Holly R. Middlekauff

Prognostic significance of atrial fibrillation in advanced heart failure. A study of 390 patients.

BackgroundAtrial fibrillation is common in advanced heart failure, but its prognostic significance is controversial. Methods and ResultsWe evaluated the relation of atrial rhythm to overall survival and sudden death in 390 consecutive advanced heart failure patients. Etiology of heart failure was coronary artery disease in 177 patients (45%) and nonischemic cardiomyopathy or valvular heart disease in 213 patients (55%). Mean left ventricular ejection fraction was 0.19 ± 0.07. Seventy-five patients (19%o) had paroxysmal (26 patients) or chronic (49 patients) atrial fibrillation. Compared with patients with sinus rhythm, patients with atrial fibrillation did not differ in etiology of heart failure, mean pulmonary capillary wedge pressure on therapy, or embolic events but were more likely to be receiving warfarin and antiarrhythmic drugs and had a slightly higher left ventricular ejection fraction. After a mean follow-up of 236 ± 303 days, 98 patients died: 56 (57%) died suddenly, and 36 (37%) died of progressive heart failure. Actuarial 1-year overall survival was 68%, and sudden death-free survival was 79%. Actuarial survival was significantly worse for atrial fibrillation than for sinus rhythm patients (52% versus 71%, p =0.0013). Similarly, sudden death-free survival was significantly worse for atrial fibrillation than for sinus rhythm patients (69% versus 82%, p = 0.0013). By Cox proportional hazards model, pulmonary capillary wedge pressure on therapy, left ventricular ejection fraction, coronary artery disease, and atrial fibrillation were independent risk factors for total mortality and sudden death. For patients who had pulmonary capillary wedge pressure of less than 16 mm Hg on therapy, atrial fibrillation was associated with poorer 1-year survival (44% versus 83%, p = 0.00001); however, in the high pulmonary capillary wedge pressure group, atrial fibrillation did not confer an increased risk (58% versus 57%). ConclusionsAtrial fibrillation is a marker for increased risk of death, especially in heart failure patients who have lower filling pressures on vasodilator and diuretic therapy. Whether aggressive attempts to maintain sinus rhythm will reduce this risk is unknown. (Circulation 1991;84:40–48)

The effects of exercise training on sympathetic neural activation in advanced heart failure ☆: A randomized controlled trial

OBJECTIVES The goal of this study was to test the hypothesis that exercise training reduces resting sympathetic neural activation in patients with chronic advanced heart failure. BACKGROUND Exercise training in heart failure has been shown to be beneficial, but its mechanisms of benefit remain unknown. METHODS Sixteen New York Heart Association class II to III heart failure patients, age 35 to 60 years, ejection fraction < or =40% were divided into two groups: 1) exercise-trained (n = 7), and 2) sedentary control (n = 9). A normal control exercise-trained group was also studied (n = 8). The four-month supervised exercise training program consisted of three 60 min exercise sessions per week, at heart rate levels that corresponded up to 10% below the respiratory compensation point. Muscle sympathetic nerve activity (MSNA) was recorded directly from peroneal nerve using the technique of microneurography. Forearm blood flow was measured by venous plethysmography. RESULTS Baseline MSNA was greater in heart failure patients compared with normal controls; MSNA was uniformly decreased after exercise training in heart failure patients (60 +/- 3 vs. 38 +/- 3 bursts/100 heart beats), and the mean difference in the change was significantly (p < 0.05) greater than the mean difference in the change in sedentary heart failure or trained normal controls. In fact, resting MSNA in trained heart failure patients was no longer significantly greater than in trained normal controls. In heart failure patients, peak VO(2) and forearm blood flow, but not left ventricular ejection fraction, increased after training. CONCLUSIONS These findings demonstrate that exercise training in heart failure patients results in dramatic reductions in directly recorded resting sympathetic nerve activity. In fact, MSNA was no longer greater than in trained, healthy controls.

