these patients. We hypothesize that trabeculae carneae serve an important role in modulating LV diastolic compliance, and during hypertrophy of the myocardium, trabeculae contribute to abnormal compliance. Methods and Results: Eight ex vivo human hearts from patients with LV diastolic dysfunction were perfused at 37[[Unable to Display Character: &#8304;]]C and had a balloon inserted into the LV through the mitral annulus. Diastolic LV pressure-volume compliance curves were measured at baseline and following trabecular cutting. LV compliance improved significantly (n=6, p<0.001), but not in the control hearts without trabecular cutting (n=2, p=0.85). The figure shows aggregate data from the six hearts before and after trabecular cutting. To determine if trabeculae serve a similar role in all mammals, 28 hearts from 10 species were obtained. We demonstrate significant relationships between circumferential wall stress and the number of trabeculae in these species, particularly trabeculae which attach nets of trabeculae to the ventricle walls (p=0.02, n=733) and trabeculae located at the apex and free wall (p=0.02, n=602). The percent of LV cardiac titin of the stiff isoform (%N2B), a determinate of LV diastolic compliance, also demonstrated a significant relationship with the number of trabeculae with the same anatomic subsets (p=0.04, n=597; and p=0.02, n=488, respectively). Conclusions: We demonstrate for the first time that rather than being an embryologic remnant, trabeculae carneae serve an important role in the maintenance of passive LV diastolic compliance, and can contribute to LV diastolic dysfunction. A new procedure, cutting trabeculae, is proposed to improve LV diastolic compliance.

Abstract 11639: Interpretation of Diastolic Function in Hemodialysis Patients: The Importance of a Load Independent Index of Left Ventricular Diastolic Compliance

Background: Prior studies of diastolic function in the setting of end-stage renal disease (ESRD) primarily utilize E/e’, a volume dependent measure of left ventricular (LV) filling pressure. While such studies show that high E/e’ is common and associated with adverse outcomes in ESRD, these findings may not be attributable to intrinsic diastolic function. In contrast to E/e’, the LV end-diastolic pressure-volume relationship (EDPVR) (a load independent index of LV diastolic compliance) describes intrinsic LV diastolic function. Therefore, we sought to examine the effects of hemodialysis on EDPVR, and to delineate correlates of EDPVR in the setting of ESRD. We hypothesized that E/e’ and other indices of diastolic function are volume dependent in ESRD, while EDPVR is not. Methods: Twenty-nine patients underwent echocardiography directly before and during the last hour of dialysis. LV diastolic compliance was quantified using a single-beat EDPVR method (P = αVβ). The LV end-diastolic volume at an idealized pressure of 20 mmHg (EDV20) was calculated as a means of comparing EDPVR curves within and between patients (smaller EDV20 = lower diastolic compliance). Results: During hemodialysis, EDV20 did not significantly change (median [IQR] pre-dialysis EDV20 112 [93-113] ml; intra-dialysis EDV20 113 [94-138] ml; p=0.2). However, E/e’ decreased on average by 1.2 absolute units (AU) (median [IQR] pre-dialysis 7.0 [6.0-8.9] AU; intra-dialysis 6.0 [5.1-9.7] AU; p=0.004). E/e’ decreased by 2 AU for every 1 L/hr ultrafiltration rate (p=0.07). Significant correlates of lower pre-dialysis EDV20 (stiffer LV) included higher diastolic blood pressure (DBP) (β=-13 ml EDV20 per 10 mmHg DBP, p=0.005) and concentric LV remodeling, (β=-5ml EDV20 per 0.1 g/ml LV mass/volume ratio, p=0.004). NT-proBNP was associated with higher E/e’, (β=0.2 E/e’ per 1000 pg/ml higher NT-proBNP, p<0.001), but was not a significant correlate of EDV20 (p=0.5). Conclusions: LV end-diastolic compliance (EDV20) is less volume dependent than LV filling pressures (E/e’) in the setting of ESRD, and thus may be a better measure of intrinsic diastolic function than E/e’. Further studies are needed to determine whether EDV20 predicts adverse outcomes in the ESRD population.