Pathological effects of alcohol septal ablation for hypertrophic obstructive cardiomyopathy.

BACKGROUND: The pathological effects and the mechanisms of action of intracoronary administration of ethanol for alcohol septal ablation (ASA) for the management of hypertrophic obstructive cardiomyopathy (HOCM) are unknown. METHODS: We examined surgical specimens and, in one case, autopsy specimens from four patients who underwent surgical septal myectomy 2 days to 14 months after unsuccessful ASA. RESULTS: Pathological examination early after ASA showed coagulative necrosis of both the myocardium and the septal perforator arteries. Affected arteries were distended and occluded by necrotic intraluminal debris, without platelet-fibrin thrombi. Late after unsuccessful ASA, excised septal tissue was heterogeneous, containing a region of dense scar, and adjacent tissue containing viable myocytes and interspersed scar. CONCLUSIONS: Intracoronary administration of ethanol in patients with HOCM causes acute myocardial infarction with vascular necrosis. The coagulative necrosis of the arteries, their distension by necrotic debris and the absence of platelet-fibrin thrombi distinguish ethanol-induced infarction from that caused by atherosclerotic coronary artery disease. The direct vascular toxicity of ethanol may be an important aspect of the mechanism of successful ASA.

Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects.

BACKGROUND: Data in normal human subjects on the factors affecting pulmonary artery systolic pressure (PASP) are limited. We determined the correlates of and established a reference range for PASP as determined by Doppler transthoracic echocardiography (TTE) from a clinical echocardiographic database of 102 818 patients, of whom 15 596 (15%) had a normal Doppler TTE study. METHODS AND RESULTS: A normal TTE was based on normal cardiac structure and function during complete Doppler TTE studies. The PASP was calculated by use of the modified Bernoulli equation, with right atrial pressure assumed to be 10 mm Hg. Among TTE normal subjects, 3790 subjects (2432 women, 1358 men) from 1 to 89 years old had a measured PASP. The mean PASP was 28.3+/-4.9 mm Hg (range 15 to 57 mm Hg). PASP was independently associated with age, body mass index (BMI), male sex, left ventricular posterior wall thickness, and left ventricular ejection fraction (P<0.001). The estimated upper 95% limit for PASP among lower-risk subjects was 37.2 mm Hg. A PASP >40 mm Hg was found in 6% of those >50 years old and 5% of those with a BMI >30 kg/m(2). CONCLUSIONS: Among 3790 echocardiographically normal subjects, PASP was associated with age, BMI, sex, wall thickness, and ejection fraction. Of these subjects, 28% had a PASP >30 mm Hg, and the expected upper limit of PASP may include 40 mm Hg in older or obese subjects. These findings support the use of age- and BMI-corrected values in establishing the expected normal range for PASP.

Vascular endothelial function in cyclosporine and tacrolimus treated renal transplant recipients.

BACKGROUND: Endothelial dysfunction is an early key event in the development of arteriosclerotic cardiovascular disease (ASCVD), thus an early marker of subclinical ASCVD. Endothelial function is impaired in renal transplant recipients (RTR) treated with cyclosporine (CyA). Tacrolimus is associated with less hyperlipidemia and hypertension than CyA, however, there are no data on endothelial function in tacrolimus-treated RTR. METHODS: High-resolution brachial ultrasonography was used to assess endothelium-dependent dilatation (EDD), and endothelium-independent dilatation (EID) in 20 stable RTR and a control group of 10 healthy subjects without clinical evidence of ASCVD. The RTR group included patients receiving CyA (n=10) and tacrolimus (n=10). EDD and EID were measured as percent increase in brachial artery diameter in response to reactive hyperemia and nitroglycerin, respectively. RESULTS AND CONCLUSIONS: EDD was significantly lower in RTR versus controls (1.7+/-0.7 vs. 7.3+/-0.7%, P<0.0001), whereas EID was similar in the two groups. No significant differences were found in EDD or in EID between CyA- and tacrolimus-treated RTR. Glomerular filtration rate, plasma homocysteine, blood pressure, and lipid profiles were similar in CyA- and tacrolimus-treated RTR.

Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice.

Background- To investigate the role of endothelial nitric oxide synthase (NOS3) in left ventricular (LV) remodeling after myocardial infarction (MI), the impact of left anterior descending coronary artery ligation on LV size and function was compared in 2- to 4-month-old wild-type (WT) and NOS3-deficient mice (NOS3(-/-)). Methods and Results- Two days after MI, both strains of mice had a similar LV size, fractional shortening, and ejection fraction by echocardiography. Twenty-eight days after MI, both strains had dilated LVs with decreased fractional shortening and lower ejection fractions. Although the infarcted fraction of the LV was similar in both strains, LV end-diastolic internal diameter, end-diastolic volume, and mass were greater, but fractional shortening, ejection fraction, and the maximum rate of developed LV pressure (dP/dt(max)) were lower in NOS3(-/-) than in WT mice. Impairment of diastolic function, as measured by the time constant of isovolumic relaxation (tau) and the maximum rate of LV pressure decay (dP/dt(min)), was more marked in NOS3(-/-) than in WT mice. Mortality after MI was greater in NOS3(-/-) than in WT mice. Long-term administration of hydralazine normalized blood pressure in NOS3(-/-) mice, but it did not prevent the LV dilatation, impaired systolic and diastolic function, and increased LV mass that followed MI. In WT mice, capillary density and myocyte width in the nonischemic portion of the LV did not differ before and 28 days after MI, whereas in NOS3(-/-) mice, capillary density decreased and myocyte width increased after MI, whether or not hydralazine was administered. Conclusions- These results suggest that the presence of NOS3 limits LV dysfunction and remodeling in a murine model of MI by an afterload-independent mechanism, in part by decreasing myocyte hypertrophy in the remote myocardium.

Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice.

BACKGROUND: To test whether deficiency in endothelial nitric oxide synthase (eNOS) affects atherosclerosis development, we compared lesion formation in apolipoprotein E (apoE)/eNOS-double knockout (DKO) and apoE-knockout (KO) control animals. METHODS AND RESULTS: After 16 weeks of "Western-type" diet, apoE/eNOS-DKO males and females showed significant increases in lesion area of 93.6% and 59.2% compared with apoE-KO mice. All apoE/eNOS-DKO animals studied developed peripheral coronary arteriosclerosis, associated with perivascular and myocardial fibrosis, whereas none of the apoE-KO mice did. Transthoracic echocardiography showed a significantly increased left ventricular wall thickness and decreased fractional shortening in DKO animals. Mean arterial pressure was increased in DKO mice and was comparable in degree to eNOS-KO animals. Male DKO animals developed atherosclerotic abdominal aneurysms and aortic dissection. CONCLUSIONS: eNOS deficiency increases atherosclerosis in Western-type diet-fed apoE-KO animals and introduces coronary disease and an array of cardiovascular complications, including spontaneous aortic aneurysm and dissection. This phenotype constitutes the first murine model to demonstrate distal coronary arteriosclerosis associated with evidence of myocardial ischemia, infarction, and heart failure. Hypertrophy and reduced left ventricular function cannot be explained by increased blood pressure alone, because eNOS-KO animals do not develop these complications.

One-year survival following early revascularization for cardiogenic shock.

