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Target organ damage in hypertension: mechanisms, prevention, and management
AJH
2002; 15:1117–1118
Report on the Third Laragh Conference
Target Organ Damage in Hypertension: Mechanisms, Prevention, and Management
T
he first session of the Third Annual John H. Laragh Conference on Advances in Hypertension Research provided an overview and focused on key clinical issues. Dr. Dan Levy discussed the relative roles of systolic (SBP) and diastolic (DBP) blood pressures and pulse pressure (PP) in determining cardiovascular risk. He pointed out that contrary to current practice, which often focuses on DBP, elevated SBP contributes twice the relative risk as DBP to cardiovascular events. This is particularly important as SBP increases with age, whereas DBP declines. This concept is reinforced by the SHEP trial, which showed that reducing SBP reduces the risk of cardiovascular events. Dr. Jay Cohn then discussed new approaches to screening for vascular and cardiac risks using arterial compliance measurements and emphasized the need for early tracking of vascular disease in the clinic and in large-scale trials. Dr. Michael Alderman reviewed studies on the relationship between elevated plasma renin activity and cardiovascular risk. He pointed out that, although the relative risk of myocardial infarction is greater for patients with high plasma renin levels, there is an inverse relation between plasma renin activity (PRA) and the incidence of stroke. The second session examined the role of angiotensin II (Ang II) type 1 (AT1) receptor antibodies, oxidative stress, and the effects of elevated BP per se on target organ damage. Dr. Friedrich Luft discussed work from his group on the role of agonistic autoantibodies directed against the angiotensin II AT1 receptor. These antibodies were initially identified in women with preeclampsia, but have now been found in patients with malignant hypertension, those with chronic vascular rejection, and in the TGR (renin overexpressing) rat model of hypertension. Dr. Luft discussed the possible molecular mechanisms of the autoantibodies suggesting that they might cause a change in the conformation of the AT1 receptor that alters its sensitivity to Ang II. This is because AT1R autoantibodies take 20 min to exert their effect through the AT1 receptor, whereas the effects of Ang II occur within milliseconds. Other speakers addressed the role of nitric oxide and other signal transduction mechanisms in target organ damage. Dr. Leopoldo Raij suggested that the downregulation
of nitric oxide synthase expression may cause target organ damage in various genetic models of hypertension and discussed the evidence for the BP-independent effects of angiotensin receptor blockers that may be mediated through improvements in endothelial function. Dr. Rhian Touyz discussed signaling pathways that couple activation of the Ang II receptor to oxidative stress leading to vascular damage in hypertension. Dr. Christopher Wilcox highlighted the contribution of oxidative stress in the pathogenesis of renal damage. Contrary to several other speakers, Dr. Karen Griffin provided evidence that the renoprotective effects of the renin-angiotensin system (RAS) blockade are largely BP dependent. Dr. Anil Bidani showed the findings from renal transplant studies that provide further evidence for the BP dependency of hypertensive target organ damage as well as evidence for genetic variation in susceptibility to hypertension-induced renal damage. Dr. Paul Saunders reviewed studies suggesting that excess dietary salt may accelerate vascular damage by increasing transforming growth factor- (TGF-) expression. Dr. Massimo Volpe discussed the evidence for a functional role of the atrial natriuretic peptide (ANP) gene in causing stroke in the SHRSP rat model. Dr. Daniel Catanzaro presented findings of gene array studies of target organ damage that suggested a dominant role of inflammatory response mediators. Drs. Mark Cooper and George Bakris reviewed data from clinical trials in diabetic patients. Dr. Cooper discussed the mechanisms of vasculopathy in the hypertensive diabetic. He provided evidence that renal damage may occur through BP-dependent and BP-independent pathways and also suggested that glucose can activate many of the same signaling pathways as Ang II. Dr. Bakris reviewed the findings of clinical trials on preserving renal function in hypertensive diabetics and discussed the issue of setting more aggressive BP goals in patients with diabetes. Drs. Peter Sleight, Curt Furberg, Bryan Williams, and Suzanne Oparil reviewed the findings of recent clinical trials. Dr. Sleight provided commentary on substudies of the HOPE trial and argued that the benefits of ramipril
Received September 17, 2002. First decision September 17, 2002. Accepted September 17, 2002.
