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Background: Autosomal dominant polycystic kidney disease (ADPKD) shows a variable clinical course suggesting that genetic modifiers might play a role. There are conflicting results about the effect of angiotensin-converting enzyme (ACE) gene polymorphism on the progression of renal failure in ADPKD. Also, the association between ACE gene polymorphism and the occurrence of left ventricular hypertrophy (LVH) has not been investigated in patients with ADPKD. Methods: ACE genotype analysis was performed in 409 Caucasian patients (137 male, 272 female) with ADPKD. Echocardiographic examination was done in 164 of these patients. Results: There were no significant differences between different ACE genotypes regarding renal function, renal volume, urinary protein excretion, blood pressure, the rate of hypertension, the age at diagnosis of hypertension, the rate of LVH and the incidence of end-stage renal disease (ESRD). Conclusion: ACE gene polymorphism does not have a significant effect on the development of ESRD and the prevalence of LVH in patients with ADPKD.

Previous studies evaluating the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism have revealed that expression of the DD genotype is associated with an increase in myocardial infarction, cardiomyopathy, and left ventricular (LV) mass in nondiabetic patients. In the present study, a cross-sectional analysis was performed to evaluate the potential relationship between the ACE I/D genotypes and the LV mass index in 289 non–insulin-dependent diabetes mellitus (NIDDM) subjects without known coronary artery disease. Two dimensional directed M-mode echocardiograms along with selected patient characteristics were obtained from the study population. The distribution of the I/D polymorphism was as follows: 63 were II (22%), 137 were ID (47%), and 89 were DD (31%). Univariately, the DD genotype was associated with an increase in LV mass in men but not in women. When subjected to a multiple regression model that included age, systolic blood pressure, duration of diabetes, duration of hypertension, presence of the black race, and the presence of the DD genotype, the DD genotype was independently associated with an increase in the LV mass index with a parameter estimate of 10.5 g/m 2 (95% CI = 3.9, 17.0; P .002) in the male subjects. Thus, in this NIDDM study population, male patients with the DD genotype are independently associated with an increased LV mass.

Angiotensin II causes pulmonary vasoconstriction in man and in animals, and angiotensin-converting enzyme (ACE) inhibitors have prevented the development of chronic pulmonary hypertension in animals models. Angiotensin II may contribute to lung vascular remodeling in pulmonary hypertensive disease, since cilazapril, an inhibitor of ACE, reduces pulmonary vascular medical thickening in chronically hypoxic rats with established pulmonary hypertension. Furthermore, the ACE DD genotype, which has been associated with increased circulating and tissue ACE activity, has been associated with left ventricular hypertrophy in human hypertensive disorders. The ACE DD genotype may also 'permit' a greater hypertrophic adaptation of the pressure-over-loaded right ventricle. In fact, we have shown that pulmonary hypertension patients with maintained cardiac output and less right-heart failure fall into the group with the DD genotype and that patients with a low cardiac output and more severe right-heart failure fall into the group with the non-DD genotype, supporting the hypothesis. We assessed cardiopulmonary hemodynamics in patients with primary (unexplained) pulmonary hypertension and segregated the patients based on their ACE genotype. For similar mean pulmonary artery pressures in the DD and non-DD groups, the cardiac output was substantially lower in the patients with the non-DD genotype, whereas the values for mean right atrial pressure and pulmonary vascular resistance were double when compared with the DD group. Our data show that the ACE DD genotype is prevalent in patients with severe pulmonary hypertension and is a marker of maintained right ventricular function.

Hypothesis/introduction A polymorphic marker within the angiotensin-converting enzyme (ACE) gene has been associated with circulating and tissue ACE activity and with a variety of forms of cardiovascular disease. Since angiotensin II (Ang II) causes pulmonary vasoconstriction and vascular and myocardial remodelling, we postulated a role for the renin-angiotensin system and the ACE DD genotype in the pathophysiology of primary pulmonary hypertension (PPH) and in the right ventricular response to pressure overload in these patients. Methods and results The incidence of the ACE DD genotype was evaluated in 60 patients with severe PPH compared with two normal control populations, a group of healthy population-based controls (n=158) and subjects found suitable for cardiac organ donation (n=79). Genomic DNA extracted from peripheral leukocytes was amplified using the polymerase chain reaction to detect polymorphic markers. Haemodynamics were determined by right heart catheterisation in a subset of the PPH patients. The frequency of the ACE DD genotype was 45% in the patients with PPH, compared with 24% in the organ donors, and 28% in populationbased healthy controls (p=0.01 for chi-square test). Of the 32 PPH patients with baseline haemodynamics, 12 exhibited the ACE DD genotype and 20 were non-DD. While the mean pulmonary artery pressure and the duration of symptoms attributable to pulmonary hypertension was not different between the DD and non-DD groups, cardiac output was significantly lower (3.29±0.27 vs. 5.07±0.37 L/minute, p=0.002) and the trouvemean right atrial pressure tended to be higher (8.85±1.29 vs. 4.92±1.27 mmHg, p=0.08) in the non-DD group. The reduction in cardiac output seen in the non-DD group was not due to a difference in heart rate, but to a significant reduction in stroke volume, consistent with a decreased contractile state. In addition, non-DD patients exhibited a significantly worse functional capacity (NYHA Class 3.14±0.12 vs. 2.40±0.28, p=0.02). Conclusions 1) The ACE DD genotype is significantly increased in patients with severe PPH compared with normal controls, suggesting that certain individuals may be genetically predisposed to developing pulmonary hypertension. 2) The ACE DD genotype is associated with preserved right ventricular function in PPH patients, supporting a compensatory myocardial or inotropic role for Ang II in the pressure overloaded right ventricle.

