Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure?

BACKGROUND: The diagnosis of diastolic heart failure is generally made in patients who have the signs and symptoms of heart failure and a normal left ventricular (LV) ejection fraction. Whether the diagnosis also requires an objective measurement of parameters that reflect the diastolic properties of the ventricle has not been established. METHODS AND RESULTS: We hypothesized that the vast majority of patients with heart failure and a normal ejection fraction exhibit abnormal LV diastolic function. We tested this hypothesis by prospectively identifying 63 patients with a history of heart failure and an echocardiogram suggesting LV hypertrophy and a normal ejection fraction; we then assessed LV diastolic function during cardiac catheterization. All 63 patients had standard hemodynamic measurements; 47 underwent detailed micromanometer and echocardiographic-Doppler studies. The LV end-diastolic pressure was >16 mm Hg in 58 of the 63 patients; thus, 92% had elevated end-diastolic pressure (average, 24+/-8 mm Hg). The time constant of LV relaxation (average, 51+/-15 ms) was abnormal in 79% of the patients. The E/A ratio was abnormal in 48% of the patients. The E-wave deceleration time (average, 349+/-140 ms) was abnormal in 64% of the patients. One or more of the indexes of diastolic function were abnormal in every patient. CONCLUSIONS: Objective measurement of LV diastolic function serves to confirm rather than establish the diagnosis of diastolic heart failure. The diagnosis of diastolic heart failure can be made without the measurement of parameters that reflect LV diastolic function.

Ventricular and myocardial function following treatment of hypertension.

This study assesses and evaluates left ventricular (LV) contractile function after treatment of hypertension, with an emphasis on LV midwall mechanics. Although prior studies have assessed cardiac function after hypertension treatment, none has performed an analysis of LV midwall mechanics. The Veterans Affairs Study of monotherapy in hypertension was a study large enough to permit analysis of midwall mechanics across a wide spectrum of mass changes accompanying hypertension treatment. LV chamber function was assessed by computing fractional shortening at the endocardial surface; LV midwall shortening was used to define myocardial function. Both shortening indexes were related to end-systolic circumferential stress in the entire population by partitioning values of mass and relative wall thickness changes. Two hundred sixty-eight patients were studied at baseline and again after a 1- or 2-year period. In the entire group, there was no significant change in circumferential shortening either at the endocardium (38 +/- 8% at baseline vs 37 +/- 7% at follow up, p = 0.29) or in shortening at the midwall (20 +/- 3% vs 20 +/- 3%, p = 0.53). However, 83 patients had a reduction in relative wall thickness and an increase in midwall shortening. The change in midwall shortening was significantly related to changes in relative wall thickness (r = -0.53, p = 0.0001). Thus, reductions in LV mass associated with antihypertensive therapy are generally not accompanied by a decrement in LV chamber or myocardial function. Improvement in midwall shortening is more closely related to normalization of LV geometry than to reduction in LV mass.

Interval-dependent potentiation of left ventricular contractility is preserved in patients with atrial fibrillation and depressed ejection fraction.

Echocardiographic techniques were used to measure left ventricular isovolumic and ejection phase indexes of contractility in 54 patients with atrial fibrillation, and the relations between cycle lengths and contractility were compared in patients with normal and depressed ejection fractions. Data indicate that variations in contractility occur in a pattern that is consistent with postextrasystolic potentiation and that such interval-dependent potentiation is preserved in patients with atrial fibrillation and depressed ejection fraction.

Effect of rhythm regularization on left ventricular contractility in patients with atrial fibrillation.

In 10 patients with atrial fibrillation, echocardiographic measures of left ventricular function-interval relations were used to assess contractility and to test the hypothesis that rhythm regularization produces a higher contractile state than is seen when the rhythm is irregular. Regularization, following direct-current cardioversion, did not augment ventricular contractility above that seen during atrial fibrillation.

The class III antiarrhythmic effect of sotalol exerts a reverse use-dependent positive inotropic effect in the intact canine heart.

