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Effects of ACE-inhibitors on progressive renal disease
A
FACULTY ABSTRACTS J
1997-VOL. 10, NO. 4, PART 2
Thursday May 29, Bayview A and B, 5:00 pm Theme I: Genetic and Molecular Models in Cardiovascular Disease Hypertensionin PregnantMice Akiyoshi Fukamizu, Univ. of Tsukuba, Japan Maternal hypertension is a common complication of pregnancy and its pathophysiology is poorly understood. This phenomenon was studied by mating transgenic mice expressing components of the renin-angiotensin system. When female mice expressing human angiotensinogen were mated with males expressing human renin, the pregnant females displayed a transient elevation of blood pressure in late pregnancy, due to secretion of human renin into the maternal circulation through placenta. Blood pressure returned to normal levels afier delivery of the pups. Histopathologic examination revealed uniform enlargement of glomeruli associated with an increase in urinary protein excretion, myocardial hypertrophy, and necrosis and edema in the placenta. Neonates in size born from hypertensive mothers were smaller than those from normotensive mothers. These mice may provide molecular insi@ts into pregnancy-associated hypertension: Keywords:renin-agiotensin system, pregnancy, transgenic mice, hypertension
Thursday May 29, Ballroom B and C, 5:00 pm Theme II: The Renin System as a Cause of Cardiovascular Disease and as a Substrate for Treatment CAUSALROLEOF PLASMARENINACTIVITY (PRA)INHEART ATTACK,STROKEAND KIDNEY FAILURE AND THE UNIQUE VALUE OF ANTI-RENIN SYSTEM ORUGS FOR PREVENTION OR TREATMENT John H. Laragh, M. D., New York Hospital-Cornell Medical Center Twenty-fiveyears ago we showed that the PRA level may be criticallyinvolvedin causationof heart attack (Ml) and stroke in untreated patientswith moderate to severe hypertension.In 219 patients followed for 8 years, the Ml and stroke rates were directly related to the entry PRA in medium and high renin patientsand mQsuch events occurred in the 59 low renin patientseven thoughthey had higher pressures and were 12 years older (Brunneret al:, New Eng J. Med 1972). In 1991 we confirmed and extended these results in an 8 year prospectivetrial of 1717 patients with mild hypertension(Alderman et al:, New Eng J. Med 1991). We also showedthat the ischemicvascular lesions in heart, brain and kidneys,with proteinuria,strokes, and early death occurringin salt fed SHRSP or Dahl S hypertensive rats are associated with escape from the initialrenin suppressionleading to enormouslyhigh PRA levels prestroke. Moreover, the cardiovascularmorbidityin both models was prevented or arrested by concurrentadministrationof Iosaftan, the specifictype I angiotensinII receptor antagonist,even when BP was not reduced. Recent clinicaltrials indicatethat, among antihypertensive agents, only beta blockeror CEI therapy or a combinationof the two can significantlyprotectfrom subsequentMl in patientswith prior Ml or CHF. These two drug classes bothsharply reduce circulatingangiotensin II levels for as longas the drug is given. Accordingly,in post Ml patients given either beta blockersor CEI inhibitors,mortalityand reinfarction rates are promptlyand persistentlyreduced and LV remodeling and subsequentCHF are also prevented (BHAT, SOLVD, SAVE,lSIS-l,GISSl3 and ISIS-4). Moreover, in CHF these benefits were shown to be confinedto those patientswhose baseline PRA were above the median (CONSENSUS I 1990). In renal failure patients, CEI therapy produces preventionof progressionof renal vascular disease. Since PRA, and cardiovasculartissue renin, is derived solely from kidney secretion,these findingsindicatethat inappropriaterenal renin secretionoften may be involvedin causation of Ml, stroke, and renal failure, as well as in congestive heart failure. At the same time, these results indicatethat drugtherapies that curtail PRA are uniquely effective for preventingor treatingthese major cardiac and vascular disorders. Key Words: Renin, Angiotensin,Heart Attack, Stroke, Renal Failure, Beta Blockade, ConvertingEnzyme Inhibition
Thursday May 29, Ballroom B and C, 5:00 pm Theme II: The Renin System as a Cause of Cardiovascular Disease and as a Substrate for Treatment EFFECTS OF ACE-INHIBITORS ON PROGRESSIVE RENAL DISEASE
Giuseppe Maschio, MD, Division of Nephrology, University Hospital, Verona, Italy A protective effect of ACE-inhibitors (ACEI) has been documented in patients with diabetic nephropathy. The AIPRI Study was performed in 583 patients with non-diabetic renal disease from 49 clinical centers in Italy, France and Germany. They were randomized to receive the ACEI benazepril or placebo plus otber antibypertensive agents, the goal being a diastolic BP< 90 mmHg. The primary end-point was the time from entry to doubling of baseline serum creatinine (Scr). At the end of the 3-year follow-up, 31 patients in tbe benazepril group and 57 in the placebo group reacbed the end-point (p< 0,001). The reduction in the risk of reaching the end-point was 530/0in benazepril-treated patients. The actuarial renal survival at 3 years was significantly better in the benazepril group. The best survival of renal function was observed in patients with glomerular diseases and proteinuria> 1.0 g/24 hours. Proteinuria was reduced by approximately 30% and diastolic BP by 3.5 to 5.0 mnlHg in the benazepril group. The number of adverse events requiring trial discontinuation was not different in the two treatment groups. The mortality rate, however, was higher in benazepril-treated patients. Conclusion: The ACE1benazepril is effective in slowing the rate of progression and in improving the survival of renal function in patients with non-diabetic renal disease. This protective effect is associated with a clinically relevant fall in both BP and proteinuria. Key
