William C. Little

Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease?

To help determine if coronary angiography can predict the site of a future coronary occlusion that will produce a myocardial infarction, the coronary angiograms of 42 consecutive patients who had undergone coronary angiography both before and up to a month after suffering an acute myocardial infarction were evaluated. Twenty-nine patients had a newly occluded coronary artery. Twenty-five of these 29 patients had at least one artery with a greater than 50% stenosis on the initial angiogram. However, in 19 of 29 (66%) patients, the artery that subsequently occluded had less than a 50% stenosis on the first angiogram, and in 28 of 29 (97%), the stenosis was less than 70%. In every patient, at least some irregularity of the coronary wall was present on the first angiogram at the site of the subsequent coronary obstruction. In only 10 of the 29 (34%) did the infarction occur due to occlusion of the artery that previously contained the most severe stenosis. Furthermore, no correlation existed between the severity of the initial coronary stenosis and the time from the first catheterization until the infarction (r2 = 0.0005, p = NS). These data suggest that assessment of the angiographic severity of coronary stenosis may be inadequate to accurately predict the time or location of a subsequent coronary occlusion that will produce a myocardial infarction.

THE PATHOGENESIS OF ACUTE PULMONARY EDEMA ASSOCIATED WITH HYPERTENSION

BACKGROUND Patients with acute pulmonary edema often have marked hypertension but, after reduction of the blood pressure, have a normal left ventricular ejection fraction (> or =0.50). However, the pulmonary edema may not have resulted from isolated diastolic dysfunction but, instead, may be due to transient systolic dysfunction, acute mitral regurgitation, or both. METHODS We studied 38 patients (14 men and 24 women; mean [+/-SD] age, 67+/-13 years) with acute pulmonary edema and systolic blood pressure greater than 160 mm Hg. We evaluated the ejection fraction and regional function by two-dimensional Doppler echocardiography, both during the acute episode and one to three days after treatment. RESULTS The mean systolic blood pressure was 200+/-26 mm Hg during the initial echocardiographic examination and was reduced to 139+/-17 mm Hg (P< 0.01) at the time of the follow-up examination. Despite the marked difference in blood pressure, the ejection fraction was similar during the acute episode (0.50+/-0.15) and after treatment (0.50+/-0.13). The left ventricular regional wall-motion index (the mean value for 16 segments) was also the same during the acute episode (1.6+/-0.6) and after treatment (1.6+/-0.6). No patient had severe mitral regurgitation during the acute episode. Eighteen patients had a normal ejection fraction (at least 0.50) after treatment. In 16 of these 18 patients, the ejection fraction was at least 0.50 during the acute episode. CONCLUSIONS In patients with hypertensive pulmonary edema, a normal ejection fraction after treatment suggests that the edema was due to the exacerbation of diastolic dysfunction by hypertension--not to transient systolic dysfunction or mitral regurgitation.

Utility of Fast Cine Magnetic Resonance Imaging and Display for the Detection of Myocardial Ischemia in Patients Not Well Suited for Second Harmonic Stress Echocardiography

BACKGROUND Some patients referred for pharmacological stress testing with transthoracic echocardiography (TTE) are unable to undergo testing owing to poor acoustic windows. Fast cine MRI can be used to assess left ventricular contraction, but its utility for detection of myocardial ischemia in patients poorly suited for echocardiography is unknown. METHODS AND RESULTS One hundred fifty-three patients (86 men and 67 women aged 30 to 88 years) with poor acoustic windows that prevented adequate second harmonic TTE imaging were consecutively referred for MRI to diagnose inducible myocardial ischemia during intravenous dobutamine and atropine. Diagnostic studies were completed in an average of 53 minutes. No patients experienced myocardial infarction, ventricular fibrillation, exacerbation of congestive heart failure, or death. In patients who underwent computer-assisted quantitative coronary angiography, the sensitivity and specificity for detecting a >50% luminal diameter narrowing were 83% and 83%, respectively. In the 103 patients with a negative MRI examination, the cardiovascular occurrence-free survival rate was 97%. CONCLUSIONS Fast cine cardiac MRI provides a mechanism to assess left ventricular contraction and diagnose inducible myocardial ischemia in patients not well suited for stress echocardiography.

Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance.