Syncope in advanced heart failure: High risk of sudden death regardless of origin of syncope

OBJECTIVES The purpose of this study was to assess the importance of syncope as a warning sign for sudden death in advanced heart failure and to determine the relative importance of cardiac syncope and syncope from other causes. BACKGROUND Despite remarkable advances in the pharmacologic approach to advanced heart failure, 20% to 40% of patients with advanced heart failure will die each year. In such patients, the relation between sudden death and the etiology of syncope has not been evaluated. METHODS The relation of syncope to sudden death was evaluated in 491 consecutive patients with advanced heart failure (New York Heart Association functional class III or IV), no history of cardiac arrest and a mean left ventricular ejection fraction of 0.20 +/- 0.07. Patients were evaluated for the presence and origin of syncope. The severity of heart failure was assessed from serum sodium levels, ejection fraction, functional class and echocardiographic and hemodynamic variables. RESULTS Sixty patients (12%) had a history of syncope; the condition had a cardiac origin in 29 (48%) and was due to other causes in 31 (52%). The origin of heart failure was coronary artery disease in 234 patients (48%) and dilated cardiomyopathy in 253 (51%) and its severity was similar in patients with and without syncope. During a mean follow-up interval of 365 +/- 419 days, 69 patients (14%) died suddenly and 66 patients (13%) died of progressive heart failure. The actuarial incidence of sudden death by 1 year was significantly greater in patients with (45%) than in those without (12%, p < 0.00001) syncope. In the Cox proportional hazards model, syncope predicted sudden death independent of atrial fibrillation, serum sodium, cardiac index, angiotensin-converting enzyme inhibition and patient age. The actuarial risk of sudden death by 1 year was similarly high in patients with either cardiac syncope or syncope from other causes (49% vs. 39%, p = NS). CONCLUSIONS Patients with advanced heart failure are at especially high risk for sudden death regardless of the etiology of syncope.

Improving survival for patients with advanced heart failure : a study of 737 consecutive patients

OBJECTIVES This study sought to determine whether survival and risk of sudden death have improved for patients with advanced heart failure referred for consideration for heart transplantation as advances in medical therapy were systematically implemented over an 8-year period. BACKGROUND Recent survival trials in patients with mild to moderate heart failure and patients after a myocardial infarction have shown that angiotensin-converting enzyme inhibitors are beneficial, type I antiarrhythmic drugs can be detrimental, and amiodarone may be beneficial in some groups. The impact of advances in therapy may be enhanced or blunted when applied to severe heart failure. METHODS One-year mortality and sudden death were determined in relation to time, baseline variables and therapeutics for 737 consecutive patients referred for heart transplantation and discharged home on medical therapy from 1986 to 1988, 1989 to 1990 and 1991 to 1993. Medical care was directed by a single team of physicians with policies established by consensus. From 1986 to 1990, the hydralazine/isosorbide dinitrate combination or angiotensin-converting enzyme inhibitors were the initial vasodilators, and class I antiarrhythmic drugs were allowed. After 1990, captopril was the initial vasodilator, given to 86% of patients compared with 46% of patients before 1989. After mid-1989, class I agents were routinely withdrawn, and amiodarone was used for frequent ventricular ectopic beats or atrial fibrillation (53% of patients after 1990 vs. 10% before 1989). RESULTS The total 1-year mortality rate decreased from 33% before 1989 to 16% after 1990 (p = 0.0001), and sudden death decreased from 20% to 8% (p = 0.0006). Adjusted for clinical and hemodynamic variables in multivariate proportional hazards models, total mortality and sudden death were lower after 1990. CONCLUSIONS The large reduction in mortality, particularly in sudden death, from advanced heart failure since 1990 may reflect an enhanced impact of therapeutic advances shown in large randomized trials when they are incorporated into a comprehensive approach in this population. This improved survival supports the growing practice of maintaining potential heart transplant candidates on optimal medical therapy until clinical decompensation mandates transplantation.

Improving survival for patients with atrial fibrillation and advanced heart failure

OBJECTIVES We attempted to determine whether changes in heart failure therapy since 1989 have altered the prognostic significance of atrial fibrillation. BACKGROUND Atrial fibrillation occurs in 15% to 30% of patients with heart failure. Despite the recognized potential for adverse effects, the impact of atrial fibrillation on prognosis is controversial. METHODS Two-year survival for 750 consecutive patients discharged from a single hospital after evaluation for heart transplantation from 1985 to 1989 (Group I, n = 359) and from 1990 to April 1993 (Group II, n = 391) was analyzed in relation to atrial fibrillation. In Group I, class I antiarrhythmic drugs and hydralazine vasodilator therapy were routinely allowed. In Group II, amiodarone and angiotensin-converting enzyme inhibitors were first-line antiarrhythmic and vasodilating drugs. RESULTS A history of atrial fibrillation was present in 20% of patients in Group I and 24% of those in Group II. Patients with atrial fibrillation in the two groups had similar clinical and hemodynamic profiles. Among patients with atrial fibrillation, those in Group II had a markedly better 2-year survival (0.66 vs. 0.39, p = 0.001) and sudden death-free survival (0.84 vs. 0.70, p = 0.01) than those in Group I. In each time period, survival was worse for patients with than without atrial fibrillation in Group I (0.39 vs. 0.55, p = 0.002) but not in Group II (0.66 vs. 0.75, p = 0.09). CONCLUSIONS The prognosis of patients with advanced heart failure and atrial fibrillation is improving. These findings support the practice of avoiding class I antiarrhythmic drugs in this group and may reflect recent beneficial changes in heart failure therapy.