Hypertension Research was held January 31–February 2, 2002, at the Ritz-Carlton Palm Beach, Manalapan, FL. Address correspondence and reprint requests to Dr. Daniel F. Catanzaro, Weill Medical College, Cornell University, Cardiovascular Center, 1300 York Avenue, Room A 863, New York, NY 10021; e-mail: [email protected]
From the Weill Medical College, Cornell University, Cardiovascular Center, New York, New York. The Third Annual John H. Laragh Conference on Advances in © 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
0895-7061/02/$22.00 PII S0895-7061(02)03142-4
1118
REPORT ON THE THIRD LARAGH CONFERENCE
therapy in HOPE were unlikely to be secondary to its effects on BP. This provoked a vigorous debate with considerable dissent among the participants suggesting the need for more careful measurements of BP in future clinical trials. Dr. Furberg provided further analysis of the SHEP trial, indicating that the change in BP after 1 year of treatment explained only 14% of the benefit in stroke reduction, whereas the achieved BP level at 1 year explained 34% of the benefit. Dr. Williams argued that BP reduction is dominant in determining the outcome of clinical trials, and discussed how apparently small effects on clinic BP can be particularly deleterious in some populations and may also reflect large effects on BP outside
AJH–December 2002–VOL. 15, NO. 12
of the clinic. Dr. Oparil discussed the design of the ALLHAT study, the results of which are scheduled for release in December 2002 and could play a major role in shaping future guidelines for the management of hypertension. Clearly, many unresolved issues remain with respect to the mechanisms, prevention, and management of target organ damage in hypertension. Because of the vast clinical implications of this topic, it is expected to be a high priority area for hypertension research well into the future. DANIEL F. CATANZARO THEODORE W. KURTZ
2002; 15:1117–1118
Report on the Third Laragh Conference
Target Organ Damage in Hypertension: Mechanisms, Prevention, and Management
T
he first session of the Third Annual John H. Laragh Conference on Advances in Hypertension Research provided an overview and focused on key clinical issues. Dr. Dan Levy discussed the relative roles of systolic (SBP) and diastolic (DBP) blood pressures and pulse pressure (PP) in determining cardiovascular risk. He pointed out that contrary to current practice, which often focuses on DBP, elevated SBP contributes twice the relative risk as DBP to cardiovascular events. This is particularly important as SBP increases with age, whereas DBP declines. This concept is reinforced by the SHEP trial, which showed that reducing SBP reduces the risk of cardiovascular events. Dr. Jay Cohn then discussed new approaches to screening for vascular and cardiac risks using arterial compliance measurements and emphasized the need for early tracking of vascular disease in the clinic and in large-scale trials. Dr. Michael Alderman reviewed studies on the relationship between elevated plasma renin activity and cardiovascular risk. He pointed out that, although the relative risk of myocardial infarction is greater for patients with high plasma renin levels, there is an inverse relation between plasma renin activity (PRA) and the incidence of stroke. The second session examined the role of angiotensin II (Ang II) type 1 (AT1) receptor antibodies, oxidative stress, and the effects of elevated BP per se on target organ damage. Dr. Friedrich Luft discussed work from his group on the role of agonistic autoantibodies directed against the angiotensin II AT1 receptor. These antibodies were initially identified in women with preeclampsia, but have now been found in patients with malignant hypertension, those with chronic vascular rejection, and in the TGR (renin overexpressing) rat model of hypertension. Dr. Luft discussed the possible molecular mechanisms of the autoantibodies suggesting that they might cause a change in the conformation of the AT1 receptor that alters its sensitivity to Ang II. This is because AT1R autoantibodies take 20 min to exert their effect through the AT1 receptor, whereas the effects of Ang II occur within milliseconds. Other speakers addressed the role of nitric oxide and other signal transduction mechanisms in target organ damage. Dr. Leopoldo Raij suggested that the downregulation
