Christopher G.A. McGregor

Endothelin in human congestive heart failure

BACKGROUND Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction. METHODS AND RESULTS The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts. CONCLUSIONS The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF.

Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary validation in humans.

Background— Diffuse myocardial fibrosis is a final end point in most cardiac diseases. It is missed by the cardiovascular magnetic resonance (CMR) late gadolinium enhancement technique. Currently, quantifying diffuse myocardial fibrosis requires invasive biopsy, with inherent risk and sampling error. We have developed a robust and noninvasive technique, equilibrium contrast CMR (EQ–CMR) to quantify diffuse fibrosis and have validated it against the current gold standard of surgical myocardial biopsy. Methods and Results— The 3 principles of EQ–CMR are a bolus of extracellular gadolinium contrast followed by continuous infusion to achieve equilibrium; a blood sample to measure blood volume of distribution (1−hematocrit); and CMR to measure pre- and postequilibrium T1 (with heart rate correction). The myocardial volume of distribution is calculated, reflecting diffuse myocardial fibrosis. Clinical validation occurred in patients undergoing aortic valve replacement for aortic stenosis or myectomy in hypertrophic cardiomyopathy (n=18 and n=8, respectively). Surgical biopsies were analyzed for picrosirius red fibrosis quantification on histology. The mean histological fibrosis was 20.5±11% in aortic stenosis and 17.1±7.4% in hypertrophic cardiomyopathy. EQ–CMR correlated strongly with biopsy histological fibrosis: aortic stenosis, r2=0.86, Kendall Tau coefficient (T)=0.71, P<0.001; hypertrophic cardiomyopathy, r2=0.62, T=0.52, P=0.08; combined r2=0.80, T=0.67, P<0.001. Conclusions— We have developed and validated a new technique, EQ–CMR, to measure diffuse myocardial fibrosis as an add-on to a standard CMR scan, which allows for the noninvasive quantification of the diffuse fibrosis burden in myocardial diseases.

Serum Cardiac Troponins and N-Terminal Pro-Brain Natriuretic Peptide: A Staging System for Primary Systemic Amyloidosis

PURPOSE Primary systemic amyloidosis (AL) is a multisystemic disorder resulting from an underlying plasma cell dyscrasia. There is no formal staging system for AL, making comparisons between studies and treatment centers difficult. Our group previously identified elevated serum cardiac troponin T (cTnT) as the most powerful predictor of overall survival. Others have reported that N-terminal pro-brain natriuretic peptide (NT-proBNP) is a valuable prognostic marker. We sought to develop a staging system for patients with AL. PATIENTS AND METHODS Two hundred forty-two patients with newly diagnosed AL who were seen at the Mayo Clinic between April 1979 and November 2000, and who had echocardiograms and stored serum samples at presentation were eligible for this retrospective review. NT-proBNP measurements were performed on 242 patients in whom cTnT and cardiac troponin I (cTnI) had been previously run. Two prognostic models were designed using threshold values of NT-proBNP and either cTnT or cTnI (NT-proBNP < 332 ng/L, cTnT < 0.035 microg/L, and cTnI < 0.1 microg/L). Depending on whether NT-proBNP and troponin levels were both low, were high for only one level, or were both high, patients were classified as stage I, II, or III, respectively. RESULTS Using the cTnT+NT-proBNP model 33%, 30%, and 37% of patients were stages I, II, and III, respectively, with median survivals of 26.4, 10.5, and 3.5 months, respectively. The alternate cTnI+NT-proBNP model predicted median survivals of 27.2, 11.1, and 4.1 months, respectively. CONCLUSION Stratification of AL patients into three stages is possible with two readily available and reproducible tests setting the stage for more consistent and reliable cross comparisons of therapeutic outcomes.

Natriuretic peptide system in human heart failure.

BACKGROUND Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are a family of structurally related peptides that participate in the integrated control of renal and cardiovascular function. Previous studies suggest a functional role for these hormonal peptides in cardiorenal regulation in congestive heart failure (CHF). METHODS AND RESULTS The present studies were performed in normal subjects (n = 6) and in patients with mild (New York Heart Association [NYHA] class I to II, n = 20) and severe (NYHA class III to IV, n = 20) CHF by use of radioimmunoassay and immunohistochemical staining (IHCS). Plasma ANP was significantly increased in both mild and severe CHF compared with normal subjects. In contrast, plasma BNP was only moderately increased in the severe CHF group, and plasma CNP concentration was unchanged in CHF compared with normal subjects. Atrial tissue concentrations of the natriuretic peptides did not parallel circulating concentrations. ANP predominated in normal atrial tissue, but BNP predominated in CHF. In ventricular tissue, IHCS staining was present for all three peptides in normal ventricular myocardium and was markedly enhanced in CHF. CONCLUSIONS These studies support a differential regulation of ANP, BNP, and CNP circulating concentrations and tissue activity in human CHF.