Long-Term Efficacy of Amiodarone for the Maintenance of Normal Sinus Rhythm in Patients With Refractory Atrial Fibrillation or Flutter

The purpose of this study was to examine the efficacy and safety of amiodarone to maintain sinus rhythm in patients with refractory atrial fibrillation or flutter. One hundred ten patients with atrial fibrillation or flutter, refractory to > or = 1 class I antiarrhythmic agents (mean +/- SD 2.5 +/- 1.5, median 2), were given low-dose amiodarone (mean maintenance dose 268 +/- 100 mg/day) to determine its efficacy to maintain normal sinus rhythm after chemical or electrical cardioversion. Fifty-three patients had chronic and 57 patients had paroxysmal atrial fibrillation or flutter. Mean age of the study population was 60 +/- 13 years, and the mean follow-up was 36 +/- 38 months (range 31 days to 137 months). Actuarial rates for maintenance of sinus rhythm were 0.87, 0.70, and 0.55 at 1, 3, and 5 years, respectively. Twenty-one patients (19%) with arrhythmia recurrence had an increase in amiodarone dose, and after a mean additional follow-up of 2.5 years, 86% remained in normal sinus rhythm. The only observed predictor of atrial fibrillation or flutter recurrence was paroxysmal arrhythmia (40% recurrence vs 9% in patients with chronic atrial fibrillation or flutter; p < 0.001). Actuarial rates for withdrawal because of adverse effects were 0.08, 0.22, and 0.30 at 1, 3, and 5 years, respectively. The most frequent adverse effects necessitating withdrawal were skin discoloration (4.5%), pulmonary fibrosis (3.6%; none fatal), and thyroid toxicity (2.7%). No deaths occurred during the study period. In conclusion, amiodarone sinus rhythm in patients with atrial fibrillation or flutter, with a relatively low incidence of adverse effects necessitating withdrawal.

Complex heart rate variability and serum norepinephrine levels in patients with advanced heart failure

OBJECTIVES This study was designed to examine the relation of the Poincaré plot heart rate variability pattern to sympathetic nervous system activity as assessed by serum norepinephrine. BACKGROUND Poincaré plots demonstrate a complexity of beat to beat behavior not readily detected by other heart rate variability measures. Previous studies have described two abnormal Poincaré patterns in patients with heart failure: a torpedo pattern with reduced beat to beat variability and a complex pattern with clustering of points. METHODS To assess the relation of these plots to sympathetic activity, plasma norepinephrine at rest and a standard deviation measure of heart rate variability were analyzed in 21 patients with heart failure (mean left ventricular ejection fraction [+/- SD] 0.22 +/- 0.05). RESULTS Eleven subjects had a torpedo-shaped and 10 subjects had a complex Poincaré plot pattern. These two groups did not differ significantly in age, functional class, disease etiology, left ventricular ejection fraction, heart rate, ventricular ectopic activity or in a standard deviation measure of heart rate variability. However, patients with a complex Poincaré plot pattern had higher norepinephrine levels (722 +/- 373 pg/ml) than patients with torpedo-shaped plots (309 +/- 134 pg/ml) (p = 0.003). Patients with a complex pattern also had more severe hemodynamic decompensation, as evidenced by their higher levels of pulmonary capillary wedge and mean pulmonary artery pressures and lower values for cardiac index than those of patients with a torpedo-shaped plot. CONCLUSIONS Complex Poincaré plots are associated with marked sympathetic activation and may provide additional prognostic information and insight into autonomic alterations and sudden cardiac death in patients with heart failure.

