Laura F. Wexler

Outcomes in Patients with Acute Non–Q-Wave Myocardial Infarction Randomly Assigned to an Invasive as Compared with a Conservative Management Strategy

Background Non–Q-wave myocardial infarction is usually managed according to an “invasive” strategy (i.e., one of routine coronary angiography followed by myocardial revascularization). Methods We randomly assigned 920 patients to either “invasive” management (462 patients) or “conservative” management, defined as medical therapy and noninvasive testing, with subsequent invasive management if indicated by the development of spontaneous or inducible ischemia (458 patients), within 72 hours of the onset of a non–Q-wave infarction. Death or nonfatal infarction made up the combined primary end point. Results During an average follow-up of 23 months, 152 events (80 deaths and 72 nonfatal infarctions) occurred in 138 patients who had been randomly assigned to the invasive strategy, and 139 events (59 deaths and 80 nonfatal infarctions) in 123 patients assigned to the conservative strategy (P=0.35). Patients assigned to the invasive strategy had worse clinical outcomes during the first year of follow-up. The numb...

Sex Differences in Medical Care and Early Death After Acute Myocardial Infarction

Background— Women receive less evidence-based medical care than men and have higher rates of death after acute myocardial infarction (AMI). It is unclear whether efforts undertaken to improve AMI care have mitigated these sex disparities in the current era. Methods and Results— Using the Get With the Guidelines–Coronary Artery Disease database, we examined sex differences in care processes and in-hospital death among 78 254 patients with AMI in 420 US hospitals from 2001 to 2006. Women were older, had more comorbidities, less often presented with ST-elevation myocardial infarction (STEMI), and had higher unadjusted in-hospital death (8.2% versus 5.7%; P<0.0001) than men. After multivariable adjustment, sex differences in in-hospital mortality rates were no longer observed in the overall AMI cohort (adjusted odds ratio [OR]=1.04; 95% CI, 0.99 to 1.10) but persisted among STEMI patients (10.2% versus 5.5%; P<0.0001; adjusted OR=1.12; 95% CI, 1.02 to 1.23). Compared with men, women were less likely to receive early aspirin treatment (adjusted OR=0.86; 95% CI, 0.81 to 0.90), early &bgr;-blocker treatment (adjusted OR=0.90; 95% CI, 0.86 to 0.93), reperfusion therapy (adjusted OR=0.75; 95% CI, 0.70 to 0.80), or timely reperfusion (door-to-needle time ≤30 minutes: adjusted OR=0.78; 95% CI, 0.65 to 0.92; door-to-balloon time ≤90 minutes: adjusted OR=0.87; 95% CI, 0.79 to 0.95). Women also experienced lower use of cardiac catheterization and revascularization procedures after AMI. Conclusions— Overall, no sex differences in in-hospital mortality rates after AMI were observed after multivariable adjustment. However, women with STEMI had higher adjusted mortality rates than men. The underuse of evidence-based treatments and delayed reperfusion among women represent potential opportunities for reducing sex disparities in care and outcome after AMI.