OBJECTIVES: We sought to study the rate related effects of sotalol on myocardial contractility and to test the hypothesis that the class III antiarrhythmic effect of sotalol has a reverse use-dependent positive inotropic effect in the intact heart. BACKGROUND: Antiarrhythmic drugs exert significant negative inotropic effects. Sotalol, a beta-adrenergic blocking agent with class III antiarrhythmic properties, may augment contractility by virtue of its ability to prolong the action potential duration (APD). METHODS: In 10 anesthetized dogs, measurements of left ventricle (LV) peak (+)dP/dt and simultaneous endocardial action potentials were made during baseline conditions and after sequential administration of esmolol and sotalol. In addition, electrical and mechanical restitution curves were constructed at a basic pacing cycle length of 600 ms by introducing a test pulse of altered cycle length ranging from 200 ms to 2,000 ms. RESULTS: In the steady state pacing experiments, sotalol prolonged the APD in a reverse use-dependent manner; such an effect was not seen with esmolol. At cycle lengths exceeding 400 ms, LV (+)dP/dt was significantly higher with sotalol than it was with esmolol. There was a direct relation between APD and LV (+)dP/dt with sotalol (r = 0.46, p < 0.001), but there was no significant relation between APD and LV (+)dP/dt with esmolol (r = 0.27, p = NS). Results in the single beat (restitution) studies were qualitatively similar to the steady state results; APD (at cycle length >400 ms) and LV (+)dP/dt (at cycle length >600 ms) were significantly higher with sotalol than they were with esmolol. CONCLUSIONS: The reverse use-dependent prolongation of APD by sotalol is associated with a positive inotropic effect.

Intravenous thrombolytic therapy for stroke: a review of recent studies and controversies.

STUDY OBJECTIVES: To review the randomized, controlled, multicenter trials of intravenous thrombolytic therapy for ischemic stroke. METHODS: Studies of ischemic stroke confirmed by computed tomography (CT) and randomization of more than 100 patients are reviewed. Streptokinase studies are the MAST-I, the MAST-E, and the ASK Trial. Studies using tissue plasminogen activator (tPA) are the NINDS Stroke Study, ECASS I, ECASS II, and ATLANTIS. One study using ancrod is STAT. We discuss significant factors common to each study, including thrombolytic agent used, CT scan interpretation, time of therapy administration in relation to stroke onset, thrombolytic dose, ancillary medication administration, safety, and neurologic outcomes. RESULTS: All streptokinase studies were stopped early because of increased mortality in the treated groups. Initial results of the STAT study are promising; publication of full study details is awaited. The ATLANTIS study was terminated early because of nonstatistical efficacy at interim analysis. The NINDS and the ECASS trials were completed; only the NINDS study demonstrated significant increase in the percentage of patients with complete recovery or minimal deficit at 3 months, without significant difference in mortality in the treated group. CONCLUSION: This review supports the use of intravenous thrombolytic therapy for ischemic stroke using tPA at a dose of.9 mg/kg body weight and a "golden window" treatment time of 3 hours. Administration without strict adherence to protocol, even within this time frame, may shift the benefit/risk profile of tPA. We recommend the treating physician have rapid access to CT scanning and to collaboration with individuals experienced in the evaluation of stroke and CT interpretation.

Trauma resuscitation/critical care fellowship for emergency physicians: a necessary step for the future of academic emergency medicine.

Emergency physicians (EPs) have long been de-facto providers of trauma resuscitation and critical care in academic and community hospital settings, and are significantly involved in out-of-hospital trauma care and trauma research. A one-year fellowship has been developed and implemented to provide advanced training in trauma resuscitation and critical care to EPs with a special interest in the field. This fellowship provides additional depth and breadth of training to prepare graduates for leadership roles in academic and specialized trauma centers. This is the first fellowship of its kind for EPs, and may serve as a model for fellowships at other institutions.