OBJECTIVES The goal of this study was to determine if cardiac cycle-dependent changes in proximal thoracic aortic area and distensibility are associated with exercise intolerance in elderly patients with diastolic heart failure (DHF). BACKGROUND Aortic compliance declines substantially with age. We hypothesized that a reduction in cardiac cycle-dependent changes in thoracic aortic area and distensibility (above that which occurs with aging) could be associated with the exercise intolerance that is prominent in elderly diastolic heart failure patients. METHODS Thirty subjects (20 healthy individuals [10 < 30 years of age and 10 > 60 years of age] and 10 individuals > the age of 60 years with DHF) underwent a magnetic resonance imaging (MRI) study of the heart and proximal thoracic aorta followed within 48 h by maximal exercise ergometry with expired gas analysis. RESULTS The patients with DHF had higher resting brachial pulse and systolic blood pressure, left ventricular mass, aortic wall thickness and mean aortic flow velocity, and, compared with healthy older subjects, they had a significant reduction in MRI-assessed cardiac cycle-dependent change in aortic area and distensibility (p < 0.0001) that correlated with diminished peak exercise oxygen consumption (r = 0.79). After controlling for age and gender in a multivariate analysis, thoracic aortic distensibility was a significant predictor of peak exercise oxygen consumption (p < 0.04). CONCLUSIONS Older patients with isolated DHF have reduced cardiac cycle-dependent changes in proximal thoracic aortic area and distensibility (beyond that which occurs with normal aging), and this correlates with and may contribute to their severe exercise intolerance.

Determination of Left Ventricular Chamber Stiffness From the Time for Deceleration of Early Left Ventricular Filling

BACKGROUND A noninvasive measure of left ventricular (LV) chamber stiffness (KLV) would be clinically useful. Our theoretical analysis predicts that KLV can be calculated from the time for deceleration of LV early filling (tdec) by [formula: see text] where p = density of blood, L = effective mitral length, and A = mitral area. METHODS AND RESULTS We tested this hypothesis in eight conscious dogs instrumented for measurement of LV pressure (P) with use of a micromanometer and volume (V) with use of sonomicrometers. KLV was determined as the slope of the late diastolic portion of the LV P-V loop. KLV was varied from 0.99 +/- 0.35 to 2.58 +/- 0.92 mm Hg/mL with use of three graded doses of phenylephrine. We assumed that p = 1.0 and that L/A = 3.4. Thus, we predicted that KLV = (0.08/tdec)2. The LV filling pattern was determined from the derivative of LV volume (dV/dt). tdec was measured from peak early filling to the end of early filling. Predicted KLV and actual KLV were closely correlated (r = .94, SEE = 0.06 mm Hg/mL, P < .05). The regression line was close to the line of identity (slope = 0.95, intercept = 0.13 mm Hg/mL). Dobutamine did not alter the relation between tdec and KLV.tdec determined from the mitral valve flow velocity measured with Doppler echocardiography correlated well with that measured by dV/dt (r = .89, P < .01) but was 0.02 seconds longer. KLV-calculated tdec from the corrected Doppler tdec provided a good estimate of measured KLV (r = .75, SEE = 0.5 mm Hg/mL, P < .01). CONCLUSIONS LV chamber stiffness can be determined from the time for deceleration of LV early filling, which can be measured noninvasively.

Statin Therapy May Be Associated With Lower Mortality in Patients With Diastolic Heart Failure A Preliminary Report

Background—No therapy has been shown to improve survival in heart failure (HF) with a normal ejection fraction (EF). There are plausible reasons to hypothesize that statins may be of benefit in HF with a normal EF. Methods and Results—We evaluated 137 patients with HF and an EF ≥0.50. The effect of treatment received at study entry on survival was determined. During a follow-up of 21±12 months, 20 deaths were observed. Treatment with an ACE inhibitor or receptor blocker, β-blocker, or calcium blocker had no significant effect on survival. In contrast, treatment with a statin was associated with a substantial improvement in survival (relative risk of death [95% CI] 0.22 [0.07 to 0.64]; P=0.006). Patients receiving statins had higher baseline LDL cholesterol than those not receiving statins (153±45 versus 98±33 mg/dL, P<0.01). After statin therapy, LDL cholesterol levels fell to a similar level (101±32 mg/dL) as in patients not receiving statins (98±33 mg/dL). After adjustment for differences in baseline clinical variables between groups (hypertension, diabetes, coronary artery disease, and serum creatinine), statin therapy was associated with lower mortality (adjusted relative risk of death [95% CI] 0.20 [0.06 to 0.62]; P=0.005). Similarly, after propensity matching, statin therapy was associated with improved survival (log-rank 6.12; P=0.013) and a trend toward improved survival without cardiovascular hospitalization (log-rank 3.02; P=0.082). Conclusions—Statin therapy may be associated with improved survival in patients with HF and a normal EF.

Mechanism of altered patterns of left ventricular filling during the development of congestive heart failure.

