Faculty Bibliography

BACKGROUND: The alpha-adducin (ADD1) Gly460Trp polymorphism has been associated with hypertension and response to diuretic therapy, but controversy exists. METHODS: The present study was conducted to prospectively investigate the relationship among the ADD1 Gly460Trp polymorphism, diuretic use, and adverse cardiovascular outcomes among 5,979 patients with hypertensive coronary artery disease, who participated in the INVEST and provided genomic DNA. The primary outcome was defined as the first occurrence of nonfatal stroke, nonfatal myocardial infarction, or all-cause death. Secondary outcomes were the components of the primary outcome. Ancestry informative markers were used to control for population stratification. RESULTS: In blacks, ADD1 variant carriers were at higher risk for a primary outcome event than wild-type homozygotes (adjusted hazard ratio 2.62, 95% CI 1.23-5.58, P = .012), with a similar trend in whites and Hispanics, albeit a smaller magnitude of effect (adjusted hazard ratio 1.43, 0.86-2.39 in Hispanics; 1.24, 0.90-1.71 in whites). Secondary outcome analysis showed that the all-cause death was driving the differences in primary outcomes by genotype. There was no interaction between the ADD1 polymorphism and diuretic use for either primary outcome or secondary outcomes. CONCLUSIONS: In hypertensive patients with coronary artery disease, black ADD1 variant carriers showed a 2.6-fold excess risk for a primary outcome event and an 8-fold increase risk of death. White and Hispanic ADD1 variant carriers showed an increased but nonsignificant excess risk. However, the effect of diuretic use on risk of cardiovascular outcomes did not vary by ADD1 carrier status

Cardiac patients often have sinus arrhythmia of nonrespiratory origin (erratic sinus rhythm [ESR]). ESR was quantified using hourly Poincare and power spectral heart rate variability plots from normal-to-normal interbeat intervals and hourly values of the short-term fractal scaling exponent and correlations of normal-to-normal intervals in n = 60 nonsurvivors and n = 66 randomly selected survivors in the Cardiac Arrhythmia Suppression Trial. Hours were coded (ABN) as normal (0), borderline (0.5), or ESR (1). t Tests compared ABN for n = 2413 paired hours at baseline and on therapy. ABN was higher in nonsurvivors (0.38 +/- 0.44 vs 0.28 +/- 0.40, baseline, and 0.51 +/- 0.45 vs 0.34 +/- 0.43, on therapy, P < .001). Increased ABN with treatment were greater in nonsurvivors. Normal hours at baseline (relative risk = 0.77; 095% confidence interval, 0.62-0.96, P = .018) and on treatment (relative risk = 0.47; 95% confidence interval, 0.39-0.58) were significantly associated with decreased mortality compared with ESR. Quantification of ESR may identify more vulnerable patients or help monitor the effects of pharmacologic treatment

In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial, carvedilol added to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers had neutral or beneficial effects on glycemic measures compared with metoprolol tartrate. For the 1235 diabetic hypertensive GEMINI patients, the authors assessed treatment differences by race (white/black/other), age (continuous variable), and sex on hemoglobin A(1c), insulin resistance (homeostasis model assessment-insulin resistance [HOMA-IR]), and blood pressure. Both treatments significantly reduced blood pressure in all subgroups, but the metabolic effects of carvedilol were more beneficial in subgroups of race and sex. Carvedilol did not affect hemoglobin A(1c) but improved HOMA-IR results in all subgroups, significantly in males and 'other race' subgroups. Metoprolol significantly increased hemoglobin A(1c) in all subgroups except 'other race,' with no effect on HOMA-IR findings. Differences vs metoprolol significantly favored carvedilol for hemoglobin A(1c) in white and female subgroups and favored carvedilol for HOMA-IR in black, 'other race,' and male subgroups. Carvedilol effects were favorable to adjustment of age as a covariate. In hypertensive patients with diabetes, carvedilol may be a more appropriate choice when beta-blockade is indicated

OBJECTIVES: We sought to determine whether polymorphisms in the large-conductance calcium and voltage-dependent potassium (BK) channel beta1 subunit gene, KCNMB1, are associated with blood pressure response to verapamil SR or adverse outcomes in the GENEtic substudy of the INternational VErapamil SR/trandolapril STudy (INVEST-GENES). BACKGROUND: KCNMB1 is involved in calcium sensitivity and hypertension. The association between variability in KCNMB1 and calcium antagonist response, however, has not been assessed. METHODS: Genetic samples were collected from 5979 patients in INVEST. Blood pressure response to verapamil SR and time to achieve blood pressure control was assessed in relation to Glu65Lys and Val110Leu genotypes. The primary outcome (all cause mortality, nonfatal myocardial infarction or nonfatal stroke) was compared between genotype groups, and interaction with verapamil SR therapy was assessed. RESULTS: Systolic blood pressure response to verapamil SR did not differ by KCNMB1 genotype. Lys65 variant carriers, however, achieved blood pressure control earlier than Glu65Glu individuals [1.47 (interquartile ratio 2.77) versus 2.83 (interquartile ratio 4.17) months, P=0.01] and were less likely to require multiple drugs at the time of blood pressure control (adjusted odds ratio 0.43, 95% confidence interval 0.19-0.95). Leu110 variant carriers had a reduced risk of primary outcome (hazard ratio 0.68, 95% confidence interval 0.47-0.998). Subgroup analysis revealed this finding to be more pronounced in verapamil SR-assigned patients (hazard ratio 0.587, 95% confidence interval 0.33-1.04) compared with atenolol-assigned patients (hazard ratio 0.946, 95% confidence interval 0.56-1.59). No difference was seen in the occurrence of the primary outcome compared by codon 65 genotype. CONCLUSIONS: Our findings suggest that KCNMB1 genotype influences responsiveness to verapamil SR and risk of adverse cardiovascular outcomes