Words: ACE.inhibitor~, No”.diabetic ~enaidi~ea~e Progression of renal failure
Thursday May 29, Ballroom A, 5:00 pm Theme III: Surrogate Endpoints in the Treatment of Hypertension Left Ventricular Mass as a Surrogate Endpoint in the Treatment of Hypertension. Richard B. Devereux, M.D. Cornell Medical Center, New York, N.Y. To assess the validity of regression of left ventricular hypertrophy (LVH) as a surrogate end-point for morbid events in hypertension treatment trials, statistical, epidemiologic and treatment trial literature was reviewed to determine whether criteria that should be met by a surrogate end-point are met by existing data concerning LVH regression. Criteria include: 1) a consistent relation between LVH mrdsubsequent morbid events; 2) prediction of lower or higher complication rates by LVH regression or progression; 3) evidence of a consistent relation between LVH regressionlprogression mrd morbidity/mortality; and 4) demonstration that a measured changed in LVH allows prediction of change in clinical risk. Results of 7 electrocardiographic and 10 echocardiographic studies (total n about 20,000 subjects) all show higher morbid event rates in individuals with than without LVH (odds ratios 1.4 to 5.4), In 4 available data sets (1,145 subjects), morbid events occurred in 13 to 590/oof individuals in whom LVH progressed vs 7 to 120/i with LVH regression, However, these data are almost entirely from white subjects, predominately male, with variable knowledge of treatment and blood pressure; no information exists on the mathematical relation between LVH change and subsequent events, A strict definition of LVY regression as a surrogate end-point for morbid events in hypertension has been partially but not completely satisfied. Initial evidence of parallelism between LVH change and prognosis need confirmation by additional studies that examine this relation in diverse populations under varied treatments, and which examine the quantitative relationship between measured change in LVH and the subsequent rates of morbid events. Key Words: Echocardiography, electrocardiography, hypertension, h~ertrophy, regression, surrogate end-point.
219A
FACULTY ABSTRACTS J
1997-VOL. 10, NO. 4, PART 2
Thursday May 29, Bayview A and B, 5:00 pm Theme I: Genetic and Molecular Models in Cardiovascular Disease Hypertensionin PregnantMice Akiyoshi Fukamizu, Univ. of Tsukuba, Japan Maternal hypertension is a common complication of pregnancy and its pathophysiology is poorly understood. This phenomenon was studied by mating transgenic mice expressing components of the renin-angiotensin system. When female mice expressing human angiotensinogen were mated with males expressing human renin, the pregnant females displayed a transient elevation of blood pressure in late pregnancy, due to secretion of human renin into the maternal circulation through placenta. Blood pressure returned to normal levels afier delivery of the pups. Histopathologic examination revealed uniform enlargement of glomeruli associated with an increase in urinary protein excretion, myocardial hypertrophy, and necrosis and edema in the placenta. Neonates in size born from hypertensive mothers were smaller than those from normotensive mothers. These mice may provide molecular insi@ts into pregnancy-associated hypertension: Keywords:renin-agiotensin system, pregnancy, transgenic mice, hypertension
Thursday May 29, Ballroom B and C, 5:00 pm Theme II: The Renin System as a Cause of Cardiovascular Disease and as a Substrate for Treatment CAUSALROLEOF PLASMARENINACTIVITY (PRA)INHEART ATTACK,STROKEAND KIDNEY FAILURE AND THE UNIQUE VALUE OF ANTI-RENIN SYSTEM ORUGS FOR PREVENTION OR TREATMENT John H. Laragh, M. D., New York Hospital-Cornell Medical Center Twenty-fiveyears ago we showed that the PRA level may be criticallyinvolvedin causationof heart attack (Ml) and stroke in untreated patientswith moderate to severe hypertension.In 219 patients followed for 8 years, the Ml and stroke rates were directly related to the entry PRA in medium and high renin patientsand mQsuch events occurred in the 59 low renin patientseven thoughthey had higher pressures and were 12 years older (Brunneret al:, New Eng J. Med 1972). In 1991 we confirmed and extended these results in an 8 year prospectivetrial of 1717 patients with mild hypertension(Alderman et al:, New Eng J. Med 1991). We also showedthat the ischemicvascular lesions in heart, brain and kidneys,with proteinuria,strokes, and early death occurringin salt fed SHRSP or Dahl S hypertensive rats are associated with escape from the initialrenin suppressionleading to enormouslyhigh PRA levels prestroke. Moreover, the cardiovascularmorbidityin both models was prevented or arrested by concurrentadministrationof Iosaftan, the