Longer Left Ventricular Electric Delay Reduces Mitral Regurgitation After Cardiac Resynchronization Therapy: Mechanistic Insights From the SMART-AV Study (SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy).

BACKGROUND: Mitral regurgitation (MR) is associated with worse survival in those undergoing cardiac resynchronization therapy (CRT). Left ventricular (LV) lead position in CRT may ameliorate mechanisms of MR. We examine the association between a longer LV electric delay (QLV) at the LV stimulation site and MR reduction after CRT. METHODS AND RESULTS: QLV was assessed retrospectively in 426 patients enrolled in the SMART-AV study (SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in CRT). QLV was defined as the time from QRS onset to the first large peak of the LV electrogram. Linear regression and logistic regression were used to assess the association between baseline QLV and MR reduction at 6 months (absolute change in vena contracta width and odds of ≥1 grade reduction in MR). At baseline, there was no difference in MR grade, LV dyssynchrony, or LV volumes in those with QLV above versus below the median (95 ms). After multivariable adjustment, increasing QLV was an independent predictor of MR reduction at 6 months as reflected by an increased odds of MR response (odds ratio: 1.13 [1.03-1.25]/10 ms increase QLV; P=0.02) and a decrease in vena contracta width (P<0.001). At 3 months, longer QLV (≥median) was associated with significant decrease in LV end-systolic volume (ΔLV end-systolic volume -28.2±38.9 versus -4.9±33.8 mL, P<0.001). Adjustment for 3-month ΔLV end-systolic volume attenuated the association between QLV and 6-month MR reduction. CONCLUSIONS: In patients undergoing CRT, longer QLV was an independent predictor of MR reduction at 6 months and associated with interval 3-month LV reverse remodeling. These findings provide a mechanistic basis for using an electric-targeting LV lead strategy at the time of CRT implant.

A Diet Rich in Medium-Chain Fatty Acids Improves Systolic Function and Alters the Lipidomic Profile in Patients With Type 2 Diabetes: A Pilot Study.

CONTEXT: Excessive cardiac long-chain fatty acid (LCFA) metabolism/storage causes cardiomyopathy in animal models of type 2 diabetes. Medium-chain fatty acids (MCFAs) are absorbed and oxidized efficiently. Data in animal models of diabetes suggest MCFAs may benefit the heart. OBJECTIVE: Our objective was to test the effects of an MCFA-rich diet vs an LCFA-rich diet on plasma lipids, cardiac steatosis, and function in patients with type 2 diabetes. DESIGN: This was a double-blind, randomized, 2-week matched-feeding study. SETTING: The study included ambulatory patients in the general community. PATIENTS: Sixteen patients, ages 37-65 years, with type 2 diabetes, an ejection fraction greater than 45%, and no other systemic disease were included. INTERVENTION: Fourteen days of a diet rich in MCFAs or LCFAs, containing 38% as fat in total, was undertaken. MAIN OUTCOME MEASURES: Cardiac steatosis and function were the main outcome measures, with lipidomic changes considered a secondary outcome. RESULTS: The relatively load-independent measure of cardiac contractility, S', improved in the MCFA group (P < .05). Weight-adjusted stroke volume and cardiac output decreased in the LCFA group (both P < .05). The MCFA, but not the LCFA, diet decreased several plasma sphingolipids, ceramide, and acylcarnitines implicated in diabetic cardiomyopathy, and changes in several sphingolipids correlated with improved fasting insulins. CONCLUSIONS: Although a diet high in MCFAs does not change cardiac steatosis, our findings suggest that the MCFA-rich diet alters the plasma lipidome and may benefit or at least not harm cardiac function and fasting insulin levels in humans with type 2 diabetes. Larger, long-term studies are needed to further evaluate these effects in less-controlled settings.

Type 2 diabetes, obesity, and sex difference affect the fate of glucose in the human heart.

