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Right Ventricle in Pulmonary Hypertension

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Abstract

During heart development chamber specification is controlled and directed by a number of genes and a fetal heart gene expression pattern is revisited during heart failure . In the setting of chronic pulmonary hypertension the right ventricle undergoes hypertrophy, which is likely initially adaptive, but often followed by decompensation, dilatation and failure. Here we discuss differences between the right ventricle and the left ventricle of the heart and begin to describe the cellular and molecular changes which characterize right heart failure. A prevention and treatment of right ventricle failure becomes a treatment goal for patients with severe pulmonary hypertension it follows that we need to understand the pathobiology of right heart hypertrophy and the transition to right heart failure. © 2011 American Physiological Society. Compr Physiol 1:525‐540, 2011.

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Figure 1. Figure 1.

The linear heart tube loops and gives rise to the ventricular and atrial chambers. The cardiac cushions give rise to the cardiac valves. The two ventricles grow independently under the control of an intricate interplay of chamber‐specific transcription factors. RV = right ventricle, LV = left ventricle. Adapted from Olson, with permission 129.

Figure 2. Figure 2.

The shape of the normal adult right ventricle (RV). The lines drawn to highlight contours can be visualized using a two‐dimensional echocardiogram show a crescentic shape (left). The three‐dimensional echocardiogram shows a more complicated structure. The ellipsoid lines indicate the RV‐inflow and outflow sites and the tricuspid and pulmonary valve planes. Image courtesy of Dr. Florence Sheehan, University of Washington, Seattle.

Figure 3. Figure 3.

Compared are the response of the normal right ventricle (RV) and left ventricle (LV) to an acute increase in the afterload. For a comparable acute rise of the pulmonary artery and aortic pressure the RV stroke volume drops more than that in the LV. Reproduced from Haddad, with permission 68.

Figure 4. Figure 4.

Mechanisms of activation of PI3K/Akt signaling in response to binding of IGF‐1 or insulin to their membrane tyrosine kinase receptors. Activation of Akt leads to activation of mTOR (molecular target of rapamycin) a central regulator of protein synthesis. Akt also phosphorylates and inhibits the kinase glycogen synthase kinase (GSK‐3). Reproduced from Dorn et al., with permission 48.

Figure 5. Figure 5.

Tracing of right ventricular systolic pressure obtained after catheterization of a rat subjected to pulmonary artery banding (PAB) and 4 weeks of exposure to chronic hypoxia. In spite of the high RV pressure, the heart does not fail. Reproduced from Bogaard et al., with permission 22.

Figure 6. Figure 6.

Illustration of the hemodynamic data which characterize the severe pulmonary arterial hypertension and the degree of right heart failure in the Su5416/chronic hypoxia rat model (RVSP = right ventricular systolic pressure, MSAP = mean systolic arterial pressure, CO = cardiac output, RV/LV + S = right ventricle/left ventricle + septum weight, E = early, 3 weeks, L = late, 5 weeks of study protocol). Reproduced from Oka et al., with permission 128.

Figure 7. Figure 7.

Human right ventricular shape variability obtained via three‐dimensional echocardiography. (Courtesy of Dr. Florence Sheehan, University of Washington, Cardiology Division). The circular or oval green lines delineate right ventricle (RV) inflow and outflow, respectively.

Figure 8. Figure 8.

Confocal microscopy of right ventricle (RV) myocardium of a normal rat and of an animal with SU5416/chronic hypoxia‐induced chronic RV failure. The image obtained after in vivo labeling of endothelial cells with tomato lectin shows significant loss or rarefaction of microvessels in failing RV. Reproduced from Bogaard et al., with permission 22.

Figure 9. Figure 9.

In the model of chronic right ventricle failure (SU5416/chronic hypoxia) there is a dramatic induction of atrial natriuretic protein (ANP) gene expression is comparison to the change observed in the matched, non‐failing left ventricle. Unpublished data, see reference 23.

Figure 10. Figure 10.

The flow diagram presents, admittedly in a speculative manner, the pathobiologically important elements as connected sequential steps, starting either with a “pure” diffuse lung tissue damage (emphysema) or a “pure” mechanical cardiac stress due to sustained left heart workload and wall stress increase (e.g., aortic banding). Given the chronicity a combination of diastolic and contractile cardiac dysfunction develops in both situations. *Although the association of pulmonary hypertension and diastolic dysfunction is well recognized, causality—as indicated by the arrows—has not been proposed. EMP = endothelial cell microparticles.

