Effect of carvedilol, lisinopril and their combination on vascular and cardiac health in patients with borderline blood pressure: the DETECT Study.

Antihypertensive therapy is aimed at improving vascular and cardiac health, as well as lowering blood pressure (BP). The benefit of such drugs in untreated patients with borderline BP has not been demonstrated. Subjects with BPs ≥130 mm Hg systolic or ≥85 mm Hg diastolic and at least one additional risk factor were randomly assigned to treatment with carvedilol, lisinopril, their combination or placebo. Cardiovascular health was assessed by a disease score (DS), which combines the following tests of cardiovascular function and structure: resting BP, large- and small-artery elasticity (SAE), BP response to exercise, retinal vasculature analysis, electrocardiogram, carotid intima-medial thickness, left ventricular mass, microalbuminuria and N-terminal pro B-type natriuretic peptide. DS was assessed at baseline, after 3 and 9 months of therapy and 1 month after discontinuation of therapy. All active treatment groups displayed a sustained reduction in BP during 9 months of treatment, with the greatest reduction in the cardvedilol+lisinopril group. DS and SAE improved in all the treatment groups but the changes were of borderline significance and exhibited no evidence for progressive improvement from 3 months (functional) to 9 months (structural). All changes were reversed within 1 month after discontinuation of therapy. We conclude that 9 months of treatment with carvedilol, lisinopril or their combination produce a sustained and well-tolerated functional improvement but not a structural improvement, perhaps because of a lack of the nitric oxide-enhancing effects of other agents that inhibit structural changes in the vasculature.

Relationship between C-reactive protein and arterial stiffness in an asymptomatic population.

Plasma concentration of high sensitive C-reactive protein (hsCRP) is used as a marker for inflammatory states and is directly correlated with the risk for coronary heart disease. Evidence concerning the role of inflammation in atheroma formation has been derived from several models of atherosclerosis. Inflammation should exert its adverse vascular effects by structural changes in the artery wall and consequently alterations in arterial elasticity, which could be detected already in asymptomatic early vascular disease. We hypothesized that CRP is related to large artery elasticity, but not to small artery elasticity in early vascular disease. Therefore, we examined the association between arterial stiffness of large and small arteries and inflammation in an asymptomatic population referred for primary prevention cardiovascular screening. Studies were performed in 391 subjects (age 21-82 years; 254 men, 137 women) who underwent screening at the Cardiovascular Disease Prevention Center. Large artery (C1) and small artery (C2) elasticity indices were obtained by the CVProfiler 2000 (HDI, Eagan, MN, USA). After overnight fasting, venous samples were taken for measurement of hsCRP, lipids, glucose. There was a significant inverse correlation between hsCRP (0.29 +/- 0.40 mg/dl) and C1 (16.7 +/- 5.8 ml/mmHg), r = -0.133, P = 0.01; there was no significant correlation between hsCRP and C2 (6.6 +/- 3.2 ml/mmHg). C2, but not hsCRP, was inversely correlated with age, abnormal lipids and glucose, whereas C1, but not hsCRP, was inversely correlated with age and systolic blood pressure (SBP). In multiple regression analysis, the relationship between hsCRP and C1 was not affected by age, body mass index, SBP, serum glucose or lipids. In conclusion, these findings support the hypothesis that hsCRP, a marker for acute and low-grade inflammation, is associated with large artery but not with small artery elasticity in asymptomatic individuals undergoing primary prevention cardiovascular screening.

Arterial compliance abnormalities in isolated systolic hypertension.

