Edgar C. Schick

Angiotensin inhibition in severe heart failure: Acute central and limb hemodynamic effects of captopril with observations on sustained oral therapy

The systemic, pulmonary, and limb circulatory responses to the angiotensin-converting enzyme inhibitor, captopril, were determined in 10 patients with severe, chronic heart failure. Immediate effects include sustained reductions in arterial pressure and pulmonary capillary wedge pressure and improvement in cardiac output, as reported with other vasodilator drugs. Calf vascular resistance did not change despite substantial lowering of total systemic vascular resistance, indicating that arteriolar dilatation occurred on a selective basis. Transient reduction in mean right atrial pressure paralleled slight calf venodilatation, but effects upon the resistance vasculature predominated. Plasma renin activity and norepinephrine concentrations increased after therapy in the acute phase as plasma aldosterone levels consistently fell. During maintenance oral treatment over 7 to 15 months (median, 11.5 months), patients displayed symptomatic benefit, improved functional capacity, and greater exercise tolerance. No major adverse reactions developed. These findings suggest that angiotensin converting enzyme inhibition with captopril in congestive heart failure patients improved cardiocirculatory function through selective arteriolar dilatation. The reordering of regional blood flow which appears to result from release of angiotensin-mediated vasoconstriction, as well as the suppression of aldosterone, may underlie the prolonged benefit observed in these patients. This oral vasodilator appears to represent an effective adjunct for the treatment of advanced, chronic heart failure refractory to conventional measures.

Determinants of clinical response and survival in patients with congestive heart failure treated with captopril

The efficacy of chronic ambulatory captopril (CPT) therapy was evaluated over an 18-month period in 36 patients with refractory chronic congestive heart failure (CHF) by cardiac catheterization, treadmill exercise, nuclear scintigraphy, echocardiography, and symptomatology. Clinical improvement to New York Heart Association functional class I or class II was observed in 63% of the patients (20 of 32) after 2 months of treatment; this amelioration of CHF symptoms was sustained in 63% of the patients (10 of 16) at 18 months. Exercise tolerance increased in 64% of the patients (16 of 25) at early follow-up and in 79% (11 of 14) at late follow-up. Univariate analysis revealed that the pre- and post-CPT stroke work indices (SWI) and the post-CPT cardiac index related to favorable long-term clinical response. Fourteen CHF patients (39%) died during the 18-month follow-up. Univariate analysis revealed that the pretreatment SWI, right atrial pressure, plasma norepinephrine concentration, and echocardiographic shortening fraction were significant predictors of mortality. Multivariate analysis indicated that the SWI was the principal determinant of survival: the 18-month cumulative survival rate for CHF patients with a SWI less than 32 gm . m/m2 was 44% compared to 88% when the SWI was greater than 32 gm . m/m2. Thus, CPT results in sustained symptomatic and functional improvements in patients with advanced CHF, but the mortality remains high and is primarily related to the severity of cardiac dysfunction.

Randomized withdrawal from nifedipine: placebo-controlled study in patients with coronary artery spasm.

A multicenter randomized double-blind withdrawal study was conducted to compare the efficacy of nifedipine to that of placebo in vasospastic angina. Following a 2-week single-blind nifedipine baseline period, during which nifedipine was maintained at prestudy levels, 38 patients, 19 taking placebo and 19 continuing nifedipine therapy, either completed a 4-week randomized phase or were prematurely withdrawn because of therapeutic failure. During the randomized phase, an increase in median anginal frequency (2.8 attacks/wk, p less than 0.003) and nitroglycerin usage (0.5 tablets/wk, p less than 0.03) occurred only in the placebo group. The randomized phase was prematurely terminated because of anginal exacerbation in 7 of 19 placebo patients (37%) (only 1 patient receiving nifedipine [p = 0.02] experienced anginal exacerbation). Double-blind therapy was judged effective in 16 patients (84%) receiving nifedipine and in 3 patients (16%) receiving placebo (p less than 0.001). Nifedipine was well tolerated. This study establishes the efficacy of nifedipine in the treatment of variant and validates previous clinical experience.