of nitric oxide synthase expression may cause target organ damage in various genetic models of hypertension and discussed the evidence for the BP-independent effects of angiotensin receptor blockers that may be mediated through improvements in endothelial function. Dr. Rhian Touyz discussed signaling pathways that couple activation of the Ang II receptor to oxidative stress leading to vascular damage in hypertension. Dr. Christopher Wilcox highlighted the contribution of oxidative stress in the pathogenesis of renal damage. Contrary to several other speakers, Dr. Karen Griffin provided evidence that the renoprotective effects of the renin-angiotensin system (RAS) blockade are largely BP dependent. Dr. Anil Bidani showed the findings from renal transplant studies that provide further evidence for the BP dependency of hypertensive target organ damage as well as evidence for genetic variation in susceptibility to hypertension-induced renal damage. Dr. Paul Saunders reviewed studies suggesting that excess dietary salt may accelerate vascular damage by increasing transforming growth factor- (TGF-) expression. Dr. Massimo Volpe discussed the evidence for a functional role of the atrial natriuretic peptide (ANP) gene in causing stroke in the SHRSP rat model. Dr. Daniel Catanzaro presented findings of gene array studies of target organ damage that suggested a dominant role of inflammatory response mediators. Drs. Mark Cooper and George Bakris reviewed data from clinical trials in diabetic patients. Dr. Cooper discussed the mechanisms of vasculopathy in the hypertensive diabetic. He provided evidence that renal damage may occur through BP-dependent and BP-independent pathways and also suggested that glucose can activate many of the same signaling pathways as Ang II. Dr. Bakris reviewed the findings of clinical trials on preserving renal function in hypertensive diabetics and discussed the issue of setting more aggressive BP goals in patients with diabetes. Drs. Peter Sleight, Curt Furberg, Bryan Williams, and Suzanne Oparil reviewed the findings of recent clinical trials. Dr. Sleight provided commentary on substudies of the HOPE trial and argued that the benefits of ramipril
Received September 17, 2002. First decision September 17, 2002. Accepted September 17, 2002.
Hypertension Research was held January 31–February 2, 2002, at the Ritz-Carlton Palm Beach, Manalapan, FL. Address correspondence and reprint requests to Dr. Daniel F. Catanzaro, Weill Medical College, Cornell University, Cardiovascular Center, 1300 York Avenue, Room A 863, New York, NY 10021; e-mail: [email protected]
From the Weill Medical College, Cornell University, Cardiovascular Center, New York, New York. The Third Annual John H. Laragh Conference on Advances in © 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
0895-7061/02/$22.00 PII S0895-7061(02)03142-4
1118
REPORT ON THE THIRD LARAGH CONFERENCE
therapy in HOPE were unlikely to be secondary to its effects on BP. This provoked a vigorous debate with considerable dissent among the participants suggesting the need for more careful measurements of BP in future clinical trials. Dr. Furberg provided further analysis of the SHEP trial, indicating that the change in BP after 1 year of treatment explained only 14% of the benefit in stroke reduction, whereas the achieved BP level at 1 year explained 34% of the benefit. Dr. Williams argued that BP reduction is dominant in determining the outcome of clinical trials, and discussed how apparently small effects on clinic BP can be particularly deleterious in some populations and may also reflect large effects on BP outside
AJH–December 2002–VOL. 15, NO. 12
of the clinic. Dr. Oparil discussed the design of the ALLHAT study, the results of which are scheduled for release in December 2002 and could play a major role in shaping future guidelines for the management of hypertension. Clearly, many unresolved issues remain with respect to the mechanisms, prevention, and management of target organ damage in hypertension. Because of the vast clinical implications of this topic, it is expected to be a high priority area for hypertension research well into the future. DANIEL F. CATANZARO THEODORE W. KURTZ