Progressive right ventricular failure is not explained by myocardial ischemia in a pig model of right ventricular pressure overload

Schmitto, Jan D.; Doerge, Hilmar; Post, Heiner; Coulibaly, M.; Sellin, C.; Popov, Aron F.; Sossalla, Samuel; Schoendube, Friedrich A.

doi:10.1016/j.ejcts.2008.09.010

Cited by 27 publications

(11 citation statements)

References 25 publications

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“…Underlining this, Kohlhardt et al described already in the 1960s a significant, moderateacidosisinduced cardiac output decrease in nonfailing cats by 25% (pH = 7.00) (13). Further investigations on acidosis-induced decrease of myocardial contractility and its effect on catecholamine response were performed using different approaches and models (14)(15)(16)(17)(18)(19)(20)(21)(22); however, there still exist no experimental data describing the specific effect of metabolic acidosis in isolated ovine hearts even though sheep are widely used as animal models (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41).…”

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confidence: 99%

Influence of Mild Metabolic Acidosis on Cardiac Contractility and Isoprenaline Response in Isolated Ovine Myocardium

Schotola¹,

Sossalla²,

Rajab

et al. 2011

Artificial Organs

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The postoperative course after major surgical procedures such as cardiothoracic operations is often accompanied by acute metabolic abnormalities due to large volume and temperature shifts. In general, those intervention-induced trauma might cause the use of catecholamines to stabilize hemodynamics. Within the cardiac community, there are still controversial discussions about standardized medical therapy to treat postoperative acidosis, for example, buffering versus nonbuffering for improving catecholaminergic response of myocardial contractility. The aim of this study was to investigate the influence of mild (and thus clinically relevant) acidosis on myocardial contractility and catecholamine response in explanted trabeculae of ovine hearts. Intact trabeculae (n = 24) were isolated from the right ventricle of healthy sheep hearts. Two different groups (group 1: pH = 7.40, n = 9 and group 2: pH = 7.20, n = 13) were investigated, and force amplitudes were measured at frequencies between 30 and 180 beats per minute and increasing catecholamine concentrations (isoprenaline 0-3 × 10(-6) mM). Force-frequency relation experiments in the presence of a physiological and/or mild acidotic pH solution showed no significant differences. Mean force amplitudes normalized to the lowest frequency showing no significant differences in force development between 0.5 and 3 Hz (n = 9 vs. 13, P = n.s.) (0.5 Hz absolute values 3.1 ± 2.6 for pH = 7.40 vs. 3.8 ± 2.6 mN/mm(2) for pH = 7.20, P = n.s.). Moreover, there was no significant difference in relaxation kinetics between the two groups. Furthermore, the experiments showed similar catecholamine responses in both groups. Force amplitudes normalized to baseline and maximum force showed no significant differences in force development between baseline and maximum isoprenaline concentrations (n = 6 vs. 9, P = n.s.) (baseline absolute values 4.3 ± 4.0 for pH = 7.40 vs. 3.9 ± 1.2 mN/mm(2) for pH = 7.20, P = n.s.). Additionally, relaxation kinetics did not show differences after catecholamine stimulation. The presented experiments revealed no significant negative inotropic effects on isometrically contracting ovine trabeculae with mild metabolic acidosis (pH = 7.2) compared with physiological pH (7.4). Additionally, similar catecholamine responses were seen in both groups. Further investigations (e.g., in vivo and/or in failing hearts with reduced compensatory reserves) will be necessary to examine optimal medical treatment for metabolic abnormalities after cardiac surgery.

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Influence of Mild Metabolic Acidosis on Cardiac Contractility and Isoprenaline Response in Isolated Ovine Myocardium

Schotola¹,

Sossalla²,

Rajab

et al. 2011

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“…We and others have shown that RV contractile dysfunction from acute RVPO can occur in the absence of detectable ischemia (3,16,17), and we previously reported that desmin, troponin-I, and spectrin (proteins that are reportedly degraded in some models of experimental ischemia/reperfusion) (18)(19)(20)(21)(22)(23)(24) are not degraded in our model of acute RVPO (7). In that study (7), we considered the possibility that we might have failed to detect the degradation of these proteins because of the relatively short period of RVPO.…”

Section: Discussionmentioning

confidence: 99%

Calpain Inhibition Preserves Talin and Attenuates Right Heart Failure in Acute Pulmonary Hypertension