BACKGROUND: Prospective data regarding blood pressure (BP) control and cardiovascular (CV) outcomes in Hispanic women are lacking. METHODS: We analyzed 5017 Hispanic and 4710 non-Hispanic white hypertensive women with coronary artery disease (CAD) in the INternational VErapamil SR/Trandolapril STudy (INVEST) to determine the impact of baseline characteristics and BP control on CV outcomes. RESULTS: At baseline, Hispanic women were younger and a had lower prevalence of most established CV risk factors than non-Hispanic white women. At 24 months, BP control (< 140/90 mm Hg) was achieved in 75% of Hispanic and 68% of non-Hispanic white women, (p < 0.001), with most women, regardless of ethnicity, requiring > or =2 antihypertensive agents. Following 26,113 patient-years of follow-up, the primary outcome (first occurrence of nonfatal myocardial infarction [MI], nonfatal stroke, or all cause death) occurred in 5.7% of Hispanic and 12.3% of non-Hispanic white women (adjusted HR = 0.84, 95% CI = 0.71-0.98, p = 0.03). There was no difference in outcome in either group of women comparing the randomized antihypertensive treatment strategies. CONCLUSIONS: Despite accounting for a lower risk profile, deployment of protocol-based antihypertensive treatment regimens resulted in superior BP control and fewer CV events in Hispanic women compared with non-Hispanic white women

The effects of beta-blockade in addition to more specific renin-angiotensin system (RAS) blockers on blood pressure (BP) in patients with diabetes are described. After washout of medications other than angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, patients were titrated to a BP level <130/80 mm Hg using therapy with carvedilol 6.25 to 25 mg bid (n=498) or metoprolol tartrate 50 to 200 mg bid (n=737). At the end of the beta-blocker titration period, a BP level <130/80 mm Hg was achieved in 37% of carvedilol-treated and 36% of metoprolol-treated participants who continued to receive a renin-angiotensin system blocker. In the approximately 60% of participants in whom a BP level <130/80 mm Hg was not attained with renin-angiotensin system blockade plus beta-blockade, hydrochlorothiazide was added in 43% and 44% of carvedilol and metoprolol groups, respectively; 25% (both arms) also required a calcium channel blocker. Among those in whom goal BP was not achieved, 42% of carvedilol- and 40% of metoprolol-treated participants were not titrated to the highest dose of beta-blocker. The use of carvedilol compared with metoprolol did not effect glycemic control

AIMS: To determine whether the beneficial effects of carvedilol on insulin resistance (IR) are affected by the concomitant use of insulin sensitizers [thiazolidinediones (TZDs) and metformin]. METHODS: Changes in HbA1c and homeostasis model assessment-insulin resistance (HOMA-IR) were assessed over 5 months, comparing carvedilol with metoprolol tartrate according to insulin sensitizer (TZDs and metformin) use. RESULTS: In TZD/metformin users, carvedilol patients showed a 5.4% decrease [95% confidence interval (CI) -11.9, 1.6; P = 0.13] and metoprolol tartrate patients showed a 2.8% decrease (95% CI -8.5, 3.2; P = 0.35) in HOMA-IR. The -2.6% difference between treatments was not significant (95% CI -10.7, 6.2; P = 0.55). In contrast, those not taking TZD/metformin experienced a 13.2% increase in HOMA-IR on metoprolol tartrate (95% CI 3.2, 24.1; P < 0.01) and a 4.8% decrease in HOMA-IR on carvedilol (95% CI -14.6, 6.0; P = 0.37), with a significant treatment difference of -15.9% favouring carvedilol (95% CI -26.6, -3.6; P = 0.01). There was no significant treatment interaction for the use of TZD/metformin and HbA1c. A statistically significant treatment difference was observed for HbA1c after 5 months favouring carvedilol after adjusting for insulin sensitizer use (-0.11%, 95% CI -0.214, -0.009; P = 0.03). CONCLUSIONS: In patients with diabetes and hypertension not taking insulin sensitizers, the use of metoprolol tartrate resulted in a worsening of insulin resistance, an effect not seen with carvedilol. However, in TZD/metformin users the difference between the beta-blockers was not statistically significant