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.

Comparison of determinants of myocardial oxygen consumption during arm and leg exercise in normal persons

Arm exercise assumes an increasingly important role in clinical cardiology as it is used in both exercise testing and training of patients with coronary artery disease. The effects of arm exercise on myocardial oxygen consumption are not well understood; they may differ from the effects of leg exercise. Previous studies have shown that the ischemic threshold is higher in patients performing arm exercise and leg exercise at the same heart rate-blood pressure product. The contribution of other determinants of myocardial oxygen consumption--left ventricular (LV) peak meridional systolic wall stress and contractility--to these observed differences were studied. Thirty healthy subjects exercised to the same peak rate-pressure product during dynamic upper- and lower-extremity exercise. Peak workload was lower during arm exercise (100 +/- 16 W) than during leg exercise (170 +/- 21 W, p less than 0.001). LV wall stress did not differ during either form of exercise (197 +/- 44 vs 204 +/- 33 dynes/cm2 X 10(3), arm vs leg, respectively). This was also true of contractility as assessed by the velocity of circumferential fiber shortening (2.8 +/- 0.6 vs 2.5 +/- 0.4 circ/s, arm vs leg, respectively) and the preejection period/LV ejection time ratio (0.33 +/- 0.11 vs 0.31 +/- 0.07, arm vs leg, respectively). Normal subjects exercising to a similar rate-pressure product showed the same levels of LV wall stress and contractility for arm and leg exercise despite the lower workload performed with arm exercise.

Symptoms and left ventricular size and function in patients with chronic aortic regurgitation

Patients with chronic aortic regurgitation (AR) are generally subject to low morbidity during a long asymptomatic period; many patients, even those with a severe regurgitant lesion, remain asymptomatic for decades. Others, while lacking clear evidence of worsening regurgitation, show evidence of

Paradoxical Embolism in the Left Main Coronary Artery: Diagnosis by Transesophageal Echocardiography

We describe a patient with a paradoxical coronary embolism diagnosed by transesophageal echocardiography. The patient developed a stroke followed by a myocardial infarction. Coronary angiography showed an obstruction of the left main coronary artery. Transesophageal echocardiography showed the mechanism of the neurologic and cardiac events to be a paradoxical embolism. Emergency surgical retrieval of the thrombus lodged in the left main coronary ostium and of a separate thrombus traversing a patent foramen ovale was performed. To our knowledge, direct visualization of the paradoxical coronary embolism by echocardiography has not been reported previously. We discuss mechanisms responsible for paradoxical coronary embolism and review the literature pertaining to this condition.

Surgical therapy for Prinzmetal's variant angina.

Fifty-two patients underwent coronary artery bypass grafting between 1973 and 1979 for variant angina, defined as pain, usually at rest, associated with S-T segment elevation. Only patients with fixed occlusive coronary artery disease, defined as greater than 70% narrowing in diameter, were included. When fixed coronary artery stenosis is present, variant angina--whether presenting as stable, unstable, or postinfarction angina, and regardless of the number of vessels diseased--is effectively treated by myocardial revascularization. Preoperative intraaortic balloon pumping is a useful therapeutic adjunct in the unstable subset refractory to medical therapy. The results of revascularization in patients with Prinzmetals variant angina and fixed coronary disease were no different from those in patients with classic angina pectoris of comparable clinical categories.

Anthropometric normalization of left ventricular size in chronic mitral regurgitation.