Occult Sleep-Disordered Breathing in Stable Congestive Heart Failure

Despite recent advances in its treatment, congestive heart failure associated with depressed left ventricular function is highly prevalent and continues to be associated with excess morbidity and mortality. Multiple factors may contribute to the progressively declining course of congestive heart failure. Severe nocturnal arterial oxyhemoglobin desaturation caused by sleep-disordered breathing could be a contributing factor, particularly because it has been associated with excess mortality in patients with chronic obstructive pulmonary disease [1]. Cheyne and Stokes were the first to observe periodic breathing in patients with heart failure (Cheyne-Stokes respiration). In a subsequent systematic study, Harrison and colleagues [2] reported that periodic breathing characterized by repeated episodes of apnea and hypopnea during sleep occurred in patients with congestive heart failure. Since this early observation, several investigators have used standard polysomnography to study periodic breathing during sleep in patients with congestive heart failure [3-7]. The differences in prevalence rates in these studies (36% to 100%) might have been caused by several factors, including the few patients studied (4 to 11), the varying inclusion of patients with risk factors predisposing them to sleep apnea (such as loud snoring, witnessed apnea, and obesity), the varying severity of heart failure and systolic dysfunction, the inclusion of patients with unstable (as opposed to stable, maximally treated) congestive heart failure, and the presence of other factors that may influence periodic breathing. These important factors, which were not considered in most of previous studies, could considerably affect the prevalence and the severity of sleep apnea. We determined the prevalence and effect of sleep-disordered breathing in a relatively large group of clinically well-defined patients with stable, optimally treated congestive heart failure. We also determined the predictors of sleep-disordered breathing in these patients. Methods Entry Criteria Forty-two ambulatory patients with stable congestive heart failure (no change in signs or symptoms of congestive heart failure and no change in medications for at least 4 weeks before polysomnography) and systolic dysfunction (left ventricular ejection fraction 45%) participated in the study. Patients were recruited from the cardiology and medical clinics of the Department of Veterans Affairs Medical Center, Cincinnati, Ohio. The cardiologist coinvestigator evaluated all patients to confirm that their condition was stable and that they were receiving optimal therapy, which included digoxin (26 patients), diuretics (38 patients), angiotensin-converting enzyme inhibitors (37 patients), or hydralazine (2 patients). At the time of recruitment, no information was sought about symptoms or risk factors for sleep apnea. The following were the exclusion criteria: unstable angina; unstable congestive heart failure; acute pulmonary edema; congenital heart disease; primary valvular heart disease; use of benzodiazepines or theophylline; intrinsic pulmonary diseases, including interstitial lung disease, moderate to severe chronic obstructive lung defect (percentage of the ratio of the predicted forced expiratory volume in 1 second and forced vital capacity < 68%); intrinsic renal and liver disorders; untreated hypothyroidism; and kyphoscoliosis. For uniformity, we studied only male patients (female patients are rarely referred to this center). Only 6 of the 48 patients who met the entry criteria and were asked to participate in the study refused. The main reasons for refusal were an unwillingness to stay in the hospital or an unwillingness to travel to the hospital because of distance. The study was approved by the Research and Development Committee of the Veterans Affairs Medical Center, Cincinnati, Ohio, and the Institutional Review Board at the University of Cincinnati College of Medicine. Baseline Studies After giving written informed consent, the patients were hospitalized for 2 consecutive nights. On the first day, a detailed history was obtained and physical examination and screening tests were done, including complete blood count; tests for serum electrolytes, digoxin, thyroid, and renal function; radionuclide ventriculography; determinations of arterial blood gases and pH; and pulmonary function tests. Strict criteria described elsewhere [8, 9] were used for doing pulmonary function tests and for obtaining arterial blood samples and their measurements. Because some studies [10] have suggested that a low baseline Paco 2 is a risk factor for periodic breathing, skin over the radial artery was anesthetized with 2% lidocaine to minimize pain (which could potentially induce hyperventilation during arterial blood sampling). While the patient was sitting, arterial blood was collected anaerobically in heparinized syringes during several breath cycles. Duplicate