To test the hypothesis that the angiotensin converting enzyme (ACE) genotype is associated with chronic beryllium disease (CBD) and disease severity, we studied 50 cases of CBD and compared their ACE genotype to that of two different control groups, consisting of: (1) 50 participants from a beryllium machining facility; and (2) 50 participants from a non-beryllium-associated workplace. We found no statistically significant difference in the frequency of the I or D allele or of the DD genotype among cases of CBD and either control group. The odds ratio (OR) for the CBD DD genotype as compared with the non-DD genotype was 1.58 (95% confidence interval [CI]: 0.68 to 3.66, p = 0.12) for the beryllium-exposed control group, and 1.09 (95% CI: 0.48 to 2.46, p = 0.56) for the non-beryllium-exposed controls. We found an association between serum ACE activity and the ACE genotype, with DD cases having the highest median serum ACE activity (p = 0.005). We evaluated the beryllium lymphocyte proliferation test (BeLPT), bronchoalveolar lavage (BAL) cell components, chest radiography, pulmonary function test results, and exercise physiology in our CBD cases. No statistically significant associations with these disease markers were found for the CBD cases with the DD genotype. Although the difference was not statistically significant, the DD cases had a shorter median duration of exposure to beryllium before diagnosis of CBD, and tended to have a weaker response in their blood and BAL BeLPT than did the non-DD cases. These findings may indicate that the ACE genotype is important in the immune response to beryllium and in progression to beryllium disease.

Background The regulation of angiotensin II receptors and the two major subtypes (AT 1 and AT 2 ) in chronically failing human ventricular myocardium has not been previously examined. Methods and Results Angiotensin II receptors were measured by saturation binding of 125 I-[Sar 1 ,Ile 8 ]angiotensin II in crude membranes from nonfailing (n=19) and failing human left ventricles with idiopathic dilated cardiomyopathy (IDC; n=31) or ischemic cardiomyopathy (ISC; n=21) and membranes from a limited number of right ventricles in each category. The AT 1 and AT 2 fractions were determined by use of an AT 1 -selective antagonist, losartan. β-Adrenergic receptors were also measured by binding of 125 I-iodocyanopindolol with the β 1 and β 2 fractions determined by use of a β 1 -selective antagonist, CGP20712A. AT 1 but not AT 2 density was significantly decreased in the combined (IDC+ISC) failing left ventricles (nonfailing: AT 1 4.66±0.48, AT 2 2.73±0.39; failing: AT 1 3.20±0.29, AT 2 2.70±0.33 fmol/mg protein; mean±SE). The decrease in AT 1 density was greater in the IDC than in the ISC left ventricles (IDC: 2.73±0.40, P P =NS versus nonfailing). β 1 but not β 2 density was decreased in the failing left ventricles. AT 1 density was correlated with β 1 density in all left ventricles ( r =.43). AT 1 density was also decreased in IDC right ventricles. In situ reverse transcription–polymerase chain reaction in sections of nonfailing and failing ventricles indicated that AT 1 mRNA was present in both myocytes and nonmyocytes. Conclusions AT 1 receptors are selectively downregulated in failing human ventricles, similar to the selective downregulation of β 1 receptors. The relative lack of AT 1 downregulation in ISC hearts may be related to differences in the degree of ventricular dysfunction.

A polymorphic marker within the ACE gene has been found to correlate with circulating and tissue ACE activities and with the incidence of severe pulmonary hypertension (Abraham et al, JACC 1994; 23: 177A). While the association of the ACE DD genotype and pulmonary hypertension suggests a role for angiotensin II (Ang II) in the pulmonary vasoconstriction and pulmonary vascular smooth muscle proliferation characteristic of this disorder, we hypothesize a compensatory role for Ang II in the maintenance of right ventricular (RV) function in such patients. We evaluated the frequency of the ACE DD genotype in 55 patients with severe primary pulmonary hypertension (PPH) and compared clinical severity and right heart hemodynamics at the time of presentation in 20 of these patients stratified on the basiw of their ACE genotype (DD vs non-DD, n = 10 in each group). The incidence of the ACE DD genotype was 49% in the PPH patients compared to 23% in a control population (n = 89, p = 0.0009). Mean ± SEM right heart hemodynamics, echocardiographic RV internal dimensions (RVID) and NYHA classifications for the 2 groups are shown below: DD Non-DD p value Mean PA Pressure (mmHg) 52 ± 4 53 ± 3 0.84 PCWP (mmHg) 5 ± 1 6 ± 1 0.59 Cardiac Output (L/min) 5.12 ± 0.43 2.65 ± 0.21 0.00007 PVR (Wood Units) 10.0 ± 1.3 19.3 ± 2.4 0.004 RA Pressure (mmHg) 5 ± 1 10 ± 2 0.08 RVID(cm) 3.1 ± 0.3 3.7 ± 0.2 0.08 NYHA Class 2.2 ± 0.3 3.3 ± 0.2 0.02 Significantly, the duration of symptoms attributable to PPH was not different between the DD and non-DD groups (35 ± 19 vs 22 ± 6 months, p = 0.58). Conclusion: The ACE DD genotype is associated with preserved RV function in PPH patients, supporting a compensatory myocardial or inotropic role for Ang II in PPH