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Insulin resistance, hypertension and type 2 diabetes
AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2
FACULTY ABSTRACTS
319A
Subjects with hypertension have increased insulin resistance which is at least partly explained by increased obesity in hypertensive subjects. Hypertensive subjects also have an increased risk of developing type 2 diabetes which may be attenuated further by the use of thiazides and beta blockers. Several studies have shown that increased blood pressure is present prior to the onset of type 2 diabetes. We have shown in the San Antonio Heart Study that prediabetic subjects have increased blood pressure prior to the onset of diabetes (Haffner JAMA 1990). Recently, we have also shown (Haffner Circulation 2000) that among prediabetic subjects, only subjects with increased insulin resistance had increased blood pressure. Our data suggest that among prediabetic subjects at increased risk of hypertension, insulin resistance is an important concomitant of hypertension.
Risk mechanisms associated with hypertensive heart disease (HHD) and left ventricular hypertrophy (LVH) will be considered in this presentation. To be emphasized are impaired coronary hemodynamics, endothelial dysfunction, and ventricular fibrosis resulting from increased collagen deposition intramurally and perivascularly. Each is of these alterations is exacerbated by aging and, perhaps, also by increased salt intake. The coronary hemodynamic alterations include diminished coronary blood flow and flow reserve, increased coronary and minimal coronary vascular resistance, structural arteriolar changes and perhaps, increased blood viscosity and diastolic as well as systolic dysfunction in HHD. Clinical endpoints of HHD include: angina pectoris (with or without epicardial coronary atherosclerosis), myocardial infarction, cardiac failure, lethal dysrhythmias, and sudden death. The major concept to be derived is that all that is clinically recognized as LVH is not solely myocytic hypertrophy; other major co-morbid changes occur that increase cardiovascular risk including ventricular fibrosis, impaired coronary hemodynamics, and endothelial dysfunction.
Key Words: Insulin resistance; hypertension; diabetes
Key Words: Risk; LVH; hemodynamics
INSULIN RESISTANCE, HYPERTENSION AND TYPE 2 DIABETES Steven M. Haffner, MD. University of Texas Health Science Center, San Antonio, TX
OBESITY HYPERTENSION: A RISK FACTOR FOR CARDIOVASCULAR AND RENAL DISEASE Efrain Reisin. Louisiana State University Health Science Center, New Orleans, Louisiana Epidemiological studies suggest that a large number of obese patients have concomitant hypertension. This association causes the following vascular and hemodynamic changes: Enhanced vascular reactivity due to impaired vascular smooth muscle calcium efflux; inadequate nitric oxide generation by vascular endothelium; expanded cardiopulmonary volume, and increased total peripheral resistance. These changes lead to structural adaptation in the heart characterized by concentric-eccentric left ventricular hypertrophy. The hypertrophic condition provides the basis for the development of congestive heart failure and cardiac arrhythmias that may explain the higher rates of cardiac sudden death in those patients. In the kidneys, obesity hypertension may initiate a derangement on renal function. The increased deposit of interstitial cells and of extracellular matrix between the tubules induces higher interstitial hydrostatic pressure and tubular sodium reabsorption. The consequent increase in renal flow and glomerular filtration enhances albuminuria excretion and the susceptibility to the development of renal damage. In Summary: The hemodynamic and structural adaptations related to obesity hypertension is the cause of greater risk for adverse cardiovascular and renal events. Key Words: Obesity; blood pressure; renal hemodynamics; cardiovascular disease
Friday, May 19, Astor Ballroom, 5:00 PM to 6:30 PM Theme I: Cardiac Hypertrophy in Hypertension RISK MECHANISMS IN HYPERTENSIVE HEART DISEASE Edward D. Frohlich, MD. Alton Ochsner Medical Foundation, New Orleans, LA
JAK-STAT PATHWAY MEDIATED ACTIVATION OF RENIN ANGIOTENSIN SYSTEM IN MYOCARDIAL HYPERTROPHY AND ISCHEMIA Eduardo Mascareno, M. El-Shafie, Yueling Guo, and M.A.Q. Siddiqui. Center for Cardiovascular and Muscle Research, Department of Anatomy and Cell Biology, State University of New York Health Science Center at Brooklyn, Brooklyn, NY 11203 We have recently demonstrated that angiotensin II (Ang II) activates the Jak/STAT pathway resulting in enhanced binding of STAT-3, STAT-5A and STAT-6 to the angiotensinogen (ANG) promoter which causes the induction of the autocrine loop of renin-angiotensin system (RAS) during development of myocardial hypertrophy. Nuclear extract isolated from the adult hypertrophic SHR hearts showed a consistent high level of activated STAT proteins whereas those from STAT 6 null (⫺/⫺) mutant mice have a significant reduced level of activated STATs. Our follow-up studies with isolated and perfused rat heart subjected to ischemic stress also showed an induction of the Jak/STAT pathway and the consequent activation of the RAS components assayed by STATs/binding to the target site DNA. Pre-conditioning of the heart to ischemic stress produced a substantial reduction in STAT/ DNA binding. Among several cytrokines that influence the Jak/STAT pathway is leptin which is important in the etiology of obesity, a known risk factor in development of essential hypertension. Leptin specific receptors are present in a variety of tissues, including the cardiovascular tissues. We observed that like Ang II, leptin also mediates the activation of specific STAT proteins via its phosphorylation and subsequent binding to target DNA. Taken together, it appears that signaling rendered by the Jak/STAT pathway constitutes an essential step in modulation of the transcriptional machinery essential for development of various pathologies associated with angiotensin II. Key Words: Signaling mechanism; ischemia; hypertrophy
FACULTY ABSTRACTS
319A
Subjects with hypertension have increased insulin resistance which is at least partly explained by increased obesity in hypertensive subjects. Hypertensive subjects also have an increased risk of developing type 2 diabetes which may be attenuated further by the use of thiazides and beta blockers. Several studies have shown that increased blood pressure is present prior to the onset of type 2 diabetes. We have shown in the San Antonio Heart Study that prediabetic subjects have increased blood pressure prior to the onset of diabetes (Haffner JAMA 1990). Recently, we have also shown (Haffner Circulation 2000) that among prediabetic subjects, only subjects with increased insulin resistance had increased blood pressure. Our data suggest that among prediabetic subjects at increased risk of hypertension, insulin resistance is an important concomitant of hypertension.
