Aldosterone has rapid nongenomic effects in the human vasculature. However, data are not uniform and little is known about chronic effects of aldosterone. Therefore, we investigated acute and chronic ...effects of elevated aldosterone levels on endothelial function in the forearm vasculature of healthy men. In a first crossover study, the effects of arterial aldosterone infusion in ascending doses (3.3 to 55 pmol/min per 1000 mL forearm volume) on forearm blood flow were investigated in 8 healthy men (26+/-2 years). In a second study, endothelium-dependent (acetylcholine; 0.08, 0.275, and 2.75 micromol/min per 1000 mL) and endothelium-independent (sodium nitroprusside 0.02 micromol/min per 1000 mL) vasodilation and basal nitric oxide formation (forearm blood flow response to blockade by N(G)-monomethyl-l-arginine 8 micromol/min per 1000 mL) were tested in 10 healthy men (age 30+/-5 years) at baseline, during infusion of 55 pmol/1000 mL per min aldosterone (acute effects), and after 0.3 mg/d oral fludrocortisone for 2 weeks (chronic effects) on separate days. Forearm blood flow was assessed by venous occlusion plethysmography. No change in forearm blood flow was seen with aldosterone infusion alone. Acute coinfusion of aldosterone increased vasodilation to sodium nitroprusside by 93% (P<0.01) and to acetylcholine by 60% (P=0.14). Response to N(G)-monomethyl-l-arginine did not change. After 2 weeks of oral fludrocortisone, response to acetylcholine was enhanced by 72% compared with baseline (P=0.03). Additionally, response to N(G)-monomethyl-l-arginine was enhanced by 80% compared with baseline (P=0.05). Aldosterone acutely enhances vasodilation to exogenous nitric oxide whereas mineralocorticoid excess for 2 weeks enhances basal nitric oxide bioactivity and improves endothelium dependent, nitric oxide-mediated vasodilation in the forearm vasculature of healthy men.
Blockade of the renin-angiotensin system by inhibition of angiotensin-converting enzyme (ACE) is beneficial for the treatment of hypertension and congestive heart failure. However, it is unclear how ...complete the blockade by ACE inhibitors is and if there is continuing angiotensin II (Ang II) formation during chronic treatment with ACE inhibitors. Indeed chymase, a serine protease, which is able to form angiotensin II from angiotensin I (Ang I) and cannot be blocked by ACE inhibitors, has been shown to be present in human heart. The goal of the present study was to evaluate the extent of renin-angiotensin system blockade and the Ang II-forming pathways in cardiac tissue of patients chronically treated with ACE inhibitors or in patients without ACE inhibition therapy. Our studies indicate an incomplete ACE inhibition in human heart tissue after chronic ACE inhibitor therapy. Moreover, ACE contributes only a small portion to the total Ang I conversion, as shown in biochemical studies in ventricular and coronary homogenates or functionally as Ang I contractions in isolated rings of coronary arteries. A serine protease was responsible for the majority of Ang II production in both the membrane preparation and Ang I-induced contractions of isolated coronary arteries. In humans, the serine protease pathway is likely to play an important role in cardiac Ang II formation. Thus, drugs such as renin inhibitors and Ang II receptor blockers might be able to induce a more complete blockade of the renin-angiotensin system, providing a more efficacious therapy.
To investigate the prognostic value of oxygen uptake (▪o2) kinetics during low-intensity exercise in patients with congestive heart failure.
Prospective cohort study.
Tertiary care center.
One ...hundred forty-six consecutive patients (128 men) with chronic heart failure, followed up for a mean (± SD) duration of 25 ± 15 months.
A treadmill exercise test was performed with “breath by breath” gas-exchange monitoring. ▪o2 kinetics were defined as the O2 deficit (ie, Δ▪o2 × timerest to steady state − Σ▪o2rest to steady state) and mean response time (MRT) ie, O2 deficit/Δ▪o2. Cardiac death, urgent cardiac transplantation, and hospitalization due to worsening heart failure were considered as the end points.
Thirty patients (21%) died, 11 patients (8%) underwent urgent transplantation, and 32 patients (22%) were hospitalized. In univariate analysis, MRT was the most powerful predictor of survival, survival free of urgent transplantation, and survival free of hospitalization (hazard ratios HRs per 10 s, 1.65, 1.72, and 1.61, respectively; all p < 0.0001). The predictive value of MRT exceeded that of peak ▪o2 (HR per mL/kg/min, 0.90; p = 0.02, 0.91; p = 0.007, and 0.95; p = 0.08, respectively). In multivariate analysis, MRT (HR per 10 s, 1.73; p = 0.0002), resting systolic BP (HR per 10 mm Hg, 0.65; p = 0.003), and the slope of the ventilatory response to exercise (HR per 10 U, 1.68; p = 0.02) were independent predictors of survival.
Our results suggest that ▪o2 kinetics are strongly related to outcome in heart failure patients. Since it has several additional advantages over peak exercise testing (eg, less time-consuming, less demanding for the patients, less dependent on motivation, and applicable in patients with limitations other than cardiopulmonary disease), it has the potential to become a prognostic test for the assessment of heart failure patients.
Background Based on a subgroup analysis of 18-month BAsel Stent Kosten Effektivitäts Trial (BASKET) outcome data, we hypothesized that very late (>12 months) stent thrombosis occurs predominantly ...after drug-eluting stent implantation in large native coronary vessel stenting. Methods To prove or refute this hypothesis, we set up an 11-center 4-country prospective trial of 2260 consecutive patients treated with ≥3.0-mm stents only, randomized to receive Cypher (Johnson & Johnson, Miami Lakes, FL), Vision (Abbott Vascular, Abbott Laboratories, IL), or Xience stents (Abbott Vascular). Only patients with left main or bypass graft disease, in-stent restenosis or stent thrombosis, in need of nonheart surgery, at increased bleeding risk, without compliance/consent are excluded. All patients are treated with dual antiplatelet therapy for 12 months. The primary end point will be cardiac death/nonfatal myocardial infarction after 24 months with further follow-up up to 5 years. Results By June 12, 229 patients (10% of the planned total) were included with a baseline risk similar to that of the same subgroup of BASKET (n = 588). Conclusions This study will answer several important questions of contemporary stent use in patients with large native vessel stenting. The 2-year death/myocardial infarction—as well as target vessel revascularization—and bleeding rates in these patients with a first- versus second-generation drug-eluting stent should demonstrate the benefit or harm of these stents compared to cobalt-chromium bare-metal stents in this relevant, low-risk group of everyday patients. In addition, a comparison with similar BASKET patients will allow to estimate the impact of 12- versus 6-month dual antiplatelet therapy on these outcomes.
This study investigated the combination of maximal and low-intensity exercise testing in predicting prognosis in chronic heart failure (CHF), using one single exercise test (two-step protocol).
Risk ...assessment based on any single factor has limited accuracy and reproducibility.
Treadmill exercise testing was performed in 202 consecutive CHF patients (174 male; mean age 52 ± 11 years) using “breath-by-breath” gas exchange monitoring. Oxygen uptake (Vo2) kinetics were defined as oxygen deficit (ΔVo2× time rest to steady state − Σ Vo2rest to steady state) and mean response time (MRT = oxygen-deficit/ΔVo2). Peak Vo2(Vo2max) was defined as the highest Vo2. Mean follow-up was 873 ± 628 days. The primary end point was cardiac mortality and the need for urgent heart transplantation.
Forty-four patients (22%) died and 15 (7%) were urgently transplanted. In both univariate and multivariate analyses, MRT >50 s was the most powerful predictor of the primary end point (hazard ratio HR 4.44), followed by predicted Vo2max <50% (HR 3.50) and resting systolic blood pressure <105 mm Hg (HR 2.49, all p < 0.001). A majority (n = 130 64%) had one or none of these risk factors, with a one-year event rate of only 3%. Patients with two risk factors (n = 45 22%) were at medium risk (one-year event rate of 33%). Twenty-seven patients (13%) had all three risk factors, with a one-year event rate of 59%. The area under the curve, using the number of risk factors, was 0.86 ± 0.04 for the primary end point at one year. These results were independent of medication, in particular, beta-blockade.
A combination of low-intensity and maximal exercise test results improves assessment of prognosis in patients with CHF.
The effect of a percutaneous coronary intervention (PCI) on the long-term prognosis of patients with silent ischemia after a myocardial infarction (MI) is not known.
To determine whether PCI compared ...with drug therapy improves long-term outcome of asymptomatic patients with silent ischemia after an MI.
Randomized, unblinded, controlled trial (Swiss Interventional Study on Silent Ischemia Type II SWISSI II) conducted from May 2, 1991, to February 25, 1997, at 3 public hospitals in Switzerland of 201 patients with a recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease. Follow-up ended on May 23, 2006.
Percutaneous coronary intervention aimed at full revascularization (n = 96) or intensive anti-ischemic drug therapy (n = 105). All patients received 100 mg/d of aspirin and a statin.
Survival free of major adverse cardiac events defined as cardiac death, nonfatal MI, and/or symptom-driven revascularization. Secondary measures included exercise-induced ischemia and resting left ventricular ejection fraction during follow-up.
During a mean (SD) follow-up of 10.2 (2.6) years, 27 major adverse cardiac events occurred in the PCI group and 67 events occurred in the anti-ischemic drug therapy group (adjusted hazard ratio, 0.33; 95% confidence interval, 0.20-0.55; P<.001), which corresponds to an absolute event reduction of 6.3% per year (95% confidence interval, 3.7%-8.9%; P<.001). Patients in the PCI group had lower rates of ischemia (11.6% vs 28.9% in patients in the drug therapy group at final follow-up; P = .03) despite fewer drugs. Left ventricular ejection fraction remained preserved in PCI patients (mean SD of 53.9% 9.9% at baseline to 55.6% 8.1% at final follow-up) and decreased significantly (P<.001) in drug therapy patients (mean SD of 59.7% 11.8% at baseline to 48.8% 7.9% at final follow-up).
Among patients with recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease, PCI compared with anti-ischemic drug therapy reduced the long-term risk of major cardiac events.
clinicaltrials.gov Identifier: NCT00387231.
Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with atherosclerosis and is therefore held to be an early feature in atherogenesis. However, the ...mechanisms by which endothelial dysfunction occurs in smoking, dyslipidaemia, hyperhomocysteinaemia, diabetes mellitus, arterial hypertension, cerebrovascular diseases, coronary artery disease and heart failure are complex and heterogeneous. Recent data indicate that endothelial dysfunction is often associated with erectile dysfunction, which can precede and predict cardiovascular disease in men. This paper will provide a concise overview of the mechanisms causing endothelial dysfunction in the different cardiovascular risk factors and disease conditions, and of the impact of the intervention measures and treatments.
Elderly heart failure (HF) patients are assumed to prefer improved quality of life over longevity, but sufficient data are lacking. Therefore, we assessed the willingness to trade survival time for ...quality-of-life (QoL) and the preferences for resuscitation.
At baseline and after 12 and 18 months, 622 HF patients aged ≥60 years (77 ± 8 years, 74% NYHA-class ≥III) participating in the Trial of Intensified vs. standard Medical therapy in Elderly patients with Congestive Heart Failure had prospective evaluation of end-of-life preferences by answering trade-off questions (willingness to accept a shorter life span in return for living without symptoms) and preferences for resuscitation if necessary. The time trade-off question was answered by 555 patients (89%), 74% of whom were not willing to trade survival time for improved QoL. This proportion increased over time (Month 12: 85%, Month 18: 87%, P < 0.001). In multivariable analysis, willingness to trade survival time increased with age, female sex, a reduced Duke Activity Status Index, Geriatric Depression Score, and history of gout, exercise intolerance, constipation and oedema, but even combining these variables did not result in reliable prediction. Of 603 (97%) patients expressing their resuscitation preference, 51% wished resuscitation, 39% did not, and 10% were undecided, with little changes over time. In 430 patients resuscitation orders were known; they differed from patients' preferences 32% of the time. End-of-life preferences were not correlated to 18-month outcome.
Elderly HF patients are willing to address their end-of-life preferences. The majority prefers longevity over QoL and half wished resuscitation if necessary. Prediction of individual preferences was inaccurate.
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