Pathology of Surgically Excised Primary Cardiac Tumors

Between 1957 and March 1991, 106 patients with 110 neoplasms that originated in the heart were treated surgically at the Mayo Clinic and had pathologic material available for review. The study group consisted of 39 male and 67 female patients, who ranged in age from 2 to 80 years. Benign atrial myxomas (64 in the left atrium and 16 in the right atrium) were the most commonly encountered neoplasm. The other benign tumors were nine fibromas, five lipomatous tumors, seven valvular fibroelastic papillomas, and one cardiac hamartoma (so-called oncocytic cardiomyopathy). In addition, eight patients had a primary cardiac malignant lesion: angiosarcoma, leiomyosarcoma, and malignant fibrous histiocytoma in two patients each and sarcoma (not otherwise specified) and osteogenic sarcoma in one patient each. The angiosarcomas originated in the right atrium, and the other malignant tumors originated in the left atrium. The histologic feature that most frequently predicted an adverse clinical outcome was the presence of mitotic figures, although highly cellular tumors and those with necrosis also tended to have a malignant course.

Predictive Power of the Relative Lymphocyte Concentration in Patients With Advanced Heart Failure

BACKGROUND The physiological stress suffered by patients with heart failure results in an increased production of cortisol and a shift in the leukocyte differential toward a decreased percentage of lymphocytes (%L). The purpose of this study was to determine the prognostic significance of a low %L in advanced heart failure. METHODS AND RESULTS Patients evaluated in our cardiac transplantation clinic between April 1988 and July 1995 were retrospectively reviewed (n=263). Fifty-two patients were excluded because they had recent trauma, infection, surgery, myocardial infarction, corticosteroid use, or history of malignancy. In the remaining 211 patients, we used Cox proportional hazards analysis to examine the association between survival and transplant-free survival with baseline variables. Univariate analysis showed a significant association between time to death and %L (P=.004), New York Heart Association (NYHA) class (P=.002), and maximal oxygen uptake (P=.05). Univariate analysis of the end point of survival free from transplantation yielded similar results. One- and 4-year survival rates for patients with a low %L (<20.3%) were 78% and 34% compared with 90% and 73% for those with a normal %L. Multivariate analysis showed NYHA class (P<.008) and %L (P<.01) were independent predictors of survival and survival free from cardiac transplantation. CONCLUSIONS The relative lymphocyte concentration is an inexpensive, readily available, simple prognostic marker in patients with symptomatic heart failure who do not have recent trauma, infection, surgery, myocardial infarction, corticosteroid use, or history of malignancy. It could be incorporated into clinical models to predict patient outcome and to aid in the selection of patients for cardiac transplantation.

Transesophageal echocardiography in critically III patients

The feasibility, safety and clinical impact of transesophageal echocardiography were evaluated in 51 critically ill intensive care unit patients (28 men and 23 women; mean age 63 years) in whom transthoracic echocardiography was inadequate. At the time of transesophageal echocardiography, 30 patients (59%) were being mechanically ventilated. Transesophageal echocardiography was performed without significant complications in 49 patients (96%), and 2 patients with heart failure had worsening of hemodynamic and respiratory difficulties after insertion of the transesophageal probe. The most frequent indication, in 25 patients (49%), was unexplained hemodynamic instability. Other indications included evaluation of mitral regurgitation severity, prosthetic valvular dysfunction, endocarditis, aortic dissection and potential donor heart. In 30 patients (59%), transesophageal echocardiography identified cardiovascular problems that could not be clearly diagnosed by transthoracic echocardiography. In the remaining patients, transesophageal echocardiography permitted confident exclusion of suspected abnormalities because of its superior imaging qualities. Cardiac surgery was prompted by transesophageal echocardiographic findings in 12 patients (24%) and these findings were confirmed at operation in all. Therefore, transesophageal echocardiography can be safely performed and has a definite role in the diagnosis and expeditious management of critically ill cardiovascular patients.