determinations of arterial blood gases and pH were immediately made with appropriate electrodes [9]. Polysomnography On the first night, patients were taken to the sleep laboratory. Surface electrodes were attached, but no recording was obtained. This adaptation night was used to minimize the first-night effect of sleeping in the laboratory. On the next night, polysomnography was done using standard techniques described previously [11-13]. For staging sleep, we recorded electroencephalograms (two channels), chin electromyograms (one channel), and electro-oculograms (two channels). Thoracoabdominal excursions were measured qualitatively by respiratory inductance plethysmography (Respitrace; Ambulatory Monitoring, Inc., Ardsley, New York) or by pneumatic respiration transducers (Grass Instrument Company, Quincy, Massachusetts) placed over the rib cage and abdomen. Airflow was qualitatively monitored using an oral-nasal thermocouple (Model TCT1R; Grass Instrument Company). Arterial oxyhemoglobin saturation was recorded using an ear oximeter (Biox IIA; BT, Inc., Boulder, Colorado). These variables were recorded on a multichannel polygraph (Model 78D; Grass Instrument Company). An apnea was defined as cessation of inspiratory airflow lasting 10 seconds or longer. An obstructive apnea was defined as the absence of airflow in the presence of rib cage and abdominal excursions. A central apnea was defined as the absence of airflow and of rib cage and abdominal excursions [11-13]. However, a central apnea may not be easily distinguished from an obstructive apnea if esophageal pressure is not measured. Hypopnea was defined as a reduction of airflow lasting 10 seconds or more that was associated with at least a 4% decrease in arterial oxyhemoglobin saturation or an arousal. An arousal was defined as the appearance of waves on an electroencephalogram that were at least 3 seconds in duration [14]. The number of episodes of apnea and hypopnea per hour is referred to as the apneahypopnea index. Scoring of polysomnograms was blinded. The prevalence of sleep-disordered breathing in patients with congestive heart failure was determined using an apneahypopnea index of more than 20 episodes per hour. In a retrospective study of patients with the sleep apnea syndrome [15], an index of more than 20 apneas per hour was associated with excess mortality. Because this study was done before hypopnea was recognized, the investigators did not include it in their calculation of the index. Lower thresholds (for example, an apneahypopnea index of 10 episodes per hour) have been used in other studies; however, the clinical importance, particularly of low cutoff points, has not been adequately determined. Other Studies Holter monitoring was done during polysomnography. Three electrocardiographic channels (leads V1, V3, and V5) were recorded using a Laser SxP Holter monitor system (Marquett Electronics Inc., Milwaukee, Wisconsin). The tapes were analyzed by computer and were manually overread by the cardiologist coinvestigator. Using standard techniques [16], we calculated right and left ventricular ejection fractions from gated first-pass and multigated radionuclide ventriculograms, respectively [16]. Statistical Analysis We used the Wilcoxon rank-sum test to assess the significance of differences between the two groups because the common variance assumption required by the t-test was not appropriate for many of the measurements. A P value of less than 0.05 was considered significant. We calculated 95% CIs using the approximate degrees of freedom for the t-statistic [17]. The relations between certain pathophysiologically important variables and the apneahypopnea index were examined by regression analysis and stepwise multiple regression analysis. Calculations were done using SAS software [17]. Results The apneahypopnea index varied from 0.3 to 82.2 episodes per hour. The frequency histogram of the index is shown in Figure 1. In 23 patients (group I), the apneahypopnea indexes varied from 0.3 to 13.4 episodes per hour (mean SD, 4.4 4 episodes per hour [CI, 2.7 to 6.0 episodes per hour; median, 3.2 episodes per hour]). In the 19 patients in group II (45%), the apneahypopnea index varied from 26.5 to 82.2 episodes per hour (mean, 44 13 episodes per hour [CI, 37.6 to 50.6 episodes per hour; median, 40.4 episodes per hour]. Figure 1. Frequency distribution of the apneahypopnea index in 10-unit intervals in 42 patients with stable, optimally treated congestive heart failure. The two groups did not differ significantly in demographic and historical data (Table 1). Congestive heart failure was caused by ischemic cardiomyopathy (16 patients in group I and 13 patients in group II), idiopathic cardiomyopathy (5 patients in group I and 6 patients in group II), and alcohol-related cardiomyopathy (2 patients in group I). Table 1. Demographics, Historical Data, and Physical Examination Findings in Patients without (Group I) or with (Group II) Sleep-Disordered Breathing* The mean values for s