PURPOSE: Patients with type 2 diabetes are commonly overweight, which can contribute to poor cardiovascular outcomes. beta-blockers may promote weight gain, or hamper weight loss, and are a concern in high-risk patients. The current analysis of the Glycemic Effect in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial evaluates the effects of carvedilol and metoprolol tartrate on weight gain in patients with type 2 diabetes and hypertension. METHODS: This prespecified secondary analysis of the GEMINI study (n=1106) evaluated change in body weight after 5 months. RESULTS: Mean (+/-SE) baseline weights were 97.5 (+/-20.1) kg for carvedilol and 96.6 (+/-20.1) kg for metoprolol tartrate. Treatment difference (c vs m) in mean (+/-SE) weight change from baseline was -1.02 (+/-0.21) kg (95% confidence interval [CI], -1.43 to -0.60; P <.001). Patients taking metoprolol had a significant mean (+/-SE) weight gain of 1.19 (+/-0.16) kg (P <.001); patients taking carvedilol did not (0.17 [+/-0.19] kg; P =.36). Metoprolol tartrate-treated patients with body mass index (BMI) >30 kg/m2 had a statistically significant greater weight gain than comparable carvedilol-treated patients. Treatment differences (c vs m) in the obese (BMI >30 kg/m2) and morbidly obese groups (BMI >40 kg/m2) were -0.90 kg (95% CI, -1.5 to -0.3; P =.002) and -1.84 kg (95% CI, -2.9 to -0.8; P =.001), respectively. Pairwise correlation analyses revealed no significant associations between weight change and change in HbA1c, HOMA-IR, or blood pressure. CONCLUSIONS: Metoprolol tartrate was associated with increased weight gain compared to carvedilol; weight gain was most pronounced in subjects with hypertension and diabetes who were not taking insulin therapy

Factors such as age and race/ethnicity might influence blood pressure (BP) response to drugs. Therapeutic response to the angiotensin-converting enzyme inhibitor trandolapril used as add-on therapy to stable calcium channel blocker therapy with verapamil sustained release 240 mg was addressed in a racially/ethnically diverse group of 1,832 hypertensive patients with coronary artery disease. Furthermore, the association with a polymorphism (1166A-->C) in the angiotensin II type 1 receptor gene (AGTR1) was tested. BP response was compared between groups using analysis of covariance after adjustment for covariates associated with BP response. Genotyping was performed using polymerase chain reaction and pyrosequencing. Trandolapril decreased mean unadjusted systolic and diastolic BPs by -9.1 +/- 17.3 (SD) and -4.1 +/- 10.1 mm Hg, respectively. The percentage of patients with BP under control (<140/90 mm Hg) increased from 6.7% to 41.3% (p <0.0001). Adjusted BP response was significantly associated with age and baseline systolic and diastolic BP (p <0.0001). Whereas the decrease in systolic BP was more pronounced in younger patients, the opposite was observed for diastolic BP decrease. Diastolic BP response was also significantly associated with race. Specifically, the adjusted diastolic BP decrease was significantly smaller in Hispanics and blacks than whites (p = 0.0032 and p = 0.0069, respectively). However, Hispanics achieved a decrease in systolic BP and an increase in BP control similar to the other ethnic groups. There was no genetic association between AGTR1 1166A-->C genotype and BP response. In conclusion, trandolapril add-on therapy was effective in increasing BP control, with age and baseline BP associated with both systolic and diastolic BP response. Race was associated with diastolic BP response, although the difference is likely not to be clinically significant and AGTR1 genotype was not associated with BP response

BACKGROUND: People of Hispanic origin are the fastest growing ethnic minority in the United States and often have hypertension and other comorbidities which increase the risk associated with coronary artery disease (CAD). METHODS AND RESULTS: An analysis of the 8045 Hispanic patients enrolled in INVEST was conducted, and comparisons were made to the 14,531 non-Hispanic patients. INVEST was a prospective, randomized, open, blinded end point study in CAD patients with hypertension. After 61,835 patient-years of follow-up, treatment with either a verapamil sustained release (SR) or atenolol antihypertensive strategy resulted in greater blood pressure control in Hispanic patients, and Hispanic patients were at significantly lower risk of experiencing a nonfatal myocardial infarction, nonfatal stroke, or death (hazard ratio [HR] 0.87, 95% CI 0.78-0.97). Hispanic ethnicity was associated with an increase (HR 1.19, 95% CI 1.04-1.36), and randomization to the verapamil SR strategy was associated with a decrease (HR 0.85, 95% CI 0.76-0.95), in the risk of new-onset diabetes. Use of trandolapril in the verapamil SR strategy was associated with reduced risk of new-onset diabetes, whereas increasing doses of atenolol and hydrochlorothiazide in the atenolol strategy were associated with increased risk of new-onset diabetes. CONCLUSIONS: The Hispanic cohort of INVEST had better blood pressure control and lower risk of adverse cardiovascular outcomes compared with the non-Hispanic cohort. A verapamil SR strategy is an alternative to an atenolol strategy for the treatment of Hispanic patients with hypertension and CAD and can reduce the risk of new-onset diabetes