Myocardial dysfunction associated with brain death: clinical, echocardiographic, and pathologic features

BACKGROUND The sequelae of severe brain injury include myocardial dysfunction. We sought to describe the prevalence and characteristics of myocardial dysfunction seen in the context of brain-injury-related brain death and to compare these abnormalities with myocardial pathologic changes. METHODS We examined the clinical course, electrocardiograms, head computed tomography scans, and echocardiographic data of 66 consecutive patients with brain death who were evaluated as heart donors. In a sub-group of patients, we compared echocardiographic findings with pathologic findings. RESULTS Echocardiographic systolic myocardial dysfunction was present in 28 (42%) of 66 patients and was not predicted by clinical, electrocardiographic, or head computed tomographic scan characteristics. Ventricular arrhythmias were more common in the patients with, compared to those without, myocardial dysfunction (32% vs 0%; p < 0.001). Myocardial dysfunction was segmental in all 8 patients with spontaneous subarachnoid or intracerebral hemorrhage. In these patients, the left ventricular apex was often spared. Myocardial dysfunction was either segmental or global in 17 patients who suffered head trauma and in 3 patients who died of other central nervous system illnesses. In 11 autopsied hearts, we found poor correlation between echocardiographic dysfunction and pathologic findings. CONCLUSIONS Systolic myocardial dysfunction is common after brain-injury-related brain death. After spontaneous subarachnoid or intracerebral hemorrhage, the pattern of dysfunction is segmental, whereas after head trauma, it may be either segmental or global. We found poor correlation between the echocardiographic distribution of dysfunction and light microscopic pathologic findings.

Determinants of survival and recovery of left ventricular function after aortic valve replacement

To determine factors that influence survival and recovery of ventricular function in patients undergoing aortic valve replacement in the current surgical era, baseline risk factors related to outcome were analyzed in 1,012 consecutive patients undergoing aortic valve replacement between 1983 and 1990. Forty-two percent of patients underwent concomitant coronary bypass. Observed survival probabilities (expressed as 30-day/5-year) were 0.97/0.81 overall, 0.99/0.89 for patients aged less than 70 years, and 0.95/0.74 for patients aged 70 years or greater. Advanced age (p < 0.0001), decreased ejection fraction (p < 0.0001), extent of coronary disease (p < 0.006), smaller prosthetic valve (p < 0.03), and advanced New York Heart Association class (p < 0.04) were incremental risk factors for mortality. In patients with preoperative ventricular dysfunction (ejection fraction < or = 0.45), ejection fraction measured 1.4 years after aortic valve replacement improved in 72% and the mean increment in ejection fraction was 0.175 (95% confidence interval, 0.154 to 0.195). The increment in ejection fraction was greater in female patients than in male patients (p < 0.02) and greater in patients without than with coronary disease (p < 0.02). Female sex (p < 0.02) and lesser extent of coronary disease (p < 0.05) were independent predictors of change in ejection fraction. In all patients, early improvement in ejection fraction conveyed an independent subsequent survival benefit (p < 0.0001). The results of aortic valve replacement in the current era are excellent, and the majority of patients with ventricular dysfunction demonstrate significant improvement. Early improvement in ejection fraction, influenced by coexistent coronary artery disease and sex-associated factors, importantly affects subsequent survival.

Endothelial Progenitor Cells Are Decreased in Blood of Cardiac Allograft Patients With Vasculopathy and Endothelial Cells of Noncardiac Origin Are Enriched in Transplant Atherosclerosis

Background—Recent studies in animals suggest that circulating recipient endothelial precursors may participate in the biology of transplant vasculopathy. It is currently unknown whether a similar interaction between recipient endothelial cells and the vessel wall occurs in human subjects undergoing allogeneic cardiac transplantation. Methods and Results—Circulating endothelial cells and endothelial progenitor cells (EPCs) were quantified in 15 cardiac transplantation subjects with and without angiographic evidence of vasculopathy. In a separate series of experiments, the origin (donor or recipient) of transplant plaque endothelial cells was assessed in subjects who had undergone a gender-mismatched cardiac transplantation and had histological evidence of severe vasculopathy at the time of heart explantation. Circulating EPC outgrowth colonies in peripheral blood were significantly reduced in subjects with transplant vasculopathy compared with those without angiographic evidence of disease (EPC colony-forming units [CFUEPC]: 4.5±1.9 versus 15.1±3.7, P <0.05). There was no significant difference in circulating endothelial cell numbers as defined by day 4 culture acetylated LDL/lectin assay in either of these patient groups. In a separate group of 5 subjects who underwent gender-mismatched cardiac transplantation, there was a significant seeding of recipient endothelial cells (range: 1% to 24% of all luminal endothelial cells) in large-vessel lumen and adventitial microvessel lumen of arteriopathic vessels. No opposite-sex chimeric cells were observed in control gender-matched transplantation scenarios. Conclusions—These data suggest that the human cardiac transplant arteriopathy is associated with reduction in circulating endothelial precursors and with seeding of recipient-derived endothelial cells at the site of plaque development.