Type 2 diabetes, obesity, and sex difference affect myocardial glucose uptake and utilization. However, their effect on the intramyocellular fate of glucose in humans has been unknown. How the heart uses glucose is important, because it affects energy production and oxygen efficiency, which in turn affect heart function and adaptability. We hypothesized that type 2 diabetes, sex difference, and obesity affect myocardial glucose oxidation, glycolysis, and glycogen production. In a first-in-human study, we measured intramyocardiocellular glucose metabolism from time-activity curves generated from previously obtained positron emission tomography scans of 110 subjects in 3 groups: nonobese, obese, and diabetes. Group and sex difference interacted in the prediction of all glucose uptake, utilization, and metabolism rates. Group independently predicted fractional glucose uptake and its components: glycolysis, glycogen deposition, and glucose oxidation rates. Sex difference predicted glycolysis rates. However, there were fewer differences in glucose metabolism between diabetic patients and others when plasma glucose levels were included in the modeling. The potentially detrimental effects of obesity and diabetes on myocardial glucose metabolism are more pronounced in men than women. This sex difference dimorphism needs to be taken into account in the design, trials, and application of metabolic modulator therapy. Slightly higher plasma glucose levels improve depressed glucose oxidation and glycogen deposition rates in diabetic patients.

Pilot study of pioglitazone and exercise training effects on basal myocardial substrate metabolism and left ventricular function in HIV-positive individuals with metabolic complications.

BACKGROUND: Individuals with HIV infection and peripheral metabolic complications have impaired basal myocardial insulin sensitivity that is related to left ventricular (LV) diastolic dysfunction. It is unknown whether interventions shown to be effective in improving peripheral insulin sensitivity can improve basal myocardial insulin sensitivity and diastolic function in people with HIV and peripheral metabolic complications. OBJECTIVE: In a pilot study, we evaluated whether the peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist pioglitazone or combined endurance and resistance exercise training improves basal myocardial insulin sensitivity and diastolic function in HIV+ adults with peripheral metabolic complications. DESIGN: Twenty-four HIV+ adults with metabolic complications including peripheral insulin resistance were randomly assigned to 4 months of pioglitazone (PIO; 30 mg/d) or supervised, progressive endurance and resistance exercise training (EXS; 90-120 min/d, 3 d/wk). Basal myocardial substrate metabolism was quantified by radioisotope tracer methodology and positron emission tomography (PET) imaging, and LV function was measured by echocardiography. RESULTS: Twenty participants completed the study. Neither PIO nor EXS resulted in a detectable improvement in basal myocardial insulin sensitivity or diastolic function. Post hoc analyses revealed sample sizes of more than 100 participants are needed to detect significant effects of these interventions on basal myocardial insulin sensitivity and function. CONCLUSIONS: PIO or EXS alone did not significantly increase basal myocardial insulin sensitivity or LV diastolic function in HIV+ individuals with peripheral metabolic complications.

Relationships among HIV infection, metabolic risk factors, and left ventricular structure and function.

Our objective was to determine if the presence of metabolic complications (MC) conveyed an additional risk for left ventricular (LV) dysfunction in people with HIV. HIV⁺ and HIV⁻ men and women were categorized into four groups: (1) HIV⁺ with MC (43±7 years, n=64), (2) HIV⁺ without MC (42±7 years, n=59), (3) HIV⁻ with MC (44±8 years, n=37), or (4) HIV⁻ controls without MC (42±8 years, n=41). All participants underwent two-dimensional (2-D), Doppler, and tissue Doppler echocardiography. Overall, the prevalence of systolic dysfunction (15 vs. 4%, p=0.02) and LV hypertrophy (9 vs. 1%, p=0.03) was greater in HIV⁺ than in HIV⁻ participants. Participants with MC had a greater prevalence of LV hypertrophy (10% vs. 1%). Early mitral annular velocity during diastole was significantly (p<0.005) lower in groups with MC (HIV⁺/MC⁺: 11.6±2.3, HIV⁻/MC⁺: 12.0±2.3 vs. HIV⁺/MC⁻: 12.4±2.3, HIV⁻/MC⁻: 13.1±2.4 cm/s) and tended to be lower in groups with HIV (p=0.10). However, there was no interaction effect of HIV and MC for any systolic or diastolic variable. Regardless of HIV status, participants with MC had reduced LV diastolic function. Although both the presence of MC and HIV infection were associated with lower diastolic function, there was no additive negative effect of HIV on diastolic function beyond the effect of MC. Also, HIV was independently associated with lower systolic function. Clinical monitoring of LV function in individuals with metabolic risk factors, regardless of HIV status, is warranted.