CONTEXT: Cardiogenic shock (CS) is the leading cause of death for patients hospitalized with acute myocardial infarction (AMI). OBJECTIVE: To assess the effect of early revascularization (ERV) on 1-year survival for patients with AMI complicated by CS. DESIGN: The SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) Trial, an unblinded, randomized controlled trial from April 1993 through November 1998. SETTING: Thirty-six referral centers with angioplasty and cardiac surgery facilities. PATIENTS: Three hundred two patients with AMI and CS due to predominant left ventricular failure who met specified clinical and hemodynamic criteria. INTERVENTIONS: Patients were randomly assigned to an initial medical stabilization (IMS; n = 150) group, which included thrombolysis (63% of patients), intra-aortic balloon counterpulsation (86%), and subsequent revascularization (25%), or to an ERV group (n = 152), which mandated revascularization within 6 hours of randomization and included angioplasty (55%) and coronary artery bypass graft surgery (38%). MAIN OUTCOME MEASURES: All-cause mortality and functional status at 1 year, compared between the ERV and IMS groups. RESULTS: One-year survival was 46.7% for patients in the ERV group compared with 33.6% in the IMS group (absolute difference in survival, 13.2%; 95% confidence interval [CI], 2.2%-24.1%; P<.03; relative risk for death, 0.72; 95% CI, 0.54-0.95). Of the 10 prespecified subgroup analyses, only age (<75 vs >/= 75 years) interacted significantly (P<.03) with treatment in that treatment benefit was apparent only for patients younger than 75 years (51.6% survival in ERV group vs 33.3% in IMS group). Eighty-three percent of 1-year survivors (85% of ERV group and 80% of IMS group) were in New York Heart Association class I or II. CONCLUSIONS: For patients with AMI complicated by CS, ERV resulted in improved 1-year survival. We recommend rapid transfer of patients with AMI complicated by CS, particularly those younger than 75 years, to medical centers capable of providing early angiography and revascularization procedures.

Intracardiac echocardiography: current uses and future directions.

Advances in transducer technology have enabled development of catheter-based ultrasound imaging devices that produce very high resolution images of vessels and cardiac structures. Although the majority of clinical use has been in the evaluation of the coronary and peripheral vasculature, a broad spectrum of cardiac applications continue to develop, including evaluations of the ventricles, valves, and great vessels, as well as the guidance of electrophysiological procedures. Specifically, introduction of the ultrasound catheter into the heart results in dynamic, real-time images for assessment and quantitation of ventricular systolic function, severity of valve stenosis, and extent of regurgitant orifices. The intracardiac applications have the potential to become the gold standard for quantitation of valve dynamics and a critical tool in the ICU for prolonged monitoring of cardiac physiology.

Evidence of reduced resting blood flow in viable myocardial regions with chronic asynergy.

OBJECTIVES: We tested the hypothesis in patients (n = 24) with ischemic heart disease that chronic contractile dysfunction occurs in myocardial regions with true reduction in rest blood flow. BACKGROUND: Whether viable myocardial regions with chronic contractile dysfunction have true reduction in rest myocardial blood flow is controversial. METHODS: Positron emission tomography (PET) 13N-ammonia was used to measure myocardial blood flow in combination with 18F-fluorodeoxyglucose (18FDG) to assess myocardial viability. Viability also was assessed by dobutamine echo and recovery of function after coronary artery bypass grafting (CABG). Segments (n = 252) were selected based on PET measured reduced resting blood flow and rest asynergy on echo. RESULTS: Regional myocardial viability was present in 20 of 23 patients by PET, 13 of 23 by dobutamine echo and 10 of 11 by postrevascularization criteria. Rest blood flow in normal regions was 1.14+/-0.52 ml/min/g and by definition exceeded (p < 0.005) that in both viable (0.48+/-0.15; n = 8 patients) and nonviable (0.45+/-0.14; n = 8 patients) regions (post-CABG criteria), which did not differ. Correction of rest myocardial blood flow in viable asynergic segments, only, for fibrosis and incomplete tracer recovery raised the level to 0.67+/-0.21 (p < 0.005 vs. normal). Finally, evidence of both stunning (rest asynergy with normal flow) and hibernation was present in 15 of 23 (65%) patients. CONCLUSIONS: Reduced rest blood flow in viable myocardial regions with chronic asynergy is common and cannot be accounted for by partial volume effect. Thus, hypotheses concerning physiologic mechanisms underlying chronic contractile dysfunction should consider the role played by chronic reduction of basal myocardial blood flow.

Transmitral Doppler: a new transthoracic contrast method for patent foramen ovale detection and quantification.

