Citations

Introduction: Patients with hypertrophic cardiomyopathy (HCM) have lower peak oxygen uptake (VO2) than healthy peers. The mechanism of peak VO2 limitation in HCM has not been fully elucidated. Hypothesis: We assessed the hypothesis that resting echocardiographic parameters are predictive of peak VO2 in HCM. Methods: A retrospective review of adult HCM patients seen at a tertiary referral center from 2006-2012 was performed. Patients who underwent a comprehensive echocardiogram and cardiopulmonary treadmill exercise test within 1 week were included. Multivariate modeling was used to identify predictors of peak VO2 adjusting for age, sex, body mass index, beta blocker use, diabetes, smoking, systolic blood pressure, and obstructive HCM. Results: Five hundred and forty one patients met the inclusion criteria. The average age was 52 +/- 0.65 years, 62% were male, 78% had obstructive HCM, and 42% were NYHA class III or IV. Independent predictors of peak VO2 included averaged left ventricular (LV) longitudinal peak systolic strain (p<0.01) and right ventricular systolic pressure (RVSP) (p<0.01) (Figure 1). Obstructive versus non-obstructive HCM, grade of diastolic dysfunction, LV mass and wall thickness, left atrial volume index, right ventricular dysfunction and moderate or greater mitral or tricuspid regurgitation were not independent predictors of peak VO2. Conclusions: In conclusion, higher RVSP and less negative LV longitudinal peak systolic strain were moderate independent predictors of lower peak VO2. These findings confirm the hypothesis that resting echocardiographic parameters are predictive of peak VO2 in HCM. Further study of the relationship between echocardiographic findings and outcomes on cardiopulmonary exercise testing may help elucidate the mechanisms of exercise limitation in HCM.

Introduction: Cross-sectional studies in patient with hypertensive heart disease (HHD) and heart failure with normal ejection fraction (HFnlEF) suggested impairment of longitudinal myocardial mechanics as assessed by tissue Doppler imaging. It has been suggested that enhanced circumferential, and/or radial LV mechanics or LV remodeling compensates for depression in longitudinal function and thus, preserves EF in HHD or HFnlEF. Hypothesis : We hypothesized that if longitudinal performance is depressed, whether due to increased afterload or to intrinsic myocardial dysfunction, circumferential and radial LV mechanics would also be effected. To test this hypothesis, we used an aged canine model of hypertension. Methods: Elderly dogs (n=22) underwent bilateral renal wrapping to induce hypertension. 2D echocardiography (mid-short axis views) was performed before and 8 weeks after renal wrapping; peak radial (PR) and peak circumferential (PC) regional strains were measured by speckle tracking averaging data from 6 segments. Ejection fraction (EF), LV mass index (LVMI), systolic blood pressure (SBP), and circumferential wall stress (CWS) were assessed as well. Results : See table . PR correlated with PC (r=0.65), EF (r=0.67), LWMI (r=0.71) and CWS (r=0.58) (p<0.005 for all). PC correlated also with EF (r=0.60), LWMI (r=0.49) and CWS (r=0.48) (p<0.01 for all). The relationship between EF and CWS (r 2 =0.64, p<0.001) was modified by the addition of either PC (r 2 =0.74, p for PC =0.005) or PR strain(r 2 =0.69, p for PR =0.04). Conclusions : These data show that development of hypertension with LV hypertrophy does not enhance but impairs circumferential and radial LV mechanics as assessed with strain imaging, and that like EF, circumferential and radial strain are related to afterload (wall stress). However, both confer additional information regarding contractility. Conclusions regarding myocardial function based on strain imaging must account for its load dependence.

Background: Exercise normally enhances LV relaxation with minimal change in filling pressure (P). We hypothesize that exercise in hypertensive (HTN) patients increases LV diastolic P through a direct effect on relaxation and ventricular-vascular coupling. Methods: Patients (n=21) with HTN, normal EF, and no coronary disease underwent simultaneous micromanometer LV P and echo-Doppler measurements at rest and with low level supine exercise (12 bicycle; 9 arm weight). Continuous volume (V) was obtained from mitral Doppler inflow and end-diastolic (ED) and end-systolic (ES) V from 2-D echo. Relaxation-corrected LV diastolic P was used for PV relationship P = α.e β*V ; to account for covariance in α and β, LV capacitance (EDV 20 = Ln[20mmHg/α]/β) was reported. Single beat method was used for LV ES elastance (Ees). Group 1 did not increase mean LV diastolic P (mDP) with exercise, Group 2 increased mDP >6mmHg. Results: LV diastolic P and arterial and LV ES elastance increased with exercise; EDV was stable; EDV 20 decreased. Compared to Group 1, Group 2 had a greater exercise-induced increase in afterload, associated with increase in LV minimal P and impaired augmentation of relaxation rate (Table & Figure ). Conclusions: In patients with HTN, impairment of ventricular relaxation plays a major role in causing LV filling P increase with exercise, which is related to ventricular-vascular coupling.