Substrate metabolism during basal and hyperinsulinemic conditions in adolescents and young-adults with Barth syndrome.

BACKGROUND: Barth syndrome (BTHS) is a rare X-linked disorder that is characterized by mitochondrial abnormalities, infantile or childhood onset of cardioskeletal myopathy, and high mortality rates. It is currently unknown if BTHS related mitochondrial dysfunction results in substrate metabolism abnormalities and thereby contributes to cardioskeletal myopathy in patients with BTHS. METHODS: Adolescents and young adults with BTHS (n = 5, 20 ± 4 yrs) and age and activity matched healthy controls (n = 5, 18 ± 4 yrs) underwent an hyperinsulinemic-euglycemic clamp procedure with stable isotopically labeled tracers for measurement of lipolysis, fatty acid oxidation, glucose disposal, and whole-body proteolysis rates; dual energy x-ray absorptiometry for measurement of body composition and 2-D and strain echocardiography for measurement of left ventricular function. RESULTS: Participants with BTHS had lower fat-free mass (FFM) (BTHS: 31.4 ± 6.9 vs. CONTROL: 46.7 ± 5.3 kg, p < 0.005), lower systolic function (strain, BTHS: -15.2 ± 2.4 vs. CONTROL: -19.0 ± 2.4 %, p < 0.05), greater insulin-stimulated glucose disposal rate per kg FFM (BTHS: 96.5 ± 16.3 vs. CONTROL: 67.4 ± 17.6 µmol/kgFFM/min, p < 0.05), lower basal (BTHS: 4.6 ± 2.7 vs. CONTROL: 11.9 ± 4.4 µmol/kgFM/min, p < 0.05) and hyperinsulinemic (BTHS: 1.6 ± 0.4 vs. CONTROL: 3.6 ± 1.6 µmol/kgFM/min, p < 0.05) lipolytic rate per kg fat mass (FM), and a trend towards higher basal leucine rate of appearance per kg FFM (BTHS: 271.4 ± 69.3 vs. CONTROL: 193.1 ± 28.7 µmol/kgFFM/hr, p = 0.07) compared to controls. Higher basal leucine rate of appearance per kg FFM (i.e. whole-body proteolytic rate) tended to be associated with lower left ventricular systolic strain (r = -0.57, p = 0.09). CONCLUSION: Whole-body fatty acid, glucose and amino acid metabolism kinetics when expressed per unit of body composition are altered and appear to be related to cardioskeletal myopathy in humans with BTHS. Further studies examining myocardial substrate metabolism and whole-body substrate metabolism during increased energy demands (e.g., exercise) and their relationships to skeletal and cardiac function are recommended.

Reduced diastolic function and left ventricular mass in HIV-negative preadolescent children exposed to antiretroviral therapy in utero.

OBJECTIVE: Abnormalities in left ventricular morphology and function have been reported in HIV-negative infants exposed to antiretroviral therapy (ART) in utero that persists throughout preschool age. The objective of this study was to determine if these abnormalities persist, resolve, or worsen during preadolescence. DESIGN: Cross-sectional observation study. METHODS: Thirty HIV-negative children born to HIV-positive women and exposed to ART in utero (mean age 8 ± 2 years, 37% female, 74% African-American) and 30 HIV-negative children born to HIV-negative women (mean age 8 ± 3 years, 37% female, 76% African-American) underwent two-dimensional Doppler, tissue Doppler, and strain echocardiography to evaluate left ventricular systolic and diastolic function. RESULTS: Weight, body surface area, heart rate and blood pressure were similar between groups. For the ART-exposed group, left ventricular mass index was lower (60 ± 9 vs. 67 ± 12 g/m, P < 0.02) and early diastolic annular velocity was lower (15.0 ± 2.2 vs. 16.3 ± 2.5 cm/s, P < 0.03) compared to controls. Left ventricular systolic function did not differ between groups. Lower maternal third trimester CD4 count was associated with lower early diastolic annular velocity; other non-HIV-related variables including cocaine use and increased maternal age correlated with lower left ventricular mass index. CONCLUSIONS: Abnormalities in left ventricular systolic performance previously reported in HIV-negative infants and preschool aged children exposed to ART in utero were not apparent in preadolescent children. Left ventricular diastolic relaxation was reduced compared with controls suggesting residual effects of ART exposure on left ventricular diastolic function. Larger, longitudinal studies are necessary to confirm these observations.