OBJECTIVES: This study compared a new transthoracic echocardiographic (TTE) method for detection of right to left bubble passage, transmitral Doppler (TMD), against two-dimensional (2D) TTE contrast study and the gold standard, of transesophageal echocardiography (TEE), and assessed its utility in quantitative assessment of patent foramen ovales (PFO). BACKGROUND: Current TTE methods are relatively insensitive in PFO detection and do not allow quantitative assessment of right to left shunt. METHODS: In 44 patients (59 years, range 34 to 76 years) saline contrast and color Doppler studies were performed in three conditions--TTE TMD, TTE 2D and TEE. Bubble transit on the TMD was measured semiquantitatively by a visual bubble score and objectively by integrating the acoustic power within the mitral velocity envelope. RESULTS: By TEE it was determined that 17 patients (39%) had PFOs; 16 had right to left contrast passage, and only 1 had left to right flow by color Doppler. Against TEE contrast study, the sensitivity of TMD and 2D contrast studies were 100% and 75%, respectively, with specificity of 96% and 100%. Greater than 10 bubbles on a single beat of the resting contrast TMD identified patients with a maximum resting TEE PFO opening diameter >2 mm with 78% sensitivity and 100% specificity. There was a strong correlation (r2 = 0.72, p<0.01) between the TMD acoustic power and PFO opening diameter. CONCLUSIONS: Transmitral Doppler is a sensitive and specific method for TTE PFO detection that allows quantification of right to left bubble passage and may obviate the need for TEE in many patients after stroke.

Congenital deficiency of nitric oxide synthase 2 protects against endotoxin-induced myocardial dysfunction in mice.

BACKGROUND: Sepsis can be complicated by severe myocardial dysfunction and is associated with increased nitric oxide (NO) production by inducible NO synthase (NOS2). To investigate the role of NOS2 in endotoxin-induced myocardial dysfunction in vivo, we studied wild-type and NOS2-deficient mice. METHODS AND RESULTS: Serial echocardiographic parameters of myocardial function were measured before and at 4, 7, 16, and 24 hours after an endotoxin challenge. Seven hours after challenge with either endotoxin or saline, systemic and left ventricular pressures were measured, and the first derivative of left ventricular developed pressure (dP/dt), slope of the end-systolic pressure-dimension relationship (Slope(LVESPD)), and time constant of isovolumic relaxation (tau) were calculated. Endotoxin challenge in wild-type mice decreased left ventricular fractional shortening, velocity of circumferential shortening, dP/dt(max), Slope(LVESPD), and dP/dt(min) and increased time constant tau. Endotoxin-induced myocardial dysfunction was associated with increased ventricular NOS2 gene expression and cGMP concentrations. Seven hours after endotoxin challenge, NOS2-deficient mice had greater fractional shortening, dP/dt(max), and Slope(LVESPD) than did endotoxin-challenged wild-type mice. Measures of diastolic function, dP/dt(min) and time constant tau, were preserved in endotoxin-challenged NOS2-deficient mice. After endotoxin challenge in wild-type mice, early (3-hour) inhibition of NOS2 with L-N:(6)-(1-iminoethyl)lysine hydrochloride prevented, whereas later (7-hour) inhibition could not reverse, endotoxin-induced myocardial dysfunction. CONCLUSIONS: These results suggest that NOS2 is required for the development of systolic and diastolic dysfunction in murine sepsis.

Echocardiographic determinants of left ventricular ejection fraction after acute myocardial infarction.