Arterial compliance measurements using intraarterial pulse contour analysis and a modified Windkessel model were carried out in 19 patients with isolated systolic hypertension (> or = 160/< or = 90 mm Hg) and compared to measurements in 29 patients with essential hypertension (diastolic blood pressure [BP] > or = 95 mm Hg) and 47 normotensive control subjects. Arterial capacitive compliance was significantly lower in isolated systolic hypertension than in essential hypertension (P < .0002) and significantly lower in essential hypertension than in normotensive control subjects (P < .0001). Although the isolated systolic hypertension group was older than the essential hypertension group, the reduction of capacitive compliance in isolated systolic hypertension persisted even when comparison was made with a more nearly age-matched group of essential hypertension. In contrast, oscillatory compliance was reduced similarly in isolated systolic hypertension and essential hypertension compared to normotensive control subjects (P < .0001). Although pulse pressure was greater in isolated systolic hypertension than in essential hypertension, only a weak correlation (r = -0.34) existed between pulse pressure and capacitive compliance. These data indicate that both essential hypertension and isolated systolic hypertension patients exhibit comparably abnormal structure or tone of the small vessels that are the site of oscillations or reflections in the arterial vasculature. In isolated systolic hypertension there is a profound reduction in large artery or capacitive compliance that accounts for the increase in systolic BP and decrease in diastolic BP. This abnormality cannot be accurately assessed by pulse pressure alone.

Arterial compliance to stratify cardiovascular risk: more precision in therapeutic decision making.

The focus of attention in preventing and treating cardiovascular (CV) disease today is shifting toward the arterial wall. Evidence has been accumulating for several years that protecting the endothelium is key to reducing CV risk. Endothelial dysfunction results in reduced compliance, or increased arterial stiffness, particularly in the smaller arteries. This abnormality is characteristic of patients with hypertension but may also be seen in normotensive patients before the appearance of clinical disease. Reduced arterial compliance is also seen in patients with diabetes and in smokers, and is part of a vicious cycle that further elevates blood pressure, aggravates atherosclerosis, and leads to increased CV risk. Although other factors are involved, the damage to the endothelium results in reduced secretion of nitric oxide, which influences smooth muscle growth, migration, and contraction, as well as influencing inflammation and clotting. Arterial compliance can be measured by several techniques, most of which are invasive or otherwise not clinically appropriate. Pulse contour analysis is a newly developed noninvasive method that allows for easy, in-office measurement of arterial elasticity to identify patients at risk for CV events before disease becomes clinically apparent. Further research is needed to confirm whether this method offers a means of improving risk stratification and therapeutic decision making.

Relationship between periventricular or deep white matter lesions and arterial elasticity indices in very old people.

OBJECTIVE: To examine the relationship between the presence of cerebral white matter lesions and large and small artery elasticity indices in a population of healthy, very old subjects. METHODS: We studied 24 subjects (14 women, 10 men) with a mean age of 84+/-5 years, who were free from overt neurological, cardiovascular or psychiatric illness. We measured blood pressure and heart rate in supine and standing positions. Elasticity indices of the large arteries (C1) and small arteries (C2) were derived from radial artery pulse waves. Each subject had multi-slice spin-echo cerebral magnetic resonance imaging. The severity of white matter lesions was graded as 0, 1 or 2. RESULTS: Cerebral white matter lesions on magnetic resonance imaging were common in very old apparently healthy subjects: grade 0 (n=4, C1=2.68+/-1.80 ml/mmHg and C2=0.045+/-0.017 ml/mmHg), grade 1 (n=7, C1=2.13+/-0.36 ml/mmHg and C2=0.040+/-0.016 ml/mmHg) and grade 2 (n=13, C1=1.12+/-0.36 ml/mmHg and C2=0.018+/-0.003 ml/mmHg). There was no significant association between elasticity indices and blood pressure. CONCLUSION: In very old, apparently healthy subjects, both large and small artery elasticity indices were inversely related to the severity of cerebral white matter lesions on magnetic resonance imaging.

New approaches to screening for vascular and cardiac risk.

Cardiovascular morbid events occur as a consequence of vascular and cardiac disease, which can be identified long before symptoms of organ involvement become apparent. Early detection of abnormalities in the small arteries, especially deficiency of endothelial nitric oxide bioactivity, and of structural changes of remodeling in the left ventricle can identify individuals at risk for morbid events. These individuals should be the target for aggressive lifestyle and pharmacologic interventions known to favorably affect the progression of disease. Techniques are now available for screening of asymptomatic individuals to detect early vascular and cardiac abnormalities likely to lead to progression of disease. Pulse wave analysis provides an assessment of small artery elasticity that appears to correlate with endothelial function. Left ventricular structural alterations can be assessed by ultrasound or by circulating levels of brain natriuretic peptide. The usefulness of these early screening techniques to encourage tailored interventions in susceptible individuals needs to be explored in large-scale trials.

Influence of carvedilol on hospitalizations in heart failure: incidence, resource utilization and costs. U.S. Carvedilol Heart Failure Study Group.

BACKGROUND: Carvedilol reduces disease progression in heart failure, but to our knowledge, its effects on hospitalizations and costs have not been evaluated. OBJECTIVES: We examined the effects on hospitalization frequency and costs in the U.S. Carvedilol Heart Failure Trials Program. This program consisted of four concurrent, multicenter, double-blind, placebo-controlled studies involving 1,094 patients with New York Heart Association class II to IV heart failure, which treated patients with placebo or carvedilol for up to 15 months (median, 6.5 months). METHODS: Detailed resource utilization data were collected for all hospitalizations occurring between randomization and the end of follow-up. In-patient care costs were estimated based on observed levels of resource use. RESULTS: Compared with placebo, carvedilol reduced the risk of hospitalization for any reason by 29% (p = 0.009), cardiovascular hospitalizations by 28% (p = 0.034) and heart failure hospitalizations by 38% (p = 0.041). Carvedilol also decreased the mean number of hospitalizations per patient (for cardiovascular reasons 30% [p = 0.02], for heart failure 53% [p = 0.03]). Among hospitalized patients, carvedilol reduced severity of illness during hospital admission, as reflected by shorter length of stay and less frequent use of intensive care. For heart failure hospital admissions, carvedilol decreased mean length of stay by 37% (p = 0.03) and mean number of intensive care unit/coronary care unit days by 83% (p = 0.001), with similar effects on cardiovascular admissions. As a result, estimated inpatient care costs with carvedilol were 57% lower for cardiovascular admissions (p = 0.016) and 81% lower for heart failure admissions (p = 0.022). CONCLUSIONS: Carvedilol added to angiotensin-converting enzyme inhibition reduces hospitalization risk as well as severity of illness and resource utilization during admission in patients with chronic heart failure.

Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction.

BACKGROUND: Black patients with heart failure have a poorer prognosis than white patients, a difference that has not been adequately explained. Whether racial differences in the response to drug treatment contribute to differences in outcome is unclear. To address this issue, we pooled and analyzed data from the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials, two large, randomized trials comparing enalapril with placebo in patients with left ventricular dysfunction. METHODS: We used a matched-cohort design in which up to four white patients were matched with each black patient according to trial, treatment assignment, sex, left ventricular ejection fraction, and age. A total of 1196 white patients (580 from the prevention trial and 616 from the treatment trial) were matched with 800 black patients (404 from the prevention trial and 396 from the treatment trial). The average duration of follow-up was 35 months in the prevention trial and 33 months in the treatment trial. RESULTS: The black patients and the matched white patients had similar demographic and clinical characteristics, but the black patients had higher rates of death from any cause (12.2 vs. 9.7 per 100 person-years) and of hospitalization for heart failure (13.2 vs. 7.7 per 100 person-years). Despite similar doses of drug in the two groups, enalapril therapy, as compared with placebo, was associated with a 44 percent reduction (95 percent confidence interval, 27 to 57 percent) in the risk of hospitalization for heart failure among the white patients (P<0.001) but with no significant reduction among black patients (P=0.74). At one year, enalapril therapy was associated with significant reductions from base line in systolic blood pressure (by a mean [+/-SD] of 5.0+/-17.1 mm Hg) and diastolic blood pressure (3.6+/-10.6 mm Hg) among the white patients, but not among the black patients. No significant change in the risk of death was observed in association with enalapril therapy in either group. CONCLUSIONS: Enalapril therapy is associated with a significant reduction in the risk of hospitalization for heart failure among white patients with left ventricular dysfunction, but not among similar black patients. This finding underscores the need for additional research on the efficacy of therapies for heart failure in black patients.

Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure.

BACKGROUND: The benefits of angiotensin-converting-enzyme inhibitors and beta-blockers may be smaller in black patients than in patients of other races, but it is unknown whether race influences the response to carvedilol in patients with chronic heart failure. METHODS: In the U.S. Carvedilol Heart Failure Trials Program, 217 black and 877 nonblack patients (in New York Heart Association class II, III, or IV and with a left ventricular ejection fraction of no more than 0.35) were randomly assigned to receive placebo or carvedilol (at doses of 6.25 to 50 mg twice daily) for up to 15 months. The effects of carvedilol on ejection fraction, clinical status, and major clinical events were retrospectively compared between black and nonblack patients. RESULTS: As compared with placebo, carvedilol lowered the risk of death from any cause or hospitalization for any reason by 48 percent in black patients and by 30 percent in nonblack patients. Carvedilol reduced the risk of worsening heart failure (heart failure leading to death, hospitalization, or a sustained increase in medication) by 54 percent in black patients and by 51 percent in nonblack patients. The ratios of the relative risks associated with carvedilol for these two outcome variables in black as compared with nonblack patients were 0.74 (95 percent confidence interval, 0.42 to 1.34) and 0.94 (95 percent confidence interval, 0.43 to 2.05), respectively. Carvedilol also improved functional class, ejection fraction, and the patients' and physicians' global assessments in both the black patients and the nonblack patients. For all these measures of outcome and clinical status, carvedilol was superior to placebo within each racial cohort (P<0.05 in all analyses), and there was no significant interaction between race and treatment (P> 0.05 in all analyses). CONCLUSIONS: The benefit of carvedilol was apparent and of similar magnitude in both black and nonblack patients with heart failure.

Blood pressure and arterial compliance in young adults: the Minnesota Children's Blood Pressure Study.

The aim of this study was to assess the relation between blood pressure (BP) and arterial compliance in a healthy sample of young adults. School children (aged 10 to 14 years at entry) were surveyed in 1977 to 1978, and 1,207 were followed once to twice yearly until age 23 years. Arterial compliance was measured in 179 adults at the last follow-up visit. The sample included individuals in the upper tertile of systolic BP during the last three follow-up visits and race- and sex-matched individuals in the lower two tertiles. We obtained radial artery waveforms using a calibrated tonometer device and characterized waveform morphology to determine large artery (C1) and oscillatory (C2) compliance. Blood pressure was measured using random zero sphygmomanometers. The mean and standard deviation of C1 was 2.13 +/- 0.59 mL/mm Hg and of C2 was 0.083 +/- 0.02 mL/mm Hg. Systolic BP was inversely related to C1 (P < .001) and C2 (P < .01) after adjustment for gender, height, weight, insulin, and HDL and LDL cholesterol. After adjustment, a 1 SD change in systolic BP was associated with a -0.30 mL/mm Hg change in C1 and a -.008 mL/mm Hg change in C2. Data from the Minnesota Children's Blood Pressure Study indicate that systolic BP is inversely related to arterial compliance, particularly C1 (the large artery, or capacitive compliance).

Left ventricle and arteries: structure, function, hormones, and disease.

The observation in the 1970s that the performance of the dysfunctional left ventricle was under the influence of aortic impedance led us to exploration of the role of the renin-angiotensin system and other hormonal systems in the progression of heart failure. The apparent efficacy of vasodilator drugs led to the first randomized, controlled trial in heart failure that demonstrated that all impedance-lowering drugs did not exert the same long-term benefit. Differences on the structural remodeling process in the myocardium and arterial vasculature were shown to account for the differential long-term response. We now recognize that the remodeling process in the left ventricle may be inhibited by nitrates, converting enzyme inhibitors, and beta-blockers, and this growth process leads to adverse outcomes. The impedance load on the left ventricle is influenced by vascular remodeling that also may be inhibited by drugs such as converting enzyme inhibitors. Thus, progression of cardiovascular disease is largely a consequence of structural changes that are hormonally mediated and may be inhibited by drug therapy.

Small and large artery elasticity indices in peripheral arterial occlusive disease (PAOD).

In peripheral arterial occlusive disease (PAOD), arterial compliance of the central arteries has been reported to be reduced. It is, however, not clear whether, in PAOD, decreased arterial compliance is also accompanied by similar changes in the peripheral arteries. Therefore the aim of the study was to determine the large (C1) and small (C2) artery elasticity indices in PAOD and their relations to its well-accepted characteristics (ankle-brachial index, ABI; pulse pressure, PP; absolute claudication distance, ACD). A total of 43 patients with PAOD (mean age 68 +/- 9 years; ABI of the limiting leg 0.65 +/- 0.14; SBP (systolic blood pressure) 149 +/- 20 mmHg, and ACD 488 +/- 187 m) were enrolled as well as 16 control subjects of comparable age (69 +/- 4 years) and blood pressure (SBP 147 +/- 27 mmHg). All subjects underwent non-invasive pulse wave analysis in order to determine arterial compliance of the aorta and major side branches (C1) and of the distal circulation (C2), using a modified Windkessel model. In PAOD, both C1 (1.41 +/- 0.56 ml/mmHg) and C2 (0.023 +/- 0.012 ml/mmHg) were comparable to values in an age and blood pressure-matched control group (C1, 1.25 +/- 0.66 ml/mmHg; C2, 0.027 +/- 0.008 ml/mmHg). C1 was significantly correlated with ACD (r = 0.36, p = 0.02), PP (r = -0.33, p < 0.02) and only borderline with ABI (r = 0.28, p = 0.07). C2 was correlated with PP (r = -0.38, p < 0.01), ABI (r = 0.36, p < 0.02) but not with ACD. Large (C1) and small (C2) artery elasticity indices in PAOD were decreased but comparable to values in an elderly group with isolated systolic hypertension. Moreover, C1 and C2 correlated with markers (ABI and PP) of severity of vascular disease.

A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.

BACKGROUND: Actions of angiotensin II may contribute to the progression of heart failure despite treatment with currently recommended drugs. We therefore evaluated the long-term effects of the addition of the angiotensin-receptor blocker valsartan to standard therapy for heart failure. METHODS: A total of 5010 patients with heart failure of New York Heart Association (NYHA) class II, III, or IV were randomly assigned to receive 160 mg of valsartan or placebo twice daily. The primary outcomes were mortality and the combined end point of mortality and morbidity, defined as the incidence of cardiac arrest with resuscitation, hospitalization for heart failure, or receipt of intravenous inotropic or vasodilator therapy for at least four hours. RESULTS: Overall mortality was similar in the two groups. The incidence of the combined end point, however, was 13.2 percent lower with valsartan than with placebo (relative risk, 0.87; 97.5 percent confidence interval, 0.77 to 0.97; P=0.009), predominantly because of a lower number of patients hospitalized for heart failure; 455 (18.2 percent) in the placebo group and 346 (13.8 percent) in the valsartan group (P<0.001). Treatment with valsartan also resulted in significant improvements in NYHA class, ejection fraction, signs and symptoms of heart failure, and quality of life as compared with placebo (P<0.01). In a post hoc analysis of the combined end point and mortality in subgroups defined according to base-line treatment with angiotensin-converting-enzyme (ACE) inhibitors or beta-blockers, valsartan had a favorable effect in patients receiving neither or one of these types of drugs but an adverse effect in patients receiving both types of drugs. CONCLUSIONS: Valsartan significantly reduces the combined end point of mortality and morbidity and improves clinical signs and symptoms in patients with heart failure, when added to prescribed therapy. However, the post hoc observation of an adverse effect on mortality and morbidity in the subgroup receiving valsartan, an ACE inhibitor, and a beta-blocker raises concern about the potential safety of this specific combination.