Risk mechanisms associated with hypertensive heart disease (HHD) and left ventricular hypertrophy (LVH) will be considered in this presentation. To be emphasized are impaired coronary hemodynamics, endothelial dysfunction, and ventricular fibrosis resulting from increased collagen deposition intramurally and perivascularly. Each is of these alterations is exacerbated by aging and, perhaps, also by increased salt intake. The coronary hemodynamic alterations include diminished coronary blood flow and flow reserve, increased coronary and minimal coronary vascular resistance, structural arteriolar changes and perhaps, increased blood viscosity and diastolic as well as systolic dysfunction in HHD. Clinical endpoints of HHD include: angina pectoris (with or without epicardial coronary atherosclerosis), myocardial infarction, cardiac failure, lethal dysrhythmias, and sudden death. The major concept to be derived is that all that is clinically recognized as LVH is not solely myocytic hypertrophy; other major co-morbid changes occur that increase cardiovascular risk including ventricular fibrosis, impaired coronary hemodynamics, and endothelial dysfunction.
Key Words: Insulin resistance; hypertension; diabetes
Key Words: Risk; LVH; hemodynamics
INSULIN RESISTANCE, HYPERTENSION AND TYPE 2 DIABETES Steven M. Haffner, MD. University of Texas Health Science Center, San Antonio, TX
OBESITY HYPERTENSION: A RISK FACTOR FOR CARDIOVASCULAR AND RENAL DISEASE Efrain Reisin. Louisiana State University Health Science Center, New Orleans, Louisiana Epidemiological studies suggest that a large number of obese patients have concomitant hypertension. This association causes the following vascular and hemodynamic changes: Enhanced vascular reactivity due to impaired vascular smooth muscle calcium efflux; inadequate nitric oxide generation by vascular endothelium; expanded cardiopulmonary volume, and increased total peripheral resistance. These changes lead to structural adaptation in the heart characterized by concentric-eccentric left ventricular hypertrophy. The hypertrophic condition provides the basis for the development of congestive heart failure and cardiac arrhythmias that may explain the higher rates of cardiac sudden death in those patients. In the kidneys, obesity hypertension may initiate a derangement on renal function. The increased deposit of interstitial cells and of extracellular matrix between the tubules induces higher interstitial hydrostatic pressure and tubular sodium reabsorption. The consequent increase in renal flow and glomerular filtration enhances albuminuria excretion and the susceptibility to the development of renal damage. In Summary: The hemodynamic and structural adaptations related to obesity hypertension is the cause of greater risk for adverse cardiovascular and renal events. Key Words: Obesity; blood pressure; renal hemodynamics; cardiovascular disease
Friday, May 19, Astor Ballroom, 5:00 PM to 6:30 PM Theme I: Cardiac Hypertrophy in Hypertension RISK MECHANISMS IN HYPERTENSIVE HEART DISEASE Edward D. Frohlich, MD. Alton Ochsner Medical Foundation, New Orleans, LA
JAK-STAT PATHWAY MEDIATED ACTIVATION OF RENIN ANGIOTENSIN SYSTEM IN MYOCARDIAL HYPERTROPHY AND ISCHEMIA Eduardo Mascareno, M. El-Shafie, Yueling Guo, and M.A.Q. Siddiqui. Center for Cardiovascular and Muscle Research, Department of Anatomy and Cell Biology, State University of New York Health Science Center at Brooklyn, Brooklyn, NY 11203 We have recently demonstrated that angiotensin II (Ang II) activates the Jak/STAT pathway resulting in enhanced binding of STAT-3, STAT-5A and STAT-6 to the angiotensinogen (ANG) promoter which causes the induction of the autocrine loop of renin-angiotensin system (RAS) during development of myocardial hypertrophy. Nuclear extract isolated from the adult hypertrophic SHR hearts showed a consistent high level of activated STAT proteins whereas those from STAT 6 null (⫺/⫺) mutant mice have a significant reduced level of activated STATs. Our follow-up studies with isolated and perfused rat heart subjected to ischemic stress also showed an induction of the Jak/STAT pathway and the consequent activation of the RAS components assayed by STATs/binding to the target site DNA. Pre-conditioning of the heart to ischemic stress produced a substantial reduction in STAT/ DNA binding. Among several cytrokines that influence the Jak/STAT pathway is leptin which is important in the etiology of obesity, a known risk factor in development of essential hypertension. Leptin specific receptors are present in a variety of tissues, including the cardiovascular tissues. We observed that like Ang II, leptin also mediates the activation of specific STAT proteins via its phosphorylation and subsequent binding to target DNA. Taken together, it appears that signaling rendered by the Jak/STAT pathway constitutes an essential step in modulation of the transcriptional machinery essential for development of various pathologies associated with angiotensin II. Key Words: Signaling mechanism; ischemia; hypertrophy