Background-The adaptation of cardiac mass to hemodynamic overload requires an adaptation of protein turnover, ie, the balance between protein synthesis and degradation. We tested 2 hypotheses: (1) chronic left ventricular hypertrophy (LVH) activates the proteasome system of protein degradation, especially in the myocardium submitted to the highest wall stress, ie, the subendocardium, and (2) the proteasome system is required for the development of LVH. Methods and Results-Gene and protein expression of proteasome subunits and proteasome activity were measured separately from left ventricular subendocardium and subepicardium, right ventricle, and peripheral tissues in a canine model of severe, chronic (2 years) LVH induced by aortic banding and then were compared with controls. Both gene and protein expressions of proteasome subunits were increased in LVH versus control (PϽ0.05), which was accompanied by a significant (PϽ0.05) increase in proteasome activity. Posttranslational modification of the proteasome was also detected by 2-dimensional gel electrophoresis. These changes were found specifically in left ventricular subendocardium but not in left ventricular subepicardium, right ventricle, or noncardiac tissues from the same animals. In a mouse model of chronic pressure overload, a 50% increase in heart mass and a 2-fold increase in proteasome activity (both PϽ0.05 versus sham) were induced. In that model, the proteasome inhibitor epoxomicin completely prevented LVH while blocking proteasome activation. Conclusions-The increase in proteasome expression and activity found during chronic pressure overload in myocardium submitted to higher stress is also required for the establishment of LVH. Key Words: heart diseases Ⅲ hypertrophy Ⅲ physiology Ⅲ pressure Ⅲ stress Ⅲ proteins L eft ventricular hypertrophy (LVH) is a key compensatory mechanism in response to pressure or volume overload that involves alterations in the regulation of signal transduction pathways, transcription factors, excitation-contraction coupling, contractile proteins, and energy metabolism. One key element of cardiac hypertrophy is an adaptation in protein turnover. Protein turnover refers to protein synthesis and degradation, and both mechanisms are activated by increased cardiac workload. 1,2 Although multiple studies have addressed the activation of protein synthesis during the acute phase of LVH that follows aortic banding, the mechanisms controlling protein degradation in the hypertrophied myocardium, especially over the long term, remain largely unknown. A key mechanism involved in protein degradation is the ubiquitin/proteasome system (UPS), 3 which is known to be an important mechanism mediating muscle atrophy. 4,5 Proteolytic substrates are ligated to multiple ubiquitin (Ub) moieties that are assembled into a chain that binds the proteasome with high affinity. The 26S proteasome contains multiple subunits in the regulatory (19S) particle that can bind multiubiquitinated (multi-Ub) proteins. 6,7 The composition of the proteasome is highl...

By subtractive hybridization, we found a significant increase in H11 kinase transcript in large mammalian models of both ischemia/reperfusion (stunning) and chronic pressure overload with hypertrophy. Because this gene has not been characterized in the heart, the goal of the present study was to determine the function of H11 kinase in cardiac tissue, both in vitro and in vivo. In isolated neonatal rat cardiac myocytes, adenoviral-mediated overexpression of H11 kinase resulted in a 37% increase in protein/DNA ratio, reflecting hypertrophy. A cardiac-specific transgene driven by the alphaMHC-promoter was generated, which resulted in an average 7-fold increase in H11 kinase protein expression. Transgenic hearts were characterized by a 30% increase of the heart weight/body weight ratio, by the reexpression of a fetal gene program, and by concentric hypertrophy with preserved contractile function at echocardiography. This phenotype was accompanied by a dose-dependent activation of Akt/PKB and p70(S6) kinase, whereas the MAP kinase pathway was unaffected. Thus, H11 kinase represents a novel mediator of cardiac cell growth and hypertrophy.

Using a definition of PASP > 45 mmHg, 7% of the patients with HF have PAH, which is associated with worse LV function, MR, and prognosis. Whether PAH is a target for therapy in this population remains to be elucidated.

Basal-to-apical LS abnormalities are similar across CA types and reflect the amyloid burden. Apical LS independently predicts MACE.

