Mechanisms of subendocardial dysfunction in response to exercise in dogs with severe left ventricular hypertrophy.

Hittinger, Luc; Shen, You‐Tang; Patrick, Thomas; Hasebe, Naoyuki; Komamura, Kazuo; Ihara, Tadashi; Manders, W. T.; Vatner, Stephen F.

doi:10.1161/01.res.71.2.423

Cited by 39 publications

(34 citation statements)

References 24 publications

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“…Interestingly, LV end-diastolic wall stress was similarly affected by both drugs and LV mean ejection wall stresses, i.e., LV afterload, was not significantly different after saline, ivabradine, or atenolol. In agreement with previous studies (3,15), atenolol decreased LV peak systolic wall stress, and this effect was accompanied by an increase in LV dimension (data not shown) Values are means Ϯ SE; n ϭ 8. Dose for ivabradine and atenolol was 1 mg/kg.…”

Section: Discussionsupporting

confidence: 92%

Contributions of heart rate and contractility to myocardial oxygen balance during exercise

Colin

Ghaleh

Monnet

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

131

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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...

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Section: Discussionsupporting

confidence: 92%

Contributions of heart rate and contractility to myocardial oxygen balance during exercise

Colin

Ghaleh

Monnet

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

131

View full text Add to dashboard Cite

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“…1 These characteristic features of HCM can occur without symptoms, but many individuals experience some dyspnea, angina, and palpitations despite overall preserved LV systolic function. Although such symptoms have been linked to subendomyocardial hypoperfusion with worsened diastolic failure, 2,3 limited systolic functional reserve may also contribute to these symptoms of HCM patients.…”

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confidence: 99%

Reduced Myocardial Sarcoplasmic Reticulum Ca ²⁺ -ATPase mRNA Expression and Biphasic Force-Frequency Relations in Patients With Hypertrophic Cardiomyopathy

et al. 2001

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Background-The relationship between left ventricular (LV) contractile functional reserve and gene expression ofCa 2ϩ -handling proteins in patients with hypertrophic cardiomyopathy (HCM) remains to be clarified. Methods and Results-We calculated the maximum first derivative of LV pressure (LV dP/dt max ) and the LV pressure half-time (T 1/2 ) during pacing in 14 patients with nonobstructive HCM (LV ejection fraction Ͼ55%) and 7 control subjects. Endomyocardial tissue was obtained, and mRNA levels of sarcoplasmic reticulum Ca 2ϩ -ATPase (SERCA2), ryanodine receptor-2, phospholamban, calsequestrin, and Na ϩ /Ca 2ϩ exchanger were quantified by use of a real-time quantitative reverse transcription-polymerase chain reaction method. Group A consisted of 7 HCM patients who showed a progressive rise in the LV dP/dt max with increased heart rate. Group B consisted of 7 HCM patients in whom the heart rate-LV dP/dt max relation was biphasic at physiological pacing rates. Both the mean maximal wall thickness and the LV hypertrophy score in group B were greater than in group A (20Ϯ5 versus 15Ϯ3 mm and 7Ϯ1 versus 5Ϯ2 points, respectively). SERCA2 mRNA levels were significantly lower in group B (SERCA2/GAPDH ratio 0.34Ϯ0.15) compared with group A (0.72Ϯ0.27) and control subjects (0.85Ϯ0.47), whereas the mRNA expression of ryanodine receptor-2, phospholamban, calsequestrin, and Na ϩ /Ca 2ϩ exchanger were similar in all groups. Conclusions-These results suggest that downregulation of SERCA2 mRNA, resulting in altered Ca 2ϩ handling, may contribute to impaired LV contractile reserve in HCM patients with severe hypertrophy, even in the absence of detectable baseline systolic dysfunction. (Circulation. 2001;104:658-663.)