specifictype I angiotensinII receptor antagonist,even when BP was not reduced. Recent clinicaltrials indicatethat, among antihypertensive agents, only beta blockeror CEI therapy or a combinationof the two can significantlyprotectfrom subsequentMl in patientswith prior Ml or CHF. These two drug classes bothsharply reduce circulatingangiotensin II levels for as longas the drug is given. Accordingly,in post Ml patients given either beta blockersor CEI inhibitors,mortalityand reinfarction rates are promptlyand persistentlyreduced and LV remodeling and subsequentCHF are also prevented (BHAT, SOLVD, SAVE,lSIS-l,GISSl3 and ISIS-4). Moreover, in CHF these benefits were shown to be confinedto those patientswhose baseline PRA were above the median (CONSENSUS I 1990). In renal failure patients, CEI therapy produces preventionof progressionof renal vascular disease. Since PRA, and cardiovasculartissue renin, is derived solely from kidney secretion,these findingsindicatethat inappropriaterenal renin secretionoften may be involvedin causation of Ml, stroke, and renal failure, as well as in congestive heart failure. At the same time, these results indicatethat drugtherapies that curtail PRA are uniquely effective for preventingor treatingthese major cardiac and vascular disorders. Key Words: Renin, Angiotensin,Heart Attack, Stroke, Renal Failure, Beta Blockade, ConvertingEnzyme Inhibition
Thursday May 29, Ballroom B and C, 5:00 pm Theme II: The Renin System as a Cause of Cardiovascular Disease and as a Substrate for Treatment EFFECTS OF ACE-INHIBITORS ON PROGRESSIVE RENAL DISEASE
Giuseppe Maschio, MD, Division of Nephrology, University Hospital, Verona, Italy A protective effect of ACE-inhibitors (ACEI) has been documented in patients with diabetic nephropathy. The AIPRI Study was performed in 583 patients with non-diabetic renal disease from 49 clinical centers in Italy, France and Germany. They were randomized to receive the ACEI benazepril or placebo plus otber antibypertensive agents, the goal being a diastolic BP< 90 mmHg. The primary end-point was the time from entry to doubling of baseline serum creatinine (Scr). At the end of the 3-year follow-up, 31 patients in tbe benazepril group and 57 in the placebo group reacbed the end-point (p< 0,001). The reduction in the risk of reaching the end-point was 530/0in benazepril-treated patients. The actuarial renal survival at 3 years was significantly better in the benazepril group. The best survival of renal function was observed in patients with glomerular diseases and proteinuria> 1.0 g/24 hours. Proteinuria was reduced by approximately 30% and diastolic BP by 3.5 to 5.0 mnlHg in the benazepril group. The number of adverse events requiring trial discontinuation was not different in the two treatment groups. The mortality rate, however, was higher in benazepril-treated patients. Conclusion: The ACE1benazepril is effective in slowing the rate of progression and in improving the survival of renal function in patients with non-diabetic renal disease. This protective effect is associated with a clinically relevant fall in both BP and proteinuria. Key
Words: ACE.inhibitor~, No”.diabetic ~enaidi~ea~e Progression of renal failure
Thursday May 29, Ballroom A, 5:00 pm Theme III: Surrogate Endpoints in the Treatment of Hypertension Left Ventricular Mass as a Surrogate Endpoint in the Treatment of Hypertension. Richard B. Devereux, M.D. Cornell Medical Center, New York, N.Y. To assess the validity of regression of left ventricular hypertrophy (LVH) as a surrogate end-point for morbid events in hypertension treatment trials, statistical, epidemiologic and treatment trial literature was reviewed to determine whether criteria that should be met by a surrogate end-point are met by existing data concerning LVH regression. Criteria include: 1) a consistent relation between LVH mrdsubsequent morbid events; 2) prediction of lower or higher complication rates by LVH regression or progression; 3) evidence of a consistent relation between LVH regressionlprogression mrd morbidity/mortality; and 4) demonstration that a measured changed in LVH allows prediction of change in clinical risk. Results of 7 electrocardiographic and 10 echocardiographic studies (total n about 20,000 subjects) all show higher morbid event rates in individuals with than without LVH (odds ratios 1.4 to 5.4), In 4 available data sets (1,145 subjects), morbid events occurred in 13 to 590/oof individuals in whom LVH progressed vs 7 to 120/i with LVH regression, However, these data are almost entirely from white subjects, predominately male, with variable knowledge of treatment and blood pressure; no information exists on the mathematical relation between LVH change and subsequent events, A strict definition of LVY regression as a surrogate end-point for morbid events in hypertension has been partially but not completely satisfied. Initial evidence of parallelism between LVH change and prognosis need confirmation by additional studies that examine this relation in diverse populations under varied treatments, and which examine the quantitative relationship between measured change in LVH and the subsequent rates of morbid events. Key Words: Echocardiography, electrocardiography, hypertension, h~ertrophy, regression, surrogate end-point.
219A