Reduction in Stroke With Gemfibrozil in Men With Coronary Heart Disease and Low HDL Cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT)

Background—A low level of HDL cholesterol has been identified as a risk factor for stroke in observational studies. Methods and Results—Our objective was to determine whether treatment aimed at raising HDL cholesterol and lowering triglycerides reduces stroke in men with coronary heart disease and low levels of both HDL and LDL cholesterol. The study was a placebo-controlled, randomized trial conducted in 20 Veterans Affairs medical centers. A total of 2531 men with coronary heart disease, with mean HDL cholesterol 0.82 mmol/L (31.5 mg/dL) and mean LDL cholesterol 2.9 mmol/L (111 mg/dL), were randomized to gemfibrozil 1200 mg/d or placebo and were followed up for 5 years. Strokes were confirmed by a blinded adjudication committee. Relative risks were derived from Cox proportional hazards models. There were 134 confirmed strokes, 90% of which were ischemic. Seventy-six occurred in the placebo group (9 fatal) and 58 in the gemfibrozil group (3 fatal), for a relative risk reduction, adjusted for baseline variables, of 31% (95% CI, 2% to 52%, P =0.036). The reduction in risk was evident after 6 to 12 months. Patients with baseline HDL cholesterol below the median may have been more likely to benefit from treatment than those with higher HDL cholesterol. Conclusions—In men with coronary heart disease, low HDL cholesterol, and low LDL cholesterol, gemfibrozil reduces stroke incidence.

Impact of Time of Presentation on the Care and Outcomes of Acute Myocardial Infarction

Background— Prior studies have demonstrated an inconsistent association between patients’ arrival time for acute myocardial infarction (AMI) and their subsequent medical care and outcomes. Methods and Results— Using a contemporary national clinical registry, we examined differences in medical care and in-hospital mortality among AMI patients admitted during regular hours (weekdays 7 am to 7 pm) versus off-hours (weekends, holidays, and 7 pm to 7 am weeknights). The study cohort included 62 814 AMI patients from the Get With the Guidelines–Coronary Artery Disease database admitted to 379 hospitals throughout the United States from July 2000 through September 2005. Overall, 33 982 (54.1%) patients arrived during off-hours. Compared with those arriving during regular hours, eligible off-hour patients were slightly less likely to receive primary percutaneous coronary intervention (adjusted odds ratio [OR], 0.93; 95% confidence interval [CI], 0.89 to 0.98), had longer door-to-balloon times (median, 110 versus 85 minutes; P<0.0001), and were less likely to achieve door-to-balloon ≤90 minutes (adjusted OR, 0.34; 95% CI, 0.29 to 0.39). Arrival during off-hours was associated with slightly lower overall revascularization rates (adjusted OR, 0.94; 95% CI, 0.90 to 0.97). No measurable differences, however, were found in in-hospital mortality between regular hours and off-hours in the overall AMI, ST-elevated MI, and non–ST-elevated MI cohorts (adjusted OR, 0.99; 95% CI, 0.93 to 1.06; adjusted OR, 1.05; 95% CI, 0.94 to 1.18; and adjusted OR, 0.97; 95% CI, 0.90 to 1.04, respectively). Similar observations were made across most age and sex subgroups and with an alternative definition for arrival time (weekends/holidays versus weekdays). Conclusions— Despite slightly fewer primary percutaneous coronary interventions and overall revascularizations and significantly longer door-to-balloon times, patients presenting with AMI during off-hours had in-hospital mortality similar to those presenting during regular hours.

Left main coronary artery stenosis: angiographic determination.

Reliability of angiographic assessment of the left main coronary artery segment was evaluated by review of 106 coronary cineangiograms from the Coronary Artery Surgery Study. The films were interpreted by three groups of angiographers: those at a clinical site, those at a quality control site, and those on a study census panel. Among the readings of these three groups, there was 41% to 59% agreement on the severity of the lesion, with 80% agreement on whether the lesion was greater or less than 50%. The severity of lesion, its location, or presence of ectasia or calcium did not affect the discrepancy rate, whereas segments that were unusually short, diffusely diseased, or obscured by overlapping vessels were especially difficult to interpret.

Enhanced sensitivity to hypoxia-induced diastolic dysfunction in pressure-overload left ventricular hypertrophy in the rat: role of high-energy phosphate depletion.