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“…This prevents subendocardial hypoperfusion and subsequent myocardial stunning after exercise. 23 However, in our experimental conditions, acute administration of these types of drugs would have induced major negative inotropic and lusitropic effects as opposed to ivabradine, 9,24 thereby aggravating isovolumic contraction and relaxation abnormalities. Metoprolol did not prevent the reduction in cardiac function and adverse remodeling in mice chronically receiving angiotensin II.…”

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confidence: 75%

Ivabradine Improves Left Ventricular Function During Chronic Hypertension in Conscious Pigs

et al. 2015

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In the normal heart, reduction of isovolumic contraction and relaxation durations is a physiological response to increase in heart rate (HR). This allows the heart to maintain a constant and controlled balance between the different phases of cardiac cycle for favoring both left ventricular (LV) ejection and filling. 1,2 We previously evaluated LV function during chronic hypertension and hypertrophy induced by continuous infusion of angiotensin II in pigs. 3 Although no clinical signs of heart failure were present, we observed early and simultaneous maladaptive LV responses to chronotropic and inotropic stimuli that altered diastolic filling time. The maladaptive LV responses displayed as 1 failure of isovolumic contraction and relaxation durations to reduce while HR accelerated and 2 abnormally blunted isovolumic contraction and relaxation responses to dobutamine infusion. In hypertrophied hearts, there is abnormal LV subendocardial blood flow and limited coronary reserve that might fail to meet myocardial oxygen consumption, leading to myocardial ischemia and dysfunction. [4][5][6] These observations led us to consider a role of increased HR in the deterioration of LV function during chronic hypertension.Accordingly, we investigated the effects of acute selective HR reduction with the I f -channel blocker ivabradine 7 on LV dysfunction in our chronic hypertensive pig model (continuous angiotensin II infusion) 3 because this drug has the advantage that it does not modify atrioventricular or intraventricular conduction, inotropy, and lusitropy in animals and humans. [8][9][10][11] Reduction in HR could facilitate diastolic filling by prolonging the diastolic period, 12,13 improving arterioventricular coupling, 14 or reducing myocardial ischemia. 15,16 Here, we hypothesized that selective HR reduction with ivabradine could restore a normal balance between the different phases of the cardiac cycle by normalizing isovolumic contraction and relaxation times. We also investigated whether ivabradine Abstract-During chronic hypertension, increases in heart rate (HR) or adrenergic stimulation are associated with maladaptive left ventricular responses as isovolumic contraction and relaxation durations failed to reduce, impeding filling. We, therefore, investigated the effects of acute selective HR reduction with ivabradine on left ventricular dysfunction during chronic hypertension. Accordingly, chronically instrumented pigs received angiotensin II infusion during 4 weeks to induce chronic hypertension. Left ventricular function was investigated while angiotensin II infusion was stopped. A single intravenous dose of ivabradine was administered at days 0 and 28. Dobutamine infusion was also performed. HR was increased at day 28 versus day 0. Paradoxically, both isovolumic contraction and relaxation times failed to reduce and remained unchanged (57±3 versus 58±3 ms and 74±3 versus 70±3 at day 28 versus day 0, respectively). At day 28, ivabradine significantly reduced HR by 27%. Concomitantly, abnormal ventricular response...

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Mechanisms of subendocardial dysfunction in response to exercise in dogs with severe left ventricular hypertrophy.

Cited by 39 publications

References 24 publications

Contributions of heart rate and contractility to myocardial oxygen balance during exercise

Contributions of heart rate and contractility to myocardial oxygen balance during exercise

Reduced Myocardial Sarcoplasmic Reticulum Ca ²⁺ -ATPase mRNA Expression and Biphasic Force-Frequency Relations in Patients With Hypertrophic Cardiomyopathy

Ivabradine Improves Left Ventricular Function During Chronic Hypertension in Conscious Pigs

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Mechanisms of subendocardial dysfunction in response to exercise in dogs with severe left ventricular hypertrophy.

Cited by 39 publications

References 24 publications

Contributions of heart rate and contractility to myocardial oxygen balance during exercise

Contributions of heart rate and contractility to myocardial oxygen balance during exercise

Reduced Myocardial Sarcoplasmic Reticulum Ca 2+ -ATPase mRNA Expression and Biphasic Force-Frequency Relations in Patients With Hypertrophic Cardiomyopathy

Ivabradine Improves Left Ventricular Function During Chronic Hypertension in Conscious Pigs

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Reduced Myocardial Sarcoplasmic Reticulum Ca ²⁺ -ATPase mRNA Expression and Biphasic Force-Frequency Relations in Patients With Hypertrophic Cardiomyopathy