Evaluation of extent of shortening versus velocity of shortening at the endocardium and midwall in hypertensive heart disease.

To assess the incremental value of velocity of shortening velocity parameters compared with simpler, more widely used, extent of shortening parameters in compensated left ventricular hypertrophy, we studied 52 patients with left ventricular hypertrophy and 63 age-matched controls. Velocity parameters did not provide incremental information beyond that obtained by extent of shortening parameters.

Appetite-suppressing drugs and valvular heart disease.

The popular diet drugs, fenfluramine and dexfenfluramine, were withdrawn from the market in the United States after the publication of an association of these drugs with valvulopathy in a small series of patients, spontaneous reports to the Food and Drug Administration, and echocardiographic surveys that suggested a valvulopathy prevalence of 32.8% among diet drug users. Subsequent publications suggested that there is an association of these agents with valvulopathy, but that the prevalence seems lower than initially suspected. This review examines the available prevalence data and attempts to account for some of the variability in these data. Potential pathophysiologic mechanisms are discussed and management guidelines for these patients are provided. This is an area of ongoing study and more information about the natural history of these lesions will certainly be forthcoming. A review of the data reveals that the withdrawal of these agents was prudent and likely prevented further harm.

Ventricular arrhythmias in adult aortic stenosis: prevalence, mechanisms, and clinical relevance.

With the longer life expectancy of the population, calcific aortic stenosis has become a common cardiac problem in the elderly. When patients with moderate to severe aortic stenosis become symptomatic, the prognosis is usually poor in absence of valve replacement and sudden death is a feared complication. It has been hypothesized that malignant ventricular arrhythmias could be responsible for the high incidence of sudden death in symptomatic patients with aortic stenosis. The purpose of this review is to analyze the prevalence, the electrophysiologic mechanisms, and the possible role of ventricular arrhythmias in the development of symptoms and in the outcome of adult subjects with aortic stenosis.

Left ventricular length-force-shortening relations before and after surgical correction of chronic mitral regurgitation.

OBJECTIVES: We tested the hypothesis that postoperative left ventricular (LV) systolic wall stress can be predicted from the change in LV diastolic dimension and ejection fraction (EF) after surgical correction of chronic mitral regurgitation (MR). We used a simple mathematic model to predict postoperative systolic stress from end-diastolic dimension and EF. The validity of this model was assessed using data from 21 patients undergoing mitral valve replacement (MVR) for chronic MR. BACKGROUND: The decline in EF after MVR for chronic MR is traditionally thought to be a consequence of a postoperative increase in afterload, caused by closure of a low resistance runoff into the left atrium. However, consideration of the Laplace relation suggests that afterload does not necessarily increase after the operation. METHODS: A spherical mathematical model of the left ventricle was used to define the relations between LV end-diastolic dimension, systolic wall stress and EF. To test the validity of this model, clinical and echocardiographic data were obtained from 21 patients with chronic MR before and 10 to 14 days after MVR. These echocardiographic data were examined with reference to plots derived from the mathematical model. RESULTS: Patients were categorized as those in whom end-diastolic dimension declined after the operation (group I, n = 15) and those with no reduction in end-diastolic dimension (group II, n = 6). Group I patients were subclassified into those undergoing MVR with chordal preservation (group Ia) and those undergoing MVR with chordal transection (group Ib). In groups Ib and II, there were significant reductions in EF (56 +/- 3% to 48 +/- 3% in group Ib and 50 +/- 2% to 40 +/- 3% in group II, both p < 0.05), but the changes in end-diastolic dimension and wall stress differed. In group Ib, end-diastolic dimension decreased and systolic wall stress was unchanged; in group II, end-diastolic dimension was unchanged and wall stress increased. In contrast, group Ia patients experienced a substantial reduction in end-diastolic dimension, no change in EF and a reduction in stress. The corresponding length-force-shortening coordinates closely approximate those predicted from a mathematic model relating end-diastolic dimension to EF and systolic wall stress. CONCLUSIONS: Concordant echocardiographic and mathematical model results indicate that postoperative changes in systolic stress are directly related to changes in chamber size and that LV afterload may fall when chordal preservation techniques are used in combination with MVR.