Limited information exists regarding the echocardiographic and clinical predictors of exercise capacity and their effects on exercise with advancing age or by sex. We hypothesized that LV diastolic function (DF) impacts exercise capacity to a greater degree with advancing age. This was a prospective cohort study of consecutive patients undergoing routine exercise echocardiography with the Bruce protocol (n=2955). DF assessments at rest and exercise were performed. Those with echocardiographic exercise-induced ischemia and significant valvular disease were excluded. Univariate and multivariate analyses were conducted to determine the strongest echocardiographic and clinical predictors of exercise capacity (METs). Results were reported as unstandardized β coefficient (Standard Error) as outlined beside each variable. Age and sex interactions of these predictors with exercise capacity were determined. The strongest independent multivariate predictors of exercise capacity were female vs. male sex [−1.98 (0.07), p<0.0001], body mass index >30 kg/m 2 [−1.24 (0.08), p<0.0001], age per 10 year increment [−0.85 (0.01), p<0.0001], mild resting diastolic dysfunction vs. normal [−0.70 (0.10), p<0.0001], and moderate/severe resting diastolic dysfunction vs. normal [−1.3 (0.13), p<0.0001]. LV filling pressures measured by a resting E/e’ ≥ 15 [−0.42 (0.14), p=0.004] or exercise E/e’≥ 15 [−0.31 (0.14), p<0.0001] similarly predicted a reduction in exercise capacity, each in separate multivariate analyses. The impact of impaired relaxation and left ventricular filling pressures on exercise capacity increased with advancing age (p<0.001 and p=0.02 respectively), and was most marked after age 50. These predictors had a similar negative effect on exercise capacity among men and women (p=NS). In conclusion, in this large population referred for exercise echocardiography and not limited by ischemia, resting DF and resting/exercise LV filling pressures independently predicted exercise capacity. The increasingly potent effect of impaired relaxation and exercise LV filling pressures with advancing age suggest that DF plays an important role in the development of exercise intolerance in the elderly.

Background: Chronic renal insufficiency (CRI) is a strong predictor of increased mortality in the presence of heart failure (HF) and its prevalence has been increasing in the US. In addition, CRI is a major contributing factor to the progression of HF as it is associated with chronic volume overload, accelerated atherosclerosis and hypertension (HTN). The first aim of the current study was to evaluate the prevalence of CRI in an adult general population. The second aim was to address whether calculated glomerular filtration rate (cGFR) adds value to the cardiac biomarkers BNP and NT-proBNP in detecting early cardiac structural and functional impairments in the general population. Methods: From 1997 to 1999 medical history, physical examination, echocardiography, BNP (Biosite) and NT-proBNP (Roche) and serum creatinine (SCr) were obtained in 1,982 randomly selected residents of Olmsted County, MN >= 45 years (range 45 – 96 years). GFR was calculated using the Cockroft Gault equation. CRI was defined as a GFR < 60 ml/min. Cardiac structure and function were evaluated by in-depth echocardiographic examination. Results: The prevalence of cardiovascular co-morbidities was coronary atherosclerosis 12%, HTN 29.5% and diabetes mellitus 7.5%. The prevalence of CRI was 22.8% when cGFR was used for its detection. Importantly, by Chi-Square model, cGFR significantly increased the ability of BNP in detecting left ventricular hypertrophy (LVH) (p=0.004), increased relative wall thickness (p=0.0036), diastolic dysfunction (DDF) (p=0.0001) and HTN (p=0.0002). Similarly, when combined with NT-proBNP, cGFR increased the predictive power of detecting DDF (p=0.0001) and HTN (p=0.0366). Conclusion: This study reports a higher than predicted prevalence of CRI in this general US population equal to 23% and closely associated with the prevalence of HTN (29.5%). Importantly, this study also demonstrates that cGFR has additive predictive power when used in combination with two cardiac biomarkers of cardiac dysfunction and remodeling, BNP and NT-proBNP. These studies underscore the increasing burden of CRI in the general population and the utility of assessing cardiorenal function by combining renal and cardiac biomarkers in assessment of cardiac structure and function.