A considerable body of clinical and experimental evidence supports the notion that a major cardiac adjustment to mitral regurgitation (MR) is enlargement of the left ventricle.1–7 However, definitions of left ventricular (LV) enlargement ostensibly require a consideration of body size. Body surface area (BSA) has long been used to normalize LV internal dimensions,3,4 but recent studies of chronic MR have utilized data without consideration of body size.5,6 Thus, there is a lack of agreement as to whether LV size should or should not be normalized for BSA, or for some other anthropometric index.8,9 In an attempt to clarify this issue, we identified 48 patients with clinical and echocardiographic color Doppler evidence of chronic MR. Anticipating a high prevalence of LV enlargement, we compared the conclusions drawn from non-normalized measurements with those normalized for BSA, the square root of BSA, and on the basis of height. In this manner, we evaluated the relative merits of the 3 normalization techniques. • • • Using a database for 1997 to 1998, patients with severe MR were identified. The echo Doppler studies were reviewed by at least 2 of the investigators and the diagnosis of severe MR was confirmed (see the following). All patients had mitral valve disease with prolapse or partially flail leaflets. Those with mitral stenosis and/or associated aortic valve disease were excluded, as were those with LV wall motion abnormalities indicating coronary heart disease. Finally, a medical record review confirmed that all patients had previous clinical, radiographic, and/or echocardiographic evidence of MR for 1 year. Thus, only patients with chronic MR were included in the study. There were 31 men and 17 women; average age was 67 12 years. Two-dimensional, M-mode, and Doppler echocardiography were performed using commercially available equipment (Hewlett-Packard Medical Products, Andover, Massachusetts). LV internal minor-axis diameter was measured, just distal to the tips of the mitral leaflets (e.g., at the mid-cordal level).10 The ejection fraction was estimated from measurements of the LV diameter at end-diastole and end-systole, using a modification of the Quinones method.11,12 The severity of MR was estimated from the relative area of the regurgitant jet (Doppler echocardiography). Severe MR was defined as a color jet reaching the posterior wall of the left atrium with a high aliasing velocity area 40% of the left atrial area.13 The upper limit of normal of the LV end-diastolic diameter (EDD) was taken as 56 mm.14 Patients were separated into those with enlarged ventricles (group A) and those whose EDD was normal (group B); subgroups of those in normal sinus rhythm and with atrial fibrillation were identified (Table 1). We then normalized the LV EDD for BSA; the upper limit of normal was taken as 32 mm/m. We also normalized the EDD by the square root of BSA; the upper limit of normal was taken as 40 mm/m. Finally, we also used the regression model developed by Vasan et al9 to categorize the degree of chamber enlargement. This latter method, based on genderand height-specific limits provides categories ranging from zero (normal), to 1 (borderline), and 2 to 4 (enlarged). We then examined the conclusions drawn from these 4 methods.8,9,14 Data in Table 1 are mean SD. Significant differences (p 0.05) were assessed with an unpaired t test. The average data from our 48 patients are listed in Table 1. By definition, the average value for LV EDD was larger in group A than that in group B. Analysis of the data in these 2 groups indicates a significantly greater left atrial enlargement in group A than group B, but age, gender, ejection fraction, and E-wave velocity did not differ in the 2 groups. The E-wave velocity was 130 cm/s in 28 of the 36 patients in group A and in 10 of the 12 patients in group B. Evidence of a partial flail leaflet and/or ruptured chordae was present in 16 of the 36 patients in group A (44%) and 6 of the 12 group B patients (50%). BSA was greater in group A than group B, but the average values for height and body mass index (BMI) (kilograms per meter) did not differ in the 2 groups. BMI was 25 kg/m in 31 of the 48 patients (64%). Data from the individual patients are shown in Figure 1. The LV EDD was 56 mm in 36 patients; by this definition, 75% of the patients exhibited LV enlargement. In contrast, EDD expressed relative to BSA exceeded the upper limits of normal (32 mm/m) in only 23 patients (44%). When the EDD was normalized by the square root of BSA, the value exFrom the Echocardiography Laboratory, Department of Cardiovascular Medicine, Lahey Clinic, Burlington, Massachusetts. Dr. Gaasch’s address is: Lahey Clinic, 41 Mall Road, Burlington, Massachusetts 01805. E-mail: William.H.Gaasch@Lahey.org. Manuscript received August 27, 2002; revised manuscript received and accepted November 14, 2002.

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.