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Berdeaux. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol 284: H676-H682, 2003. First published October 24, 2002 10.1152/ajpheart.00564.2002The respective contributions of heart rate (HR) reduction and left ventricular (LV) negative inotropy to the effects of antianginal drugs are debated. Accordingly, eight instrumented dogs were investigated during exercise at spontaneous and paced HR (250 beats/min) after administration of either saline, atenolol, or ivabradine (selective pacemaker current channel blocker). During exercise, atenolol and ivabradine (both 1 mg/kg iv) similarly reduced HR (Ϫ30% from 222 Ϯ 5 beats/ min), and LV mean ejection wall stress was not altered. LV dP/dtmax was reduced by atenolol but not ivabradine. Diastolic time (DT) was increased by atenolol versus saline (195 Ϯ 6 vs. 123 Ϯ 4 ms, respectively) and to a greater extent by ivabradine (233 Ϯ 11 ms). Myocardial oxygen consumption (MV O2) was lower under ivabradine and atenolol versus saline (6.7 Ϯ 0.6 and 4.7 Ϯ 0.4 vs. 8.1 Ϯ 0.6 ml/min, respectively, P Ͻ 0.05). Under pacing, DT and MV O2 were similar between ivabradine and saline but significantly reduced with atenolol. Thus HR reduction and negative inotropy equally contribute to the reduction in MV O2 during exercise in the normal heart. The negative inotropy limits the increase in DT afforded by HR reduction. metabolic demand; chronotropy; inotropy; diastolic time ALTHOUGH IT IS WELL KNOWN that reductions in heart rate and myocardial contractility are both major mechanisms involved in the antianginal effect of ␤-blockers, the relative contributions of these two parameters to the therapeutic properties of these drugs are still debated. Heart rate reduction is indeed critical to reduce exercise-induced ischemia by increasing subendocardial myocardial blood flows and diastolic perfusion time (12) and by decreasing myocardial oxygen consumption (MV O 2 ). Accordingly, Guth et al. (13) abolished the anti-ischemic effect of atenolol through atrial pacing during exercise-induced ischemia, suggesting that the negative inotropic effect of this ␤-blocker was negligible in this setting. Furthermore, zatebradine and ivabradine, two selective heart rate-reducing agents devoid of any negative inotropic effect, afforded significant anti-ischemic effects during exercise-induced ischemia in conscious dogs (12, 18) and pigs (16). In contrast, Buck et al. (2) reported only a partial attenuation of the beneficial effects of ␤-blockade on myocardial blood flow distribution and dynamic severity of a proximal coronary artery stenosis after atrial pacing. Two clinical trials using zatebradine failed to reveal any antianginal activity secondary to the sole reduction in heart rate (8, 9). However, in these studies, reduction in heart rate might have induced changes in other determinants of MV O 2 , e.g., loading conditions. Furthermore, in these studies, the potential beneficial effects of heart rate reduction on diastolic time, i.e., o...

Lowering heart rate reduces myocardial oxygen consumption (MVO 2 ) and produces potent anti-ischemic effects. The development of selective heart rate-reducing agents represents an alternative approach to the use of ␤-blockers. Therefore, our goal was to establish the dose-response curve of the effects of ivabradine (I f channel inhibitor) on MVO 2 and diastolic time. Seven conscious and chronically instrumented dogs were investigated during exercise at spontaneous and paced heart rate (250 beats/min) after administration of increasing doses of ivabradine (0.25, 0.5, and 1 mg/kg i.v.). During exercise, ivabradine dose dependently and significantly reduced the exercise-induced tachycardia (Ϫ17, Ϫ21, and Ϫ32% at 0.25, 0.5, and 1 mg/kg, respectively, versus saline) without altering myocardial contractility nor mean ejection wall stress. A linear relationship between heart rate (HR) and MVO 2 was demonstrated (MVO 2 ϭ 0.044 ϫ HR Ϫ 1.4; r ϭ 0.987). These effects of ivabradine on MVO 2 were abolished by atrial pacing. Similarly, ivabradine dose dependently increased diastolic time without altering the inverse and non linear relationship between diastolic time and heart rate observed with saline. In conclusion, selective heart rate reduction with ivabradine dose dependently increases diastolic time and reduces MVO 2 with a linear relationship between heart rate and MVO 2 . The lack of "on-off" pharmacological profile will predict the possibility of using a wide range of dose regimen.Antianginal drugs such as ␤-blockers or some calcium antagonists exhibit part of their beneficial effects by reducing heart rate. On the one hand, reduction in heart rate decreases myocardial oxygen demand and on the other hand increases diastolic perfusion time, a major determinant of subendocardial blood flow (Braunwald, 1971). Indeed, a 1% increase in diastolic time fraction (the quotient of the duration of diastole by the entire heart beat) increases subendocardial flow by 2.6 to 6% in the normal heart (Bache and Cobb, 1977). In this respect, the development of a selective heart rate-reducing agent such as ivabradine, a novel inhibitor of the sino-atrial inward hyperpolarization-activated I f current (Thollon et al., 1994;Vilaine et al., 2003), is an original alternative approach to ␤-blockers, because this drug is devoid of any intrinsic negative inotropic effect and does not alter either the global left ventricular systolic and diastolic functions or coronary vasomotion in conscious dogs, both at rest and during exercise (Simon et al., 1995;Colin et al., 2002). Although it is known that lowering heart rate reduces myocardial oxygen consumption per minute (Boerth et al., 1969), the relationship between the level of heart rate reduction and of MVO 2 remains unknown in vivo. Accordingly, we investigated the effect of increasing doses of ivabradine at rest and during treadmill exercise on myocardial oxygen consumption and diastolic perfusion time in conscious and chronically instrumented dogs. These responses were also investigated...

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