Isolated buffer-perfused rat hearts with pressure-overload hypertrophy develop a greater decrease in left ventricular (LV) diastolic distensibility and a greater impairment in extent of LV relaxation in response to hypoxia than do normal hearts. Using 31P-NMR spectroscopy, we tested the hypothesis that the enhanced susceptibility of hypertrophied hearts to develop hypoxia-induced diastolic dysfunction is due to an accelerated rate of ATP and/or creatine phosphate depletion. Twelve minutes of hypoxia were imposed on isolated isovolumic (balloon-in-left-ventricle) buffer-perfused hearts from 14 rats with pressure-overload hypertrophy (LVH; LV/body wt ratio = 3.43 ± 17) secondary to hypertension induced by uninephrectomy plus deoxycorticosterone and salt treatment and from 17 age-matched controls (LV/body wt ratio = 2.22 ± 0.12, p<0.001). Coronary artery flow per gram left ventricle was matched in the LVH and control groups during baseline oxygenated conditions and held constant thereafter. Balloon volume was held constant throughout the experiment so that an increase in LV end-diastolic pressure during hypoxia represented a decrease in LV diastolic distensibility. LV systolic pressure was 165 ± 9 mm Hg in the LVH group compared with 120 ± 5 mm Hg in the controls during baseline aerobic perfusion (p<0.001). LV end-diastolic pressure rose significantly more in response to 12 minutes of hypoxia in the LVH group (12 ± 1 to 44 ± 10 mm Hg) than in the controls (12 ± 1 to 20 ± 3 mm Hg, p = 0.04). During baseline aerobic conditions, ATP content was the same in the LVH (17.1 ± 0.5 jjimol/g dry LVwt, n = 4) and control (18.8 ± 0.6 (imol/g dry LV wt, n = 4, p=NS) groups. During hypoxia, ATP declined at the same rate in the LVH and control groups (3.2 ± 0.5 versus 3.0 ± 0.5%/min, p = NS) despite the greater rise in end-diastolic pressure in the LVH group. Creatine phosphate content during baseline aerobic perfusion was 14% lower in the LVH group compared with controls, but the rate of creatine phosphate depletion during 12 minutes of hypoxia was the same. During hypoxia, intracellular pH declined modestly and to the same degree in both groups. Thus, the greater susceptibility to hypoxia-induced diastolic dysfunction observed in isolated buffer-perfused hypertrophied rat hearts cannot be explained by an initially lower total ATP content or by an accelerated rate of decline of ATP or creatine phosphate. Alternatively, the greater impairment of diastolic distensibility during hypoxic stress in hypertrophied hearts may be related to inherent differences in intracellular calcium regulation.

Reversible Orthodeoxia and Platypnea Due to Right-to-Left Intracardiac Shunting Related to Pericardial Effusion

Excerpt The rare phenomena of platypnea (dyspnea exacerbated by upright posture and relieved by recumbency) and orthodeoxia (hypoxemia exacerbated by upright posture and relieved by recumbency) hav...

The influence of pressure overload left ventricular hypertrophy on diastolic properties during hypoxia in isovolumically contracting rat hearts.