Background Patients with heart failure and preserved ejection fraction (HFpEF) have diastolic dysfunction, but are traditionally considered to have normal left ventricular (LV) systolic function. However, ventricular remodeling can result in preservation of EF despite abnormal myocardial contractility. Methods We performed echo-Doppler characterization of LV chamber and myocardial systolic properties in a population-based study, comparing patients with HFpEF (N=244) to healthy controls (CON, N=617), and hypertensives without HF (HTN, N=719), then examined long term outcome. Results All subjects had a normal EF (>50%). However, systolic chamber function, measured by wall stress-corrected endocardial fractional shortening (sc-eFS), was impaired in HFpEF (96±12%) compared to both CON (100±8%, p<0.0001) and HTN (108±11%, p<0.0001). Myocardial contractility, assessed by wall stress-corrected midwall shortening (sc-mFS), was also reduced in HFpEF (91±13%) compared to CON (100±10%, p<0.0001) and HTN (105±12%, p<0.0001). HTN had increased sc-eFS and sc-mFS compared with both HFpEF and CON (p<0.0001). In HFpEF, impaired sc-mFS was associated with increased mortality, independent of age (Figure ), while EF and sc- eFS were not. Conclusions Despite preservation of EF, unselected HFpEF patients from the community have significantly impaired systolic chamber function and depressed myocardial contractility. Abnormal myocardial contractility in HFpEF is associated with increased mortality. These data suggest that myocardial systolic dysfunction contributes to the pathophysiology of HFpEF and may represent a potential therapeutic target.

Introduction: Impaired peak VO2 and obesity are known predictors of morbidity and mortality in Hypertrophic Cardiomyopathy (HCM). The purpose of this study is to determine the degree of exercise impairment due to excess weight in patients with HCM. Methods: Adult HCM patients who underwent cardiopulmonary treadmill testing at our tertiary referral center from 2006 - 2012 and had consented to research participation were identified retrospectively. Percent predicted peak VO2 was calculated by the Astrand formula for men and the Jones formula for women which adjust for age and gender. Baseline echocardiographic features obtained within 1 week of exercise testing and % predicted peak VO2 were compared among four groups of patients stratified by body mass index (BMI). Results: 510 patients were identified, with a mean age at diagnosis of 44.3 ± 16.1 years, 186 (36.5%) female. Mean BMI at the time of cardiopulmonary exercise testing was 29.7 ± 5.3 and 227 (44.6%) patients had a BMI ≥ 30. Overweight and obese patients were older and were more likely to be male than their normal weight peers. However, there was no significant difference in ejection fraction (EF), resting left ventricular outflow tract gradient, right ventricular systolic pressure (RVSP), or septal thickness among the groups. HCM patients show impaired peak VO2 across all BMI groups. While peak VO2 increased progressively across BMI groups consistent with greater O2 demand generated by higher body weight, the adjusted peak VO2 in mL/kg/min fell progressively, indicating progressively greater performance impairment with increasing BMI despite similar degrees of cardiac impairment (p <0.0001) (Table 1). Conclusion: Increased BMI is associated with reduced exercise performance in a graded manner in HCM patients independent of cardiac impairment identified on echocardiography.

Introduction: The prevalence of bicuspid aortic valves (BAV) is enriched thirty-fold in women with Turner Syndrome (TS) in comparison with the general population. Hypothesis: Common autosomal variants influence the development of BAV in TS women, who may be uniquely sensitized to these variants by the loss of one X chromosome. We sought to identify autosomal BAV susceptibility genes in a cohort of TS women (average age 30 years, 38% BAV, 18% coarctation). Methods: A total of 106 TS women of European ancestry with BAV and 173 TS women with tricuspid aortic valves were genotyped on Illumina Omni-Express arrays. Valve phenotypes were determined by independent review of echocardiograms from the enrolling sites. Tests of association were performed using logistic regression without adjustment for covariates and were summarized in a meta-analysis. Results: Xp dosage was inversely and quantitatively associated with BAV status (P=0.02). Large, recurrent copy number variants in 1p36.13, 3q29, 8p23.1 and 9p24.3 were significantly enriched in BAV cases. After exclusion of 26 outlier samples in multidimensional scaling analysis, there was no significant genomic inflation (lambda= 1.02). The strongest genome-wide association signals were observed in 1p36.23, 3q23, 12q21.2, 18q21 and 22q13.31, and did not overlap with previously reported loci for BAV. A total of 13 SNPs in 18q21 were positively associated with BAV (OR=2.5-4.3) with a minimum P value of 1x10-7. Replication of these regions in independent groups of cases is ongoing. Conclusion: Our results demonstrate that autosomal variants with large magnitudes of effect contribute to BAV in TS women, confirming our hypothesis, and provide evidence for gene-gene interactions in BAV formation.