Potential mechanisms underlying the effect of gender on response to cardiac resynchronization therapy: insights from the SMART-AV multicenter trial.

BACKGROUND: Recent studies demonstrate that women may respond more favorably to cardiac resynchronization therapy (CRT) than do men. The mechanisms remain unclear. OBJECTIVES: To describe the effects of gender on response to CRT and to explore potential mechanisms behind these differences. METHODS: Data for 846 patients from the SMART-AV trial were used to evaluate the mechanisms behind the effects of gender on CRT response. Atrioventricular optimization (AVO) was performed via SmartDelay or echocardiography. Baseline and 6-month left ventricular end systolic volume index (LVESVi) were fitted to a linear regression model with gender predicting change in LVESVi and adjusted for baseline covariates significantly differing by gender. The interaction variable for AVO and gender was also assessed for its effect on change in LVESVi. RESULTS: Baseline variables, including age, body mass index, left ventricular ejection fraction, QRS width, and severity of heart failure symptoms, were comparable between men and women. Women had a higher incidence of left bundle branch block conduction and nonischemic cardiomyopathy and exhibited greater reductions in LVESVi even after adjustment for these differences (13.4 mL/m(2) vs 8.5 mL/m(2); P = .002). In addition, women had greater percentages of biventricular pacing and appeared to derive greater reductions in left ventricular volume with AVO than did men. CONCLUSIONS: Women demonstrated greater reductions in LVESVi with CRT than did men. These observations are not explained by differences in baseline characteristics. Greater degrees of biventricular pacing and enhanced response to AVO in women may partly explain the reason for the gender effect on CRT response.

Effects of human immunodeficiency virus and metabolic complications on myocardial nutrient metabolism, blood flow, and oxygen consumption: a cross-sectional analysis.

BACKGROUND: In the general population, peripheral metabolic complications (MC) increase the risk for left ventricular dysfunction. Human immunodeficiency virus infection (HIV) and combination anti-retroviral therapy (cART) are associated with MC, left ventricular dysfunction, and a higher incidence of cardiovascular events than the general population. We examined whether myocardial nutrient metabolism and left ventricular dysfunction are related to one another and worse in HIV infected men treated with cART vs. HIV-negative men with or without MC. METHODS: Prospective, cross-sectional study of myocardial glucose and fatty acid metabolism and left ventricular function in HIV+ and HIV-negative men with and without MC. Myocardial glucose utilization (GLUT), and fatty acid oxidation and utilization rates were quantified using 11C-glucose and 11C-palmitate and myocardial positron emission tomography (PET) imaging in four groups of men: 23 HIV+ men with MC+ (HIV+/MC+, 42 ± 6 yrs), 15 HIV+ men without MC (HIV+/MC-, 41 ± 6 yrs), 9 HIV-negative men with MC (HIV-/MC+, 33 ± 5 yrs), and 22 HIV-negative men without MC (HIV-/MC-, 25 ± 6 yrs). Left ventricular function parameters were quantified using echocardiography. RESULTS: Myocardial glucose utilization was similar among groups, however when normalized to fasting plasma insulin concentration (GLUT/INS) was lower (p < 0.01) in men with metabolic complications (HIV+: 9.2 ± 6.2 vs. HIV-: 10.4 ± 8.1 nmol/g/min/µU/mL) than men without metabolic complications (HIV+: 45.0 ± 33.3 vs. HIV-: 60.3 ± 53.0 nmol/g/min/µU/mL). Lower GLUT/INS was associated with lower myocardial relaxation velocity during early diastole (r = 0.39, p < 0.001). CONCLUSION: Men with metabolic complications, irrespective of HIV infection, had lower basal myocardial glucose utilization rates per unit insulin that were related to left ventricular diastolic impairments, indicating that well-controlled HIV infection is not an independent risk factor for blunted myocardial glucose utilization per unit of insulin. TRIAL REGISTRATION: NIH Clinical Trials NCT00656851.