BACKGROUND The mechanism of the alterations in the pattern of left ventricular (LV) filling during the development of congestive heart failure (CHF) is not fully understood. METHODS AND RESULTS We studied six conscious dogs instrumented to measure LV and left atrial (LA) pressures and LV volume as CHF was induced by rapid pacing. Diastolic filling dynamics were serially measured over 4 weeks during normal sinus rhythm. Four days after we initiated pacing, the peak early diastolic filing rate decreased from 108 +/- 24 to 88 +/- 27 mL/s (P < .05) as the maximal early diastolic LA-LV pressure gradient decreased associated with a slowing of the rate of LV relaxation. Subsequently, the peak early filling rate progressively increased, returning to control at 1 week, and by the fourth week, it had increased to 168 +/- 39 mL/s (P < .05). These changes in early filling rates occurred as the maximal early diastolic LA-LV pressure gradient increased in association with a progressive increase in LV pressure despite further progressive slowing of the rate of LV relaxation. Throughout the development of CHF, peak early filling rate and the maximal LA-LV pressure gradient correlated (r = .99, P < .001). The early filling deceleration rate increased and deceleration time progressively decreased over the 4 weeks as LV stiffness and net LA plus LV stiffness increased (P < .05). As predicted by a theoretical analysis, the deceleration time was linearly related to the reciprocal of the square root of LV stiffness (r = .94, P < .01). CONCLUSIONS Early in CHF, slowing of LV relaxation reduces the maximal early diastolic LA-LV pressure gradient, decreasing the peak early filling rate. As CHF progresses, this is overcome by an increase in LA pressure that augments the early diastolic LA-LV pressure gradient, increasing peak early filling rate. Increasing LV stiffness during the development of CHF progressively shortens the early filling deceleration time and augments the early filling deceleration rate. These observations suggest that the early filling deceleration time reflects LV stiffness.

Thrombogenic Factors and Recurrent Coronary Events

BACKGROUND Thrombosis is a pivotal event in the pathogenesis of coronary disease. We hypothesized that the presence of blood factors that reflect enhanced thrombogenic activity would be associated with an increased risk of recurrent coronary events during long-term follow-up of patients who have recovered from myocardial infarction. METHODS AND RESULTS We prospectively enrolled 1045 patients 2 months after an index myocardial infarction. Baseline thrombogenic blood tests included 6 hemostatic variables (D-dimer, fibrinogen, factor VII, factor VIIa, von Willebrand factor, and plasminogen activator inhibitor-1), 7 lipid factors [cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, lipoprotein(a), apolipoprotein (apo)A-I, and apoB], and insulin. Patients were followed up for an average of 26 months, with the primary end point being coronary death or nonfatal myocardial infarction, whichever occurred first. The hemostatic, lipid, and insulin parameters were dichotomized into their top and the lower 3 risk quartiles and evaluated for entry into a Cox survivorship model. High levels of D-dimer (hazard ratio, 2.43; 95% CI, 1.49, 3.97) and apoB (hazard ratio, 1.82; 95% CI, 1.10, 3.00) and low levels of apoA-I (hazard ratio, 1.84; 95% CI, 1.10, 3.08) were independently associated with recurrent coronary events in the Cox model after adjustment for 6 relevant clinical covariates. CONCLUSIONS Our findings indicate that a procoagulant state, as reflected in elevated levels of D-dimer, and disordered lipid transport, as indicated by low apoA-1 and high apoB levels, contribute independently to recurrent coronary events in postinfarction patients.

The cardiovascular effects of erythropoietin

Erythropoietin is a hypoxia-induced hormone that is essential for normal erythropoiesis. The production of recombinant human erythropoietin (rHuEpo) has revolutionized the treatment of anemia associated with chronic renal failure and chemotherapy, and has been used as prophylaxis to prevent anemia after surgery. The erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells, smooth muscle cells and cardiomyocytes. Epo has potentially beneficial effects on the endothelium including anti-apoptotic, mitogenic and angiogenic activities. On the other hand, some reports suggest that rHuEpo may have pro-thrombotic or platelet-activating effects. Hypertension develops in 20-30% of renal patients treated with rHuEpo. Many patients with heart failure have anemia. Despite some potential adverse effects, early studies in heart failure patients with anemia suggest that rHuEpo therapy is safe and effective in reducing left ventricular hypertrophy, enhancing exercise performance and increasing ejection fraction. Further studies are warranted to define the role of rHuEpo in chronic heart failure and other cardiovascular settings.

Mode of Death in Patients With Heart Failure and a Preserved Ejection Fraction Results From the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) Trial

Background— The mode of death has been well characterized in patients with heart failure and a reduced ejection fraction; however, less is known about the mode of death in patients with heart failure and a preserved ejection fraction (HFPEF). The purpose of this study was to examine the mode of death in patients with HFPEF enrolled in the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial and to determine whether irbesartan altered the distribution of mode of death in HFPEF. Methods and Results— All deaths were reviewed by a clinical end-point committee, and the mode of death was assigned by consensus of the members. The annual mortality rate was 5.2% in the I-Preserve trial. There were no significant differences in mortality rate between the placebo and irbesartan groups. The mode of death was cardiovascular in 60% (including 26% sudden, 14% heart failure, 5% myocardial infarction, and 9% stroke), noncardiovascular in 30%, and unknown in 10%. There were no differences in the distribution of mode-specific mortality rates between placebo and irbesartan. Conclusions— Sixty percent of the deaths in patients with HFPEF were cardiovascular, with sudden death and heart failure death being the most common. Treatment with irbesartan did not affect overall mortality or the distribution of mode-specific mortality rates. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.