OBJECTIVE: This study was performed to determine if factors other than the size of regional dysfunction influence the global left ventricular ejection fraction after acute myocardial infarction. BACKGROUND: Left ventricular ejection fraction is an important prognostic variable after acute myocardial infarction. Although infarct size is known to affect the subsequent global left ventricular ejection fraction, it remains unclear whether other factors such as site or severity of the wall motion abnormality influence the ejection fraction after acute myocardial infarction. METHODS: Sixty-nine consecutive patients (mean age 61 +/- 14 years, 46 [67%] male) who did not receive thrombolytic therapy or undergo early revascularization were studied by echocardiography 1 week after Q-wave myocardial infarction. The absolute size of the region of abnormal wall motion (AWM) and the percentage of the endocardium involved (%AWM) were quantitated along with the wall motion score. A severity index was then derived as the mean wall motion score within the region of AWM. Site of myocardial infarction was classified as either anterior or inferior from the endocardial map. Left ventricular ejection fraction was measured by Simpson's method with 2 apical views. RESULTS: Twenty-nine (42%) patients had anterior and 40 had inferior myocardial infarction. The mean left ventricular ejection fraction was significantly lower in anterior than in inferior myocardial infarction (44.8% +/- 11.5% vs 53% +/- 8.6%; P =. 001). The mean %AWM was greater in anterior than in inferior myocardial infarction (32.1 +/- 15.5 vs 22.4 +/- 14.1; P =.01). The mean wall motion score was greater in anterior than in inferior myocardial infarction (9.8 +/- 6.4 vs 6.4 +/- 4.4; P =.01). The mean severity index did not differ by site. Multiple regression analysis demonstrated that, in descending order of importance, %AWM, extent of apical involvement, and site of myocardial infarction were independent determinants of global left ventricular ejection fraction. CONCLUSIONS: For myocardial infarctions of similar size, left ventricular ejection fraction is lower when apical involvement is extensive and the site of infarction is anterior. This site-dependent difference may be related to characteristics specific to the apex.

Regional patterns of left ventricular systolic dysfunction after subarachnoid hemorrhage: evidence for neurally mediated cardiac injury.

Although left ventricular (LV) dysfunction has been described after subarachnoid hemorrhage (SAH), its pathophysiology, regional distribution, and reversibility remain uncertain. To test the hypothesis that regional wall motion patterns in SAH patients do not match the typical patterns observed in coronary artery disease, a segmental wall motion analysis was performed in 30 SAH patients with LV dysfunction. Both regional (n = 21) and global (n = 9) wall motion patterns were observed. Preservation of apical function relative to the base was observed in 17 (57%) of the 30 patients. Many of the wall motion patterns were atypical of coronary artery disease but correlated with the distribution of the myocardial sympathetic nerve terminals. Five subjects had follow-up echocardiograms with resolution of LV dysfunction in all cases. In conclusion, a previously unreported, apex-sparing pattern of LV dysfunction is described, providing indirect evidence for a neurally mediated mechanism of cardiac injury. Limited data indicate that LV dysfunction in SAH patients is potentially reversible.

Regional myocardial perfusion after experimental subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The pathophysiology of cardiac injury after subarachnoid hemorrhage (SAH) remains controversial. Data from animal models suggest that catecholamine-mediated injury is the most likely cause of cardiac injury after SAH. However, researchers also have proposed myocardial ischemia to be the underlying cause, as a result of coronary artery disease, coronary artery spasm, or hypertension and tachycardia. To test the hypothesis that SAH-induced cardiac injury occurs in the absence of myocardial hypoperfusion, we developed an experimental canine model that reproduces the clinical and pathological cardiac lesions of SAH and defines the epicardial and microvascular coronary circulation. METHODS: Serial ECG, hemodynamic measurements, coronary angiography, regional myocardial blood flow measurements by radiolabeled microspheres, 2D echocardiography, and myocardial contrast echocardiography were performed in 9 dogs with experimental SAH and 5 controls. RESULTS: Regional wall motion abnormalities were identified in 8 of 9 SAH dogs and 1 of 5 controls (Fisher's Exact Test, P=0.02) but no evidence was seen of coronary artery disease or spasm by coronary angiography and of significant myocardial hypoperfusion by either regional myocardial blood flow or myocardial contrast echocardiography. CONCLUSIONS: In this experimental model of SAH, a unique form of regional left ventricular dysfunction occurs in the absence of myocardial hypoperfusion. Future studies are justified to determine the cause of cardiac injury after SAH.