Abnormalities in cardiac structure and function in adults with sickle cell disease are not associated with pulmonary hypertension.

BACKGROUND: In sickle cell disease (SCD), pulmonary hypertension (assessed by tricuspid regurgitant jet [TRJ] velocity ≥ 2.5 m/sec) is associated with increased mortality. The relationships among TRJ velocity and left ventricular (LV) and right ventricular (RV) systolic and diastolic function (i.e., relaxation and compliance) have not been well characterized in SCD. METHODS: A prospective study was conducted in 53 ambulatory adults with SCD (mean age, 34 years; range, 21-65 years) and 33 African American controls to define the relationship between LV and RV function and TRJ velocity using echocardiography. RESULTS: Subjects with SCD had larger left and right atrial volumes and increased LV mass compared with controls. When patients with SCD were compared with controls, LV and RV relaxation (i.e., E') were similar. Among subjects with SCD, pulmonary hypertension (TRJ ≥ 2.5 m/sec) was present in 40%. Higher TRJ velocity was correlated with larger left atrial volumes in patients with SCD. Additionally, some measures of LV (peak A, lateral and septal annular E/E' ratio) and RV (tricuspid valve E/E' ratio) compliance were correlated with TRJ velocity. No other measures of LV and RV systolic function or LV diastolic function (i.e., relaxation and compliance) were associated with TRJ velocity. CONCLUSIONS: Ambulatory adults with SCD exhibited structural (i.e., LV and RV chamber enlargement) and functional (i.e., higher surrogate measures of LV and RV filling pressure) abnormalities compared with the control group. In subjects with SCD, few abnormalities of LV and RV structure and function were associated with TRJ velocity.

Myocardial oxygen consumption change predicts left ventricular relaxation improvement in obese humans after weight loss.

Obesity adversely affects myocardial metabolism, efficiency, and diastolic function. Our objective was to determine whether weight loss can ameliorate obesity-related myocardial metabolism and efficiency derangements and that these improvements directly relate to improved diastolic function in humans. We studied 30 obese (BMI >30 kg/m2) subjects with positron emission tomography (PET) (myocardial metabolism, blood flow) and echocardiography (structure, function) before and after marked weight loss from gastric bypass surgery (N = 10) or moderate weight loss from diet (N = 20). Baseline BMI, insulin resistance, hemodynamics, left ventricular (LV) mass, systolic function, myocardial oxygen consumption (MVO2), and fatty acid (FA) metabolism were similar between the groups. MVO2/g decreased after diet-induced weight loss (P = 0.009). Total MVO2 decreased after dietary (P = 0.02) and surgical weight loss (P = 0.0006) and was related to decreased BMI (P = 0.006). Total myocardial FA utilization decreased (P = 0.03), and FA oxidation trended lower (P = 0.06) only after surgery. FA esterification and LV efficiency were unchanged. After surgical weight loss, LV mass decreased by 23% (Doppler-derived) E/E' by 33%, and relaxation increased (improved) by 28%. Improved LV relaxation related significantly to decreased BMI, insulin resistance, total MVO2, and LV mass but not FA utilization. Decreased total MVO(2) predicted LV relaxation improvement independent of BMI change (P = 0.02). Weight loss can ameliorate the obesity-related derangements in myocardial metabolism and LV structure and diastolic function. Decreased total MVO2 independently predicted improved LV relaxation, suggesting that myocardial oxygen metabolism may be mechanistically important in determining cardiac relaxation.

Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy.