Increasing age is a major risk factor for calcific aortic valve disease (CAVD). Interestingly, SIRT6 knockout mice have a marked progeroid phenotype, and we recently reported that sirtuin enzyme expression is dramatically reduced with aging and that SIRT6 expression is reduced further in valves from patients with end-stage CAVD. It is unknown, however, whether experimentally reducing SIRT6 promotes osteogenic signaling in the valve and ultimately accelerates progression of CAVD. Thus, we used cultured mouse aortic valve interstitial cells and ldlr-deficient, apolipoprotein B100-only mice (LA) that were SIRT6 wild-type (LA-SIRT6 +/+ ) or heterozygous (LA-SIRT6 +/- ) and fed a Western diet for 3 or 12 months to determine the role of SIRT6 in valve calcification. In vitro , reduction of SIRT6 increased histone acetylation and significantly increased mRNA and protein levels of the osteogenic genes Runx2 and Sp7 in response to bone morphogenetic protein 2 (100ng/ml BMP2 for 18 hours), and siRNA knockdown of SIRT6 increased mRNA levels of Sp7 even in the absence of exogenous bone morphogens. Using high-resolution ultrasound to evaluate aortic valve function in vivo, we found that 3 month old LA-SIRT6 +/- mice did not have significant impairments in valve function compared to LA-SIRT6 +/+ mice. In contrast, 12 month old LA-SIRT6 +/- had dramatically worsened aortic valve dysfunction and stenosis compared to LA-SIRT6 +/+ mice, which was also associated with reductions in left ventricular ejection fraction. Collectively, our data strongly suggest SIRT6 plays a critical role in the tonic repression of osteogenic signaling in the aortic valve, and that age-related reductions in SIRT6 are likely to increase susceptibility to valve calcification in response to risk factors for CAVD such as hypercholesterolemia. Collectively, increasing activity of SIRT6 or reducing acetylation of its targets may serve as viable therapeutic strategies to slow progression of age-related valvular calcification and stenosis.

Endothelial cell senescence promotes inflammation and impairs endothelium-dependent vasodilation. While aging, hypercholesterolemia, and caloric excess are known to drive cellular senescence in part through activation of mTOR, it is unknown whether reducing mTOR signaling can improve vasomotor function in aging mice. Here, we used hypercholesterolemic mice (Ldlr -/- /apoB 100/100 , or LA) carrying intact copies of mTOR (LA-mTOR +/+ ) or were deficient in one copy of mTOR (LA- mTOR +/- ). Mice were fed Western Diet for 6 or 12 months, and vasomotor function in aorta was evaluated using isolated organ chamber baths. Maximum relaxation to acetylcholine (MR ACH ) was progressively impaired from 6 months to 12 months in LA-mTOR +/+ mice (55±4% and 30±4%, respectively). In contrast to our hypothesis, however, MR ACH was not significantly improved in LA-mTOR +/- mice at either time point (62±3% and 35±5%, respectively). Interestingly, a subgroup analysis showed significant improvement in MR ACH in male mice at the 6-month point (male LA-mTOR +/+ mice = 30 ± 9% vs male LA-mTOR +/- mice = 55±4%; p < 0.01), whereas vasomotor function in female mice was nearly identical across groups. There was no significant difference at the 12-month point (male LA-mTOR +/+ mice = 19 ± 3% vs male LA-mTOR +/- mice = 22 ± 5%). Relaxation to acetylcholine was attenuated by L-NAME at 6 months and 12 months (but identical between genotypes) and relaxation to nitroprusside was identical between strains at each time point, suggesting that changes in endothelial function were not masked by compensatory mechanisms (e.g., endothelium-derived hyperpolarizing factors). Furthermore, reduction of mTOR did not elicit changes in maximal tension generated in response to Prostaglandin F 2 α at either time point. Collectively, despite compelling evidence from in vitro model systems, genetic reduction of mTOR signaling in vivo does not appear to be sufficient to improve vasomotor function in our model of aging hypercholesterolemic mice. Our data do, however, shed light on a potential role of sex in dictating phenotypic changes in early to moderate stages of disease, which warrants further investigation.