We tested the hypothesis that there is an enhanced susceptibility in hypertrophied cardiac muscle to develop decreased diastolic distensibility of the left ventricle in response to hypoxia. The effects of brief hypoxia (3 minutes) were studied in rats with and without chronic left ventricular pressure overload hypertrophy using an isolated buffer-perfused and isovolumic (balloon-in-left ventricle) heart preparation with excised pericardium and vented right ventricle. We compared hypertrophied hearts from hearts from hypertensive uninephrectomized Wistar- Kyoto rats (n = 12) with normotensive uninephrectomized age-matched controls (n = 13). Coronary flow was held constant and adjusted so that an identical flow per gram left ventricular weight was achieved in both groups. The left ventricular balloon volume was adjusted to produce an initial left ventricular end-diastolic pressure of 10 mm Hg in both groups and was held constant thereafter so that changes in left ventricular end-diastolic pressure during hypoxia represented changes in diastolic chamber distensibility. Under aerobic conditions, left ventricular systolic pressure was 66percent; higher in the hypertrophied hearts than in the controls, but there was no difference in the rate or extent of left ventricular relaxation as estimated by the exponential time constant of pressure decay and the asymptote to which pressure decayed. In response to hypoxia, left ventricular end-diastolic pressure was significantly higher in the hypertrophied hearts than in the controls (37 ± 5 vs. 22 ± 5 mm Hg, P < 0.001). In response to hypoxia, the rate of left ventricular relaxation was depressed to a comparable degree in both groups, but there was a greater upward shift in the asymptote to which pressure decayed in the hypertrophied hearts. Hypoxia-induced coronary vasodilation as assessed by the change in coronary vascular resistance was similar in the hypertrophied and control hearts (2.9 ± 0.5 vs. 2.3 ± 0.9 mm Hg/[(ml/min)/g], NS). The degree of hypoxia-induced anaerobic metabolism as estimated by the coronary arterial-venous lactate concentration difference was also similar in both groups (−0.72 ± 0.23 vs. −0.73 ± 0.16 mM/liter, NS). It is concluded that brief hypoxia results in a greater decrease in diastolic distensibility of the left ventricle in the presence of chronic pressure overload hypertrophy than in its absence.

Acute alterations in diastolic left ventricular chamber distensibility: mechanistic differences between hypoxemia and ischemia in isolated perfused rabbit and rat hearts.

Changes in diastolic chamber distensibility (DCD) during hypoxemia and ischemia were studied in isolated-buffer-perfused rabbit hearts. Two minutes of hypoxemia (low Po2 coronary flow) resulted in a shift of the diastolic pressure-volume curve to the left, i.e., distensibility was decreased (hypoxemic contracture). In contrast, 2 minutes of ischemia (zero coronary flow) resulted in an initial shift of the diastolic pressure-volume curve to the right indicating increased distensibility, which was followed by a later (30 minutes) shift to the left (ischemic contracture). Two minutes of ischemia superimposed on hypoxemia caused complete reversal of contracture. A quick stretch and release applied to the myocardium reversed late ischemic contracture but did not effect early hypoxemic contracture. The role of intracellular pH in modulating changes in DCD during hypoxia and ischemia was studied using phosphorus-31 nuclear magnetic resonance spectroscopy of isolated-buffer-perfused rat hearts that demonstrated changes in DCD similar to rabbit hearts during hypoxemia and ischemia. Intracellular pH decreased from 7.03 ± 0.02 to 6.87 ± 0.03 (p < .01) during 2 minutes of ischemia but did not change significantly during 4 minutes of hypoxemia. When 2 minutes of ischemia were superimposed on hypoxemia, pH decreased from 6.99 ± 0.01 during hypoxemia to 6.88 ± 0.02 after 2 minutes of ischemia (p < .01), concomitant with the complete reversal of hypoxemic contracture. These results suggest different mechanisms for late ischemic and early hypoxemic contracture and also suggest an explanation for the opposite initial changes in DCD seen after brief periods of ischemia and hypoxemia. The early development of contracture during hypoxemia and rapid redevelopment of diastolic tension after quick stretching are consistent with the hypothesis that hypoxemic contracture results from persistent Ca-activated diastolic tension secondary to impaired calcium resequestration by the sarcoplasmic reticulum. In contrast, the late development of contracture during global ischemia and reversal by quick stretching is compatible with rigor bond formation. The initial increase in distensibility during early ischemia and the reversal of hypoxemic contracture by a brief period of superimposed ischemia probably is the result of two factors present during ischemia but not during hypoxemia: 1) the collapse of the coronary vasculature and loss of the erectile effect and, 2) the rapid development of intracellular acidosis, which has been shown to affect myofibrillar calcium sensitivity, and this may lead to a decrease in Ca++ activated diastolic tension.