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Hypertrophic response to hemodynamic overload: role of load vs. renin-angiotensin system activation
M Koide1, B A Carabello, C C Conrad
1Cardiology Section, Department of Medicine and Physiology, Gazes Cardiac Research Institute, Medical University of South Carolina, Veterans Affairs Medical Center, Charleston, South Carolina 29401, USA.
Insights
Cardiac hypertrophy can be triggered by pressure overload, independent of the renin-angiotensin system (RAS). Blocking the RAS with losartan or captopril did not affect the hypertrophic response to pulmonary artery banding in cats.
Area of Science:
- Cardiology
- Physiology
- Molecular Biology
Background:
- Myocardial hypertrophy is a cardiac compensation mechanism for hemodynamic overload.
- The precise signaling pathways linking hemodynamic overload to cardiac hypertrophy are not fully understood.
- The renin-angiotensin system (RAS) and angiotensin II receptor (AT1) stimulation are potential mediators.
Purpose of the Study:
- To test the hypothesis that mechanical load alone, independent of the RAS, can stimulate cardiac growth.
- To investigate the role of RAS activation in load-induced cardiac hypertrophy.
Main Methods:
- Utilized a feline model with pulmonary artery banding (PAB) to induce right ventricular (RV) pressure overload.
- Administered losartan (AT1 blocker) or captopril (ACE inhibitor) to PAB cats.
- Assessed RV hypertrophy via RV mass-to-body weight ratio and cardiocyte size.
- Measured RV systolic and diastolic pressures to quantify hemodynamic overload.
Main Results:
- Neither losartan nor captopril altered the degree of RV pressure overload or RV hypertrophy in PAB cats.
- Pharmacological blockade of the RAS did not impact the hypertrophic response to PAB.
- RV systolic pressure increased significantly in PAB cats, irrespective of RAS blockade.
Conclusions:
- Mechanical load, independent of the renin-angiotensin system, is sufficient to induce cardiac hypertrophy.
- RAS activation and AT1 receptor stimulation are not obligatory components in the signaling pathway coupling load to hypertrophy.
- These findings suggest alternative pathways mediate load-induced cardiac growth.
Abstract:
Myocardial hypertrophy is one of the basic mechanisms by which the heart compensates for hemodynamic overload. The mechanisms by which hemodynamic overload is transduced by the cardiac muscle cell and translated into cardiac hypertrophy are not completely understood. Candidates include activation of the renin-angiotensin system (RAS) and angiotensin II receptor (AT1) stimulation. In this study, we tested the hypothesis that load, independent of the RAS, is sufficient to stimulate cardiac growth. Four groups of cats were studied: 14 normal controls, 20 pulmonary artery-banded (PAB) cats, 7 PAB cats in whom the AT1 was concomitantly and continuously blocked with losartan, and 8 PAB cats in whom the angiotensin-converting enzyme (ACE) was concomitantly and continuously blocked with captopril. Losartan cats had at least a one-log order increase in the ED50 of the blood pressure response to angiotensin II infusion. Right ventricular (RV) hypertrophy was assessed using the RV mass-to-body weight ratio and ventricular cardiocyte size. RV hemodynamic overload was assessed by measuring RV systolic and diastolic pressures. Neither the extent of RV pressure overload nor RV hypertrophy that resulted from PAB was affected by AT1 blockade with losartan or ACE inhibition with captopril. RV systolic pressure was increased from 21 +/- 3 mmHg in normals to 68 +/- 4 mmHg in PAB, 65 +/- 5 mmHg in PAB plus losartan and 62 +/- 3 mmHg in PAB plus captopril. RV-to-body weight ratio increased from 0.52 +/- 0.04 g/kg in normals to 1.11 +/- 0.06 g/kg in PAB, 1.06 +/- 0.06 g/kg in PAB plus losartan and 1.06 +/- 0.06 g/kg in PAB plus captopril. Thus 1) pharmacological modulation of the RAS with losartan and captopril did not change the extent of the hemodynamic overload or the hypertrophic response induced by PAB; 2) neither RAS activation nor angiotensin II receptor stimulation is an obligatory and necessary component of the signaling pathway that acts as an intermediary coupling load to the hypertrophic response; and 3) load, independent of the RAS, is capable of stimulating cardiac growth.