Which indexes of filling behavior should be used to characterize left ventricular diastolic function when changes in heart rate and atrioventricular delay occur?

The routine use of the peak early-to-peak atrial velocity, early velocity integral-to-atrial velocity integral, and early velocity integral-to-the total filling velocity integral ratios are limited because they are influenced by heart rate and atrioventricular delay. Hence, we sought to establish whether these ratios could be normalized to account for the differences in cycle length (RR interval) and diastolic filling period when heart rate and atrioventricular delay were altered in 18 patients with programmable dual-chamber pacemakers. We further explored whether these and other parameters of the mitral velocity profile could be used to characterize the mitral filling pattern during isoproterenol and methoxamine infusions-interventions that are likely to change both heart rate and left ventricular filling. The early velocity integral-to-atrial velocity integral and early velocity integral-to-the total filling velocity integral ratios were more sensitive to minor variations in heart rate and atrioventricular delay than the peak early-to-peak atrial velocity ratio. The early velocity integral-to-atrial velocity integral and early velocity integral-to-total filling velocity integral ratios could not be normalized to account for differences in RR interval or diastolic filling period, whereas the peak early-to-peak atrial velocity ratio became less sensitive to changes in heart rate when it was divided by the RR interval, or diastolic filling period, or square root of diastolic filling period. Because the diastolic filling period is affected by atrioventricular delay independent of changes in the RR interval, these ratios were also corrected for the functional cycle length, defined as the interval from R-wave of the electrocardiogram to the end of the diastolic filling period. When corrected for either the functional cycle length or diastolic filling period or square root of diastolic filling period, only the peak early-to-peak atrial velocity ratio became less sensitive to variations in the atrioventricular delay. The ratio of diastolic filling period expressed as a proportion of RR interval or functional cycle length changed significantly when heart rate and atrioventricular delay were altered and did not improve when diastolic filling period was divided by the square root of RR or square root of functional cycle length. However, when the square root of diastolic filling period was divided by the RR interval or functional cycle length, the effects of heart rate and atrioventricular delay were not apparent. Of all the ratios, the ratio of square root of diastolic filling period expressed as a proportion of RR interval or functional cycle length was the most useful to differentiate the confounding effects of heart rate (+/-atrioventricular delay) from the effects of isoproterenol and methoxamine on left ventricular filling. Hence, this ratio appeared to be a heart rate- and atrioventricular delay-independent index of left ventricular diastolic function.

Interval-dependent changes in left ventricular contractile state in lone atrial fibrillation and in atrial fibrillation associated with coronary artery disease.

In atrial fibrillation (AF), beat-to-beat changes in left ventricular (LV) systolic performance are caused by variations in filling (preload), aortic pressure (afterload), and ventricular inotropic or contractile state. These factors are known to be influenced by the preceding diastolic or RR interval (RR1), but the independent impact of variations in the pre-preceding RR interval (RR2) on contractile state is not well defined. This aspect was studied in 10 patients with lone AF and 8 with coronary artery disease by measuring LV peak ejection velocity (V[pe] Doppler echocardiography) in 80 to 100 consecutive cardiac cycles. V(pe) was plotted against RR1 for beats with a short RR2 and for beats with a long RR2. Such function-interval plots indicate a direct relation between V(pe) and RR1 (for RR1 = 500 to 1,000 ms). In lone AF, the slope (linear fit) of V(pe) versus RR1 was similar for short and long RR2 (slopes = 46 and 50 s[-1]). V(pe), calculated from best linear fit and a common RR1, was consistently higher when RR2 was short than when it was long. At an RR1 = 750 ms, V(pe) (% of max) was 87 +/- 6% when RR2 was short versus 76 +/- 6% when RR2 was long, p <0.05. Results were similar in patients with coronary artery disease and the observed interval-dependent potentiation of contractile state was preserved in patients with a low ejection fraction. By comparing V(pe) at a common RR1, the effects of time-dependent changes in LV preload and afterload are minimized if not abolished. Thus, differences in V(pe) reflect differences in contractile state caused by variations in RR2. Data confirm interval-dependent alterations in contractile state that are likely an expression of the force-frequency relation. Studies of LV function in AF should incorporate a consideration of cycle length-dependent changes in LV contractile state.