Myocardial perfusion and wall motion in infarction border zone: assessment by myocardial contrast echocardiography.

Several mechanisms have been proposed to explain the decreased wall motion (WM) at the borders of myocardial infarction (MI). We used myocardial contrast echocardiography (MCE) to investigate the relation of perfusion to WM in infarcted border zones (BZs) 6 weeks after MI in 5 sheep. After quantifying the extent of WM abnormality and the perfusion defect, normal (NL), infarcted, and BZs were defined. Peak intensity after contrast was measured in acoustic units (AU). Radiolabeled microspheres were injected to measure regional blood flow. The heart was stained with 2,3, 5-triphenyltetrazolium chloride (TTC). The perfusion defect on MCE was 33% +/- 7% of the total myocardial area and correlated well with TTC (r = 0.92, P <.03). The BZ was 8% +/- 5% of the total myocardial area. Peak intensity after contrast was decreased in MI compared with BZ and NL (MI: 2.5 +/- 1.9 AU, BZ: 8.0 +/- 3.8 AU, P <.005; NL: 10.2 +/- 6.9 AU, P <.02) and comparable in NL and BZ. The blood flow measured by microspheres was not different in NL and BZ but was decreased in MI (NL: 1.6 mL/g/min, BZ: 1.5 +/- 0.5 mL/g/min, MI: 0.7 +/- 0.5 mL/g/min; P <.0001). In this model of chronic ovine MI, the BZ was small and its perfusion was preserved. These findings support the hypothesis that tethering of normal myocardial segments explains the abnormal wall motion noted at the borders of MI.

The echocardiographic diagnosis, characterization, and extraction guidance of cardiac foreign bodies.

Echocardiography is ideal for localizing cardiac foreign bodies and for characterizing associated cardiac and vascular injury before and during extraction. We report 5 cases of traumatic and iatrogenic cardiac foreign bodies that illustrate the central role of transthoracic and transesophageal ultrasonography in the management of these patients.

Transesophageal echocardiographic (TEE) evaluation of the mitral and tricuspid valves.

In skilled hands, multiplane TEE provides a comprehensive assessment of the anatomy and function of the mitral and tricuspid valves. TEE is uniquely effective in the evaluation of the diverse pathophysiologic processes that cause valvular heart disease.

Moderate-high intensity exercise training after myocardial infarction: effect on left ventricular remodeling.

BACKGROUND: Regular exercise increases exercise capacity and physical fitness, but questions remain about the effects of exercise on left ventricle (LV) remodeling after myocardial infarction. This study investigated the effects of moderate to high intensity exercise training on LV remodeling after a first myocardial infarction. METHODS: An exercise group of 68 patients in cardiac rehabilitation after a first myocardial infarction had an initial echocardiogram and exercise stress test. Thirty patients completed the 12 weeks of training and had echocardiograms suitable for quantitative analysis. Follow-up echocardiograms and exercise tests were performed. A carefully matched control group of 30 patients with echocardiograms at fixed intervals after myocardial infarction and no formal exercise training were also studied. LV size was expressed as the endocardial surface area-to-body surface area (ESAi), whereas infarct size was characterized by the percent abnormal wall motion (%AWM) by echocardiography using an endocardial surface area mapping technique. Indices of LV shape (sphericity) were also assessed. RESULTS: In the exercise group, no significant changes were seen in ESAi (57.95 +/- 13.1 vs 57.80 +/- 12.04 cm2/m2) or in %AWM (19.33 +/- 15.27 vs 20.11 +/- 15.95) from the initial to the final echo. The indices of sphericity were also unchanged. None of these parameters changed in the control group. Within each group was found heterogeneity in LV remodeling. Multivariate regression analysis revealed initial ESAi and initial %AWM to predict change in ESAi over time. CONCLUSIONS: In this study of patients with predominately small infarcts, exercise training did not adversely affect LV remodeling after myocardial infarction. Remodeling is heterogeneous and appears related to infarct and LV size.