Predicting death from progressive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

Data were retrospectively reviewed on 528 consecutive patients hospitalized for treatment of advanced heart failure (left ventricular ejection fraction 0.2 +/- 0.07) and cardiac transplant evaluation, who were stabilized with medical therapy and discharged home. Predictors of heart failure death or rehospitalization for urgent transplantation were identified using the Cox proportional-hazards model. Within 1 year, 59 patients (11%) died suddenly and 70 (13%) died of heart failure or required urgent transplantation. A serum sodium < or = 134 mEq/liter, pulmonary arterial diastolic pressure > 19 mm Hg, left ventricular diastolic dimension index > 44 mm/m2, peak oxygen consumption during exercise testing < 11 ml/kg/min and the presence of a permanent pacemaker were independent predictors of hemodynamic deterioration. In the absence of these risk factors the risk of hemodynamic deterioration within 1 year from this study was only 2%. This risk increased to > 50% in the presence of hyponatremia and any 2 additional risk factors. Thus, patients with advanced heart failure at highest risk for progressive hemodynamic deterioration can be identified from clinical variables that could aid in triaging such patients to earlier cardiac transplantation.

Increased muscle sympathetic nerve activity predicts mortality in heart failure patients

BACKGROUND Previous studies have associated neurohumoral excitation, as estimated by plasma norepinephrine levels, with increased mortality in heart failure. However, the prognostic value of neurovascular interplay in heart failure (HF) is unknown. We tested the hypothesis that the muscle sympathetic nerve activity (MSNA) and forearm blood flow would predict mortality in chronic heart failure patients. METHODS One hundred and twenty two heart failure patients, NYHA II-IV, age 50+/-1 ys, LVEF 33+/-1%, and LVDD 7.1+/-0.2 mm, were followed up for one year. MSNA was directly measured from the peroneal nerve by microneurography. Forearm blood flow was obtained by venous occlusion plethysmography. The variables were analyzed by using univariate, stepwise multivariate Cox proportional hazards analysis, and Kaplan-Meier analysis. RESULTS After one year, 34 pts died from cardiac death. The univariate analysis showed that MSNA, forearm blood flow, LVDD, LVEF, and heart rate were significant predictors of mortality. The multivariate analysis showed that only MSNA (P=0.001) and forearm blood flow (P=0.003) were significant independent predictors of mortality. On the basis of median levels of MSNA, survival rate was significantly lower in pts with >49 bursts/min. Similarly, survival rate was significantly lower in pts with forearm blood flow <1.87 ml/min/100 ml (P=0.002). CONCLUSION MSNA and forearm blood flow predict mortality rate in patients with heart failure. It remains unknown whether therapies that specifically target these abnormalities will improve survival in heart failure.

Relation of pace mapping QRS configuration and conduction delay to ventricular tachycardia reentry circuits in human infarct scars

OBJECTIVES This study sought to determine the relation of the paced QRS configuration and conduction delay during pace mapping to reentry circuit sites in patients with ventricular tachycardia late after myocardial infarction. BACKGROUND The QRS configuration produced by ventricular pacing during sinus rhythm (pace mapping) can locate focal idiopathic ventricular tachycardias during catheter mapping, but postinfarction reentry circuits may be relatively large and contain regions of slow conduction. We hypothesized that for postinfarction ventricular tachycardia, 1) pacing during sinus rhythm at reentry circuit sites distant from the exit from the scar would produce a QRS configuration different from the tachycardia; and 2) a stimulus to QRS delay during pace mapping may be a useful guide to reentry circuit slow conduction zones. METHODS Catheter mapping and ablation were performed in 18 consecutive patients with ventricular tachycardia after myocardial infarction. At 85 endocardial sites in 13 patients, 12-lead electrocardiograms (ECGs) were recorded during pace mapping, and participation of each site in a reentry circuit was then evaluated by entrainment techniques during induced ventricular tachycardia or by application of radiofrequency current. RESULTS Pace maps resembled tachycardia at < 30% of likely reentry circuit sites identified by entrainment criteria and at only 1 (9%) of 11 sites where radiofrequency current terminated tachycardia. Analysis of the stimulus to QRS interval during entrainment with concealed fusion showed that the conduction time from the pacing site to the exit from the scar was longer at sites where the pace map did not resemble tachycardia. Evidence of slow conduction during pace mapping, with a stimulus to QRS interval > 40 ms was observed at > or = 70% of reentry circuit sites. CONCLUSIONS At many sites in postinfarction ventricular reentry circuits, the QRS configuration during pace mapping does not resemble the ventricular tachycardia QRS complex, consistent with relatively large reentry circuits or regions of functional conduction block during ventricular tachycardia. A stimulus to QRS delay during pace mapping is consistent with slow conduction and may aid in targeting endocardial sites for further evaluation during tachycardia.