Force pattern of hypoxic myocardium applied to oxygenated muscle preparations: comparison with effects of regional ischemia on the contraction of non-ischemic myocardium.

OBJECTIVE: To examine the basis for local wall motion abnormalities commonly seen in patients with ischemic heart disease, computer-controlled isolated muscle studies were carried out. METHODS: Force patterns of physiologically sequenced contractions (PSCs) from rat left ventricular muscle preparations under well-oxygenated conditions and during periods of hypoxia and reoxygenation were recorded and stored in a computer. Force patterns of hypoxic-reoxygenating and oxygenated myocardium were applied to oxygenated and hypoxic-reoxygenating myocardium, respectively. RESULTS: Observed patterns of shortening and lengthening closely resemble those obtained from ischemic and non-ischemic myocardial segments using ultrasonic crystals in intact dog hearts during coronary occlusion and reperfusion, and are similar to findings reported in angiographic studies of humans with coronary artery disease. CONCLUSION: The current study, demonstrating motions of oxygenated isolated muscle preparations which are similar to those in perfused segments of intact hearts with regional ischemia, supports the concept that the multiple motions of both ischemic and non-ischemic segments seen in regional myocardial disease can be explained by interactions of strongly and weakly contracting muscle during the physiologic cardiac cycle.

Vasoactive drugs in chronic regurgitant lesions of the mitral and aortic valves.

This review examines the results of vasodilator therapy in patients with chronic regurgitant lesions of the aortic and mitral valves. The analysis includes those studies which provide data on hemodynamic measurements, left ventricular systolic function, ventricular volumes and regurgitant flow. In patients with chronic aortic or mitral regurgitation, the short-term administration of nitroprusside, hydralazine, nifedipine or an angiotensin-converting enzyme (ACE) inhibitor produces salutary hemodynamic effects. The major difference in the response to combined preload and afterload reduction (i.e., nitroprusside) in patients with aortic versus mitral regurgitation was that forward stroke volume generally increased and ejection fraction remained unchanged in mitral regurgitation, whereas ejection fraction generally increased and forward stroke volume remained unchanged in aortic regurgitation. These observations suggest that a reciprocal relation between regurgitant and forward flow characterizes the response to preload and afterload reduction in mitral regurgitation (through a preload-dependent dynamic regurgitant orifice), whereas correction of afterload mismatch dominates the response in aortic regurgitation. In studies of long-term vasodilator therapy in patients with chronic aortic regurgitation, a reduction in left ventricular volumes and regurgitant fraction, with or without an increase in ejection fraction, has been observed during treatment with hydralazine, nifedipine and ACE inhibitors. Patients with the largest, sickest hearts generally benefit the most from treatment with vasoactive drugs. Nonetheless, favorable ventricular remodeling has been reported in asymptomatic patients, and long-term nifedipine use has delayed the need for operation in asymptomatic patients with chronic aortic regurgitation. For patients with chronic mitral regurgitation, definition of the etiology of the lesion is a prerequisite for choosing appropriate therapy. Excluding patients with obstructive hypertrophic cardiomyopathy and mitral valve prolapse, and some with fixed-orifice (i.e., rheumatic) mitral regurgitation, the signal importance of preload reduction suggests that the preferred long-term therapy for symptomatic chronic mitral regurgitation is an ACE inhibitor. There are no long-term studies that support the use of vasodilator therapy in asymptomatic patients with chronic mitral regurgitation.