[Show abstract][Hide abstract] ABSTRACT: Prominent features of myocardial remodeling in heart failure with preserved ejection fraction (HFPEF) are high cardiomyocyte resting tension (F(passive)) and cardiomyocyte hypertrophy. In experimental models, both reacted favorably to raised protein kinase G (PKG) activity. The present study assessed myocardial PKG activity, its downstream effects on cardiomyocyte F(passive) and cardiomyocyte diameter, and its upstream control by cyclic guanosine monophosphate (cGMP), nitrosative/oxidative stress, and brain natriuretic peptide (BNP). To discern altered control of myocardial remodeling by PKG, HFPEF was compared with aortic stenosis and HF with reduced EF (HFREF).
Patients with HFPEF (n=36), AS (n=67), and HFREF (n=43) were free of coronary artery disease. More HFPEF patients were obese (P<0.05) or had diabetes mellitus (P<0.05). Left ventricular myocardial biopsies were procured transvascularly in HFPEF and HFREF and perioperatively in aortic stenosis. F(passive) was measured in cardiomyocytes before and after PKG administration. Myocardial homogenates were used for assessment of PKG activity, cGMP concentration, proBNP-108 expression, and nitrotyrosine expression, a measure of nitrosative/oxidative stress. Additional quantitative immunohistochemical analysis was performed for PKG activity and nitrotyrosine expression. Lower PKG activity in HFPEF than in aortic stenosis (P<0.01) or HFREF (P<0.001) was associated with higher cardiomyocyte F(passive) (P<0.001) and related to lower cGMP concentration (P<0.001) and higher nitrosative/oxidative stress (P<0.05). Higher F(passive) in HFPEF was corrected by in vitro PKG administration.
Low myocardial PKG activity in HFPEF was associated with raised cardiomyocyte F(passive) and was related to increased myocardial nitrosative/oxidative stress. The latter was probably induced by the high prevalence in HFPEF of metabolic comorbidities. Correction of myocardial PKG activity could be a target for specific HFPEF treatment.
[Show abstract][Hide abstract] ABSTRACT: Diabetes mellitus (DM) is highly prevalent and is an important risk factor for congestive heart failure (HF). Increased left ventricular (LV) diastolic stiffness is recognized as the earliest manifestation of DM-induced LV dysfunction, but its pathophysiology remains incompletely understood. Mechanisms whereby DM increases LV diastolic stiffness differ between HF with normal LV ejection fraction (EF) (HFNEF) and HF with reduced LVEF (HFREF). In diabetic HFREF, fibrosis and deposition of advanced glycation end products (AGEs) are the most important contributors to high LV diastolic stiffness, whereas in diabetic HFNEF, elevated resting tension of hypertrophied cardiomyocytes is the most important contributor to high LV diastolic stiffness. As HF mortality remains high in DM despite proven efficacy of current treatments, better understanding of the pathophysiology of high LV diastolic stiffness could be beneficial for novel therapeutic strategies.
Current Diabetes Reports 03/2009; 9(1):79-86. · 3.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess changes in cardiac adrenergic activity with cardiac resynchronization therapy (CRT), and to investigate whether these changes are related to improvement in left ventricular ejection fraction (LVEF).
Sixteen patients (13 males, age 66 +/- 7 years) were studied at baseline and after > or =6 months of CRT (mean follow-up 9.2 +/- 3.2 months). LVEF was assessed by nuclear angiography. Responders were defined as patients showing > or =5% absolute increase in LVEF + improvement in > or =1 NYHA class + absence of heart failure hospitalization. Cardiac sympathetic nerve activity was studied by (123)I-metaiodobenzyl-guanidine ((123)I-MIBG) scintigraphy. Responders (n = 8) showed lower (123)I-MIBG washout at follow-up when compared with non-responders (P = 0.002), indicating lower cardiac sympathetic nerve activity. The decrease in (123)I-MIBG washout at follow-up when compared with baseline was only seen in the responder group (P = 0.036). There was a moderate correlation between increase in LVEF and decrease in (123)I-MIBG washout (r = 0.52, P = 0.04).
CRT induces a reduction in cardiac sympathetic nerve activity in responders, that parallels an improvement in LVEF, whereas non-responders do not show any significant changes.
[Show abstract][Hide abstract] ABSTRACT: Biventricular pacemakers are usually programmed with the default setting of synchronous biventricular pacing, although the ventricles may be paced sequentially. Whether this parameter is important for optimizing resynchronization therapy is not clear.
The purpose of this study was to investigate whether sequential pacing acutely improves left ventricular ejection fraction (LVEF) and dyssynchrony and to assess the feasibility of nuclear ventriculography for device optimization.
Twenty-seven patients implanted with a biventricular pacemaker or implantable cardioverter-defibrillator for heart failure were studied. LVEF was measured using planar radionuclide ventriculography during simultaneous biventricular pacing and during sequential pacing at four different interventricular intervals ranging from LV-40 (preexciting the left ventricle by 40 ms) to LV+40 (preexciting the right ventricle). Interventricular and intraventricular dyssynchrony were analyzed by phase analysis at each setting.
There was great heterogeneity in individual response to VV interval programming. Twenty-four of 27 patients (89%) had significant changes (both favorable and unfavorable) in LVEF at different interventricular delays, with variations of up to 10% in absolute terms. Simultaneous biventricular pacing yielded maximal LVEF in 9 of 27 patients (33%), with a relative increase in LVEF of 18 +/- 14% by optimized sequential pacing in the remaining patients. Interventricular dyssynchrony varied significantly, with least dyssynchrony at the LV-20 setting (P = .024). There were no significant differences in intraventricular dyssynchrony at the different settings.
Programming VV intervals has considerable impact on LVEF. However, there is a great degree of variation between patients in response to these settings, requiring individual assessment for device optimization.