BACKGROUND: one variable that may influence cardiac resynchronization therapy response is the programmed atrioventricular (AV) delay. The SmartDelay determined av optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial prospectively randomized patients to a fixed empirical AV delay (120 milliseconds), echocardiographically optimized AV delay, or AV delay optimized with SmartDelay, an electrogram-based algorithm. METHODS AND RESULTS: a total of 1014 patients (68% men; mean age, 66 ± 11 years; mean left ventricular ejection fraction, 25 ± 7%) who met enrollment criteria received a cardiac resynchronization therapy defibrillator, and 980 patients were randomized in a 1:1:1 ratio. All patients were programmed (DDD-60 or DDDR-60) and evaluated after implantation and 3 and 6 months later. The primary end point was left ventricular end-systolic volume. Secondary end points included New York Heart Association class, quality-of-life score, 6-minute walk distance, left ventricular end-diastolic volume, and left ventricular ejection fraction. The medians (quartiles 1 and 3) for change in left ventricular end-systolic volume at 6 months for the SmartDelay, echocardiography, and fixed arms were -21 mL (-45 and 6 mL), -19 mL (-45 and 6 mL), and -15 mL (-41 and 6 mL), respectively. No difference in improvement in left ventricular end-systolic volume at 6 months was observed between the SmartDelay and echocardiography arms (P=0.52) or the SmartDelay and fixed arms (P=0.66). Secondary end points, including structural (left ventricular end-diastolic volume and left ventricular ejection fraction) and functional (6-minute walk, quality of life, and New York Heart Association classification) measures, were not significantly different between arms. CONCLUSIONS: neither SmartDelay nor echocardiography was superior to a fixed AV delay of 120 milliseconds. The routine use of AV optimization techniques assessed in this trial is not warranted. However, these data do not exclude possible utility in selected patients who do not respond to cardiac resynchronization therapy.

Are normative values for LV geometry and mass based on fundamental imaging valid with use of harmonic imaging?

BACKGROUND: Multiple studies have reported echocardiographically determined normal reference values for left ventricular (LV) mass (LVM) derived using fundamental imaging (FI). Modern ultrasound systems now use harmonic imaging (HI) because of the improved LV endomyocardial definition. However, the 2005 American Society of Echocardiography (ASE) recommendations noted that the applicability of the reference values to HI-derived measurements has not been established. METHODS: LVM and LV end-diastolic volume, diameter, and wall thickness were determined using HI in healthy subjects (n = 251), including normal-weight (NW) (body mass index < 25 kg/m², n = 149, 68% women) and otherwise healthy, overweight (OW) (body mass index ≥ 25 and <30 kg/m², n = 102, 41% women) groups. Measurements were compared with ASE-endorsed reference values. The agreement between FI and HI was determined in a prospective cohort of 51 subjects. RESULTS: Two-dimensional (2D) derived LV volumes were similar between NW and OW subjects, although M-mode (MM)-derived LV diameters were slightly greater in OW subjects. 2D and MM-derived LVM was greater in OW compared with NW subjects, including after adjustment by height or height²·7; however, indexing to body surface area eliminated these differences. The partition values for abnormal 2D and MM-derived LVM were generally greater in NW and OW subjects of both sexes compared with the ASE-endorsed values (except MM-derived LVM in NW men). However, there were no significant differences in LVM determined by HI compared with FI in a prospectively studied cohort. CONCLUSIONS: Reference values for LVM derived from NW and OW cohorts are generally higher than the ASE-endorsed referenced values. The difference between NW and ASE-endorsed values is unlikely to result from the use of HI rather than FI, because there is excellent agreement between these two imaging modalities. This study emphasizes the need to update normal reference values to reflect modern imaging methods.

Central aortic pressure is independently associated with diastolic function.

BACKGROUND: Studies investigating the association between central aortic pressures and diastolic function have been limited. METHODS: Consecutive ambulatory patients (n = 281, mean age 49 +/- 13 years, 49% male) with normal left ventricular (LV) systolic function were included. The LV filling pressure (E/Em) was estimated by Doppler-derived ratio of mitral inflow velocity (E) to septal (Em) by tissue Doppler, LV relaxation by Em, and central aortic pressures by radial tonometry. Central aortic systolic (cSBP), diastolic (cDBP), mean (cMAP) and pulse pressure (cPP) were entered individually into stepwise linear regression models to determine their association with E/Em or Em. RESULTS: In univariate analysis, cPP correlated most strongly with E/Em (Spearman's rho = 0.45, P < .001), whereas cSBP correlated most strongly with Em (Spearman's rho = -0.51, P < .001). Multivariate analysis demonstrated that the pulsatile component of afterload, cPP, contributed most to E/Em (partial r(2) = 23%); meanwhile, the nonpulsatile components (cDBP and cMAP) were significant but small contributors (partial r(2) of 6% and 5%, respectively) of LV relaxation (Em). CONCLUSION: The nonpulsatile components of aortic afterload (cMAP and cDBP) exhibited a weak but significant association with LV relaxation, whereas the pulsatile component of afterload, cPP, exhibited strong association with LV filling pressure.

Association and interaction of PPAR-complex gene variants with latent traits of left ventricular diastolic function.

BACKGROUND: Abnormalities in myocardial metabolism and/or regulatory genes have been implicated in left ventricular systolic dysfunction. However, the extent to which these modulate left ventricular diastolic function (LVDF) is uncertain. METHODS: Independent component analysis was applied to extract latent LVDF traits from 14 measured echocardiography-derived endophenotypes of LVDF in 403 Caucasians. Genetic association was assessed between measured and latent LVDF traits and 64 single nucleotide polymorphisms (SNPs) in three peroxisome proliferator-activated receptor (PPAR)-complex genes involved in the transcriptional regulation of fatty acid metabolism. RESULTS: By linear regression analysis, 7 SNPs (4 in PPARA, 2 in PPARGC1A, 1 in PPARG) were significantly associated with the latent LVDF trait, whereas a range of 0-4 SNPs were associated with each of the 14 measured echocardiography-derived endophenotypes. Frequency distribution of P values showed a greater proportion of significant associations with the latent LVDF trait than for the measured endophenotypes, suggesting that analyses of the latent trait improved detection of the genetic underpinnings of LVDF. Ridge regression was applied to investigate within-gene and gene-gene interactions. In the within-gene analysis, there were five significant pair-wise interactions in PPARGC1A and none in PPARA or PPARG. In the gene-gene analysis, significant interactions were found between rs4253655 in PPARA and rs1873532 (p = 0.02) and rs7672915 (p = 0.02), both in PPARGC1A, and between rs1151996 in PPARG and rs4697046 in PPARGC1A (p = 0.01). CONCLUSIONS: Myocardial metabolism PPAR-complex genes, including within and between genes interactions, may play an important role modulating left ventricular diastolic function.

SmartDelay determined AV optimization: a comparison of AV delay methods used in cardiac resynchronization therapy (SMART-AV): rationale and design.

BACKGROUND: The clinical benefit of cardiac resynchronization therapy (CRT) for patients with moderate-to-severely symptomatic heart failure, left ventricular systolic dysfunction, and ventricular conduction delay is established. However, some patients do not demonstrate clinical improvement following CRT. It is unclear whether systematic optimization of the programmed atrioventricular (AV) delay improves the rate of clinical response. METHODS: SMART-AV is a randomized, multicenter, double-blinded, three-armed trial that will investigate the effects of optimizing AV delay timing in heart failure patients receiving CRT + defibrillator (CRT-D) therapy. A minimum of 950 patients will be randomized in a 1:1:1 ratio using randomly permuted blocks within each center programmed to either DDD or DDDR with a lower rate of 60. The study will include echocardiographic measurements of volumes and function [e.g., left ventricular end-systolic volume (LVESV)], biochemical measurements of plasma biomarker profiles, and functional measurements (e.g., 6-minute hall walk) in CRT-D patients who are enrolled and randomized to fixed AV delay (i.e., 120 ms), AV delay determined by electrogram-based SmartDelay, or an AV delay determined by echocardiography (i.e., mitral inflow). Patients will be evaluated prior to initiation of CRT, 3 and 6 months post-implant. The primary endpoint is the relative change in LVESV at 6 months between the groups. Patient enrollment commenced in May 2008 and the study is registered at clinicaltrials.gov. CONCLUSION: SMART-AV is a randomized, clinical trial designed to evaluate three different methods of AV delay optimization to determine whether systematic AV optimization is beneficial for patients receiving CRT for 6 months post-implant.