Figure 11. Figure 11.

This schematic illustrates the concept that RV failure can be distinguished from compensated RV hypertrophy and RV decompensation by the loss of the RV microcirculation which may be caused by a loss of expression of critically important angiogenesis (vessel maintenance) factors. EMT = endothelial mesenchymal transition 165.



Figure 1.

The linear heart tube loops and gives rise to the ventricular and atrial chambers. The cardiac cushions give rise to the cardiac valves. The two ventricles grow independently under the control of an intricate interplay of chamber‐specific transcription factors. RV = right ventricle, LV = left ventricle. Adapted from Olson, with permission 129.



Figure 2.

The shape of the normal adult right ventricle (RV). The lines drawn to highlight contours can be visualized using a two‐dimensional echocardiogram show a crescentic shape (left). The three‐dimensional echocardiogram shows a more complicated structure. The ellipsoid lines indicate the RV‐inflow and outflow sites and the tricuspid and pulmonary valve planes. Image courtesy of Dr. Florence Sheehan, University of Washington, Seattle.



Figure 3.

Compared are the response of the normal right ventricle (RV) and left ventricle (LV) to an acute increase in the afterload. For a comparable acute rise of the pulmonary artery and aortic pressure the RV stroke volume drops more than that in the LV. Reproduced from Haddad, with permission 68.



Figure 4.

Mechanisms of activation of PI3K/Akt signaling in response to binding of IGF‐1 or insulin to their membrane tyrosine kinase receptors. Activation of Akt leads to activation of mTOR (molecular target of rapamycin) a central regulator of protein synthesis. Akt also phosphorylates and inhibits the kinase glycogen synthase kinase (GSK‐3). Reproduced from Dorn et al., with permission 48.



Figure 5.

Tracing of right ventricular systolic pressure obtained after catheterization of a rat subjected to pulmonary artery banding (PAB) and 4 weeks of exposure to chronic hypoxia. In spite of the high RV pressure, the heart does not fail. Reproduced from Bogaard et al., with permission 22.



Figure 6.

Illustration of the hemodynamic data which characterize the severe pulmonary arterial hypertension and the degree of right heart failure in the Su5416/chronic hypoxia rat model (RVSP = right ventricular systolic pressure, MSAP = mean systolic arterial pressure, CO = cardiac output, RV/LV + S = right ventricle/left ventricle + septum weight, E = early, 3 weeks, L = late, 5 weeks of study protocol). Reproduced from Oka et al., with permission 128.



Figure 7.

Human right ventricular shape variability obtained via three‐dimensional echocardiography. (Courtesy of Dr. Florence Sheehan, University of Washington, Cardiology Division). The circular or oval green lines delineate right ventricle (RV) inflow and outflow, respectively.



Figure 8.

Confocal microscopy of right ventricle (RV) myocardium of a normal rat and of an animal with SU5416/chronic hypoxia‐induced chronic RV failure. The image obtained after in vivo labeling of endothelial cells with tomato lectin shows significant loss or rarefaction of microvessels in failing RV. Reproduced from Bogaard et al., with permission 22.



Figure 9.

In the model of chronic right ventricle failure (SU5416/chronic hypoxia) there is a dramatic induction of atrial natriuretic protein (ANP) gene expression is comparison to the change observed in the matched, non‐failing left ventricle. Unpublished data, see reference 23.



Figure 10.

The flow diagram presents, admittedly in a speculative manner, the pathobiologically important elements as connected sequential steps, starting either with a “pure” diffuse lung tissue damage (emphysema) or a “pure” mechanical cardiac stress due to sustained left heart workload and wall stress increase (e.g., aortic banding). Given the chronicity a combination of diastolic and contractile cardiac dysfunction develops in both situations. *Although the association of pulmonary hypertension and diastolic dysfunction is well recognized, causality—as indicated by the arrows—has not been proposed. EMP = endothelial cell microparticles.



Figure 11.

This schematic illustrates the concept that RV failure can be distinguished from compensated RV hypertrophy and RV decompensation by the loss of the RV microcirculation which may be caused by a loss of expression of critically important angiogenesis (vessel maintenance) factors. EMT = endothelial mesenchymal transition 165.

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Norbert F. Voelkel, Ramesh Natarajan, Jennifer I. Drake, Herman J. Bogaard. Right Ventricle in Pulmonary Hypertension. Compr Physiol 2011, 1: 525-540. doi: 10.1002/cphy.c090008