Ahmad

Lu²,

Ye³

et al. 2012

Am J Respir Cell Mol Biol

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Right heart failure from right ventricular (RV) pressure overload is a major cause of morbidity and mortality, but its mechanism is incompletely understood. We tested the hypothesis that right heart failure during 4 hours of RV pressure overload is associated with alterations of the focal adhesion protein talin, and that the inhibition of calpain attenuates RV dysfunction and preserves RV talin. Anesthetized open-chest pigs treated with the calpain inhibitor MDL-28170 (n ¼ 20) or inactive vehicle (n ¼ 23) underwent 4 hours of RV pressure overload by pulmonary artery constriction (initial RV systolic pressure, 64 6 1 and 66 6 1 mm Hg in MDL-28170 and vehicle-treated pigs, respectively). Progressive RV contractile dysfunction was attenuated by MDL-28170: after 4 hours of RV pressure overload, RV systolic pressure was 44 6 4 mm Hg versus 49 6 6 mm Hg (P ¼ 0.011), and RV stroke work was 72 6 5% of baseline versus 90 6 5% of baseline, (P ¼ 0.027), in vehicle-treated versus MDL-28170-treated pigs, respectively. MDL-28170 reduced the incidence of hemodynamic instability (death or systolic blood pressure of , 85 mm Hg) by 46% (P ¼ 0.013). RV pressure overload disrupted talin organization. MDL-28170 preserved talin abundance in the RV free wall (P ¼ 0.039), and talin abundance correlated with the maintenance of RV free wall stroke work (r ¼ 0.58, P ¼ 0.0039). a-actinin and vinculin showed similar changes according to immunohistology. Right heart failure from acute RV pressure overload is associated with reduced talin abundance and disrupted talin organization. Calpain inhibition preserves the abundance and organization of talin and RV function. Calpain inhibition may offer clinical utility in treating acute cor pulmonale.Keywords: right ventricular dysfunction; pulmonary hypertension; calpain; talin; heart failure Right ventricular (RV) failure from acute right ventricular pressure overload (RVPO) is a major cause of morbidity and mortality in conditions such as pulmonary embolism and hypoxic pulmonary vasoconstriction, and in the early period after cardiopulmonary bypass or cardiac transplantation (1, 2). In the past, the conventional understanding of the pathophysiology of acute RV failure attributed it either to RV ischemia or to abnormal loading conditions during RVPO. However, we and others (3-5) previously demonstrated that the pathophysiology is more complex: a brief period of RVPO without RV ischemia results in intrinsic RV contractile dysfunction that persists beyond the period of RVPO itself, despite the restoration of normal loading conditions. Thus, the mechanism of intrinsic contractile dysfunction provoked by RVPO remains uncertain.Current clinical treatments for acute RV failure from RVPO depend almost exclusively on inotropic therapy or measures intended to relieve the underlying RVPO, such as thrombolysis, pulmonary thromboendarterectomy, and pulmonary vasodilators. These measures often result in serious complications, do not fully mitigate the high mortality, and do not directly address the mechanisms o...

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“…Ultimately, the inability to maintain the cardiac index and arterial pressure leads to cardiogenic shock (fig. 3) [15,16]. Thus, RV dysfunction is the critical hemodynamic event and an important determinant of the clinical presentation, course and prognosis of PE.…”

Section: Pathophysiology Of Right Ventricular Dysfunction and Failurementioning

confidence: 99%

The Right Ventricle in Health and Disease: Insights into Physiology, Pathophysiology and Diagnostic Management

Apostolakis

Konstantinides²

2012

Cardiology

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Until recently, the right ventricle (RV) received little attention in adult patients with congenital heart disease and even less attention in the setting of acquired heart failure. However, in the last two decades, our perspective towards the right side of the heart has begun to change. Advances in imaging modalities have permitted the accurate study of RV physiology and made it apparent that RV function is an important determinant of prognosis in heart failure irrespective of the underlying etiology. This article summarizes the existing data on the unique anatomical and physiological features of the RV. The hemodynamic conditions and cellular and biochemical pathways that lead to right heart failure are presented. Moreover, the imaging modalities that aid in the assessment of RV structure and function are described and the importance of the diagnostic and prognostic information they provide is discussed.

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Progressive right ventricular failure is not explained by myocardial ischemia in a pig model of right ventricular pressure overload

Abstract: We conclude that in our model RV failure during PAC develops in spite of increased coronary blood flow and MVO(2). Thus, mechanisms different from ischemia may contribute to progressive RV failure after pulmonary embolism.

Cited by 27 publications

References 25 publications

Influence of Mild Metabolic Acidosis on Cardiac Contractility and Isoprenaline Response in Isolated Ovine Myocardium

Influence of Mild Metabolic Acidosis on Cardiac Contractility and Isoprenaline Response in Isolated Ovine Myocardium

Calpain Inhibition Preserves Talin and Attenuates Right Heart Failure in Acute Pulmonary Hypertension

The Right Ventricle in Health and Disease: Insights into Physiology, Pathophysiology and Diagnostic Management

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