CLINICAL STUDY: HYPERTENSION
Myocardial cell damage in human hypertension
Guillem Pons-Lladó, MD*,
Manel Ballester, MD*,
Xavier Borrás, MD*,
Francesc Carreras, MD*,
Ignasi Carrió, MD ,
Joaquín López-Contreras, MD ,
Alex Roca-Cusachs, MD,
Jaume Marrugat, MD and
Jagat Narula, MD, PhD||
* Servei de Cardiologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Servei de Medicina Nuclear, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Unitat d’Hipertensió del Servei de Medicina Interna, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Institut Municipal d’Investigació Mèdica, Barcelona, Spain
|| Division of Cardiology, Allegheny University Hospitals, Philadelphia, Pennsylvania, USA
Manuