Methods and Results: Effects of 6-hour infusions of tezosen-tan at 5, 20, 50 and 100 mg/h were compared with placeboin 61 patients with New York Heart Association class III toIV heart failure. Plasma endothelin-1 and tezosentan con-centrations were also determined. Treatment with tezosen-tan caused a dose-dependent increase in cardiac indexranging from 24.4% to 49.9% vs. 3.0% with placebo.Tezosentan also dose dependently reduced pulmonary cap-illary wedge pressure and pulmonary and systemic vascularresistances, with no change in heart rate. Additional hemo-dynamic variables, including both systemic and pulmonaryvascular resistance, demonstrated comparable favorable re-sponse. Tezosentan administration resulted in dose-relatedincreased plasma endothelin-1 concentrations.Conclusions: The present study demonstrated that tezosen-tan can be safely administered to patients with moderate-to-severe heart failure and that by virtue of its ability toantagonize the effects of endothein-1, it induced vasodila-tory responses leading to a significant improvement incardiac index.Perspective: This reports adds to prior studies which suggestthat blockade of the endothelin receptor(s) is physiologi-cally relevant, with potential clinical application, in heartfailure. The dose-dependent features of the response areparticularly intriguing. This suggests that there is no satu-ration of receptors with concentrations well above the likelypathophysiologic level of the endogenous endothelins inheart failure. The absence of rebound was also important,given the marked displacement of endogenous endothelinreflected in circulating levels. No information is providedregarding the potential cross-reactivity of the endothelinimmunoassay with the tezosentan molecule however.While a short-term acute role for tezosentan is clinicallyrelevant, longer-term response for chronic therapy remainsthe ultimate goal of endothelin blockade. RC

Relationship of Current and Past Smoking toMortality and Morbidity in Patients With LeftVentricular Dysfunction

Suskin N, Sheth T, Negass A, Yusuf S. J Am Coll Cardiol 2001;37:1677– 82.

Study Question: The aim of this study was to evaluate theimpact of smoking in patients with left ventricular dysfunc-tion, as the impact of smoking on the clinical feature so forleft ventricular dysfunction remain uncertain.Methods: The authors compared the incidence of death,hospitalization due to heart failure and myocardial infarc-tion (MI) in current smokers to ex-smokers of #2 years andex-smokers of .2 years duration to never-smokers amongparticipants of the Study Of Left Ventricular Dysfunction(SOLVD) Prevention and Intervention trials. Participants allhad left ventricular ejection fraction (LVEF) ,35% andfollow-up was over a mean of 41 months.

Results: Complete smoking status and outcome data wereavailable in 6704 subjects. Current smoking was associatedwith a significantly increased all-cause mortality (relativerisk [RR]: 1.41, 95% confidence interval [CI]: 1.25 to 1.58,p,0.001) compared with ex-smokers and never-smokers.The incidence of death or recurrent congestive heart failurerequiring hospitalization or MI was significantly greater(RR: 1.39, 95% CI:1.26 to 1.52, p,0.001) in currentsmokers compared with ex-smokers and never-smokers.There were no significant differences in the number ofdeaths or hospitalizations due to heart failure betweenex-smokers and never-smokers. This effect was consistentacross both the SOLVD Prevention and Treatments trials.Conclusions: Current smoking is a powerful independentpredictor of morbidity (recurrent heart failure and MI) andmortality in patients with left ventricular dysfunction. Quit-ting smoking appears to have a substantial and early effecton decreasing morbidity and mortality in patients with leftventricular dysfunction, which is at least as large as provendrug treatments recommended in patients with left ventric-ular dysfunction.Perspective: These observations from an archival databaseare still noteworthy. They provide strong evidence to sup-port recommendations for discontinuance of cigarettesmoking among heart failure patients, and strong evidenceto exclude heart transplantation in those individuals whocontinue to smoke. RC

Moderate Alcohol Consumption and Risk of HeartFailure Among Older PersonsAbramson JL, Williams SA, Krumholz HM, Vaccarino V. JAMA.2001;285:1971–7.

Study Question: Heavy consumption of alcohol can lead toheart failure, but the relationship between moderate alcoholconsumption and risk of heart failure is largely unknown.To determine whether moderate alcohol consumption pre-dicts heart failure risk among older persons, independent ofthe association of moderate alcohol consumption withlower risk of myocardial infarction (MI).Methods: This was a prospective cohort study conductedfrom 1982 through 1996, with a maximum follow-up of 14years. The population-based sample of 2235 noninstitu-tionalized elderly persons (mean age, 73.7 years; 41.2%male; 21.3% nonwhite) residing in New Haven, CT werefree of heart failure at baseline. Persons who reported alco-hol consumption of more than 70 oz in the month prior tobaseline were excluded. The major end point was time tofirst fatal or nonfatal heart failure event, according to theamount of alcohol consumed in the month prior to base-line.Results: Increasing alcohol consumption in the moderaterange was associated with decreasing heart failure rates. Forpersons consuming no alcohol (50.0%), 1 to 20 oz (40.2%),and 21 to 70 oz (9.8%) in the month prior to baseline, crude

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heart failure rates per 1000 years of follow-up were 16.1,12.2, and 9.2, respectively. After adjustment for age, sex,race, education, angina, history of MI and diabetes, MIduring follow-up, hypertension, pulse pressure, body massindex and current smoking, the relative risks of heart failurefor those consuming no alcohol, 1 to 20 oz, and 21 to 70 ozin the month prior to baseline were 1.00, 0.79, and 0.53.Conclusion: Increasing levels of moderate alcohol consump-tion are associated with a decreasing risk of heart failureamong older persons. This association is independent of anumber of confounding factors and does not appear to beentirely mediated by a reduction in MI risk.Perspective: This is an interesting outcome of a cohort dataanalysis. Before we recommend that our elderly patientsconsume alcohol to reduce the risk of heart failure, it wouldbe import to know why some patients were drinking alco-hol and others were not. The authors made a good effort tolook at confounding variables. The variable of financialindependence was difficult to assess. Could it be that pa-tients who could not afford to drink 21–70 oz of alcohol perday could not afford their heart failure medications aswell? RC

Effects of Multisite Biventricular Pacing in PatientsWith Heart Failure and Intraventricular ConductionDelayCazeau S, Leclercq C, Lavergne T, et al., for the MultisiteStimulation in Cardiomyopathies (MUSTIC) Study Investigators.N Engl J Med 2001;344:873– 80.

Study Question: One third of patients with chronic heartfailure have electrocardiographic evidence of a major intra-ventricular conduction delay, which may worsen left ven-tricular systolic dysfunction through asynchronous ventric-ular contraction. Uncontrolled studies suggest thatmultisite biventricular pacing improves hemodynamics andwell being by reducing ventricular asynchrony.Methods: 67 patients with severe heart failure (New YorkHeart Association class III) due to chronic left ventricularsystolic dysfunction, with normal sinus rhythm and a du-

ration of the QRS interval of more than 150 msec, receivedtransvenous atriobiventricular pacemakers (with leads inone atrium and each ventricle). This study compared theresponses of the patients during two periods: a 3-monthperiod of inactive pacing (ventricular inhibited pacing at abasic rate of 40 bpm) and a 3-month period of active(atriobiventricular) pacing. The primary end point was thedistance walked in 6 minutes; the secondary end pointswere quality of life as measured by questionnaire, peakoxygen consumption, hospitalizations related to heart fail-ure, the patients’ treatment preference (active vs. inactivepacing) and the mortality rate.Results: Nine patients were withdrawn from the study be-fore randomization, and 10 failed to complete both studyperiods. Thus, 48 patients completed both phases of thestudy. The mean (6SD) distance walked in 6 minutes was23% greater with active pacing (3996100 m vs. 3266134m, p,0.001), the quality of life score improved by 32%(p,0.001), peak oxygen uptake increased by 8%(p,0.03), hospitalizations were decreased by two thirds(p,0.05) and active pacing was preferred by 85% of thepatients (p,0.001).Conclusions: Although it is technically complex, atriobiven-tricular pacing significantly improves exercise toleranceand quality of life in patients with chronic heart failure andintraventricular conduction delay.Perspective: A major limitation of this study is the with-drawal of possible candidates for the study, and moreimportantly, those patients who did not complete bothsegments of randomization. These features underscore thecomplexity of studying patients with severe heart failure inthe context of mechanical intervention. Additionally, theinability to completely blind exercise outcomes in the pres-ence of pacing is one of several known limitations of usingan end point of exercise tolerance and the estimated peakoxygen uptake. An increase of peak VO2 of 8% is encour-aging but not overwhelming. Despite these limitations,biventricular pacing offers a potential option for those pa-tients without clinical improvement during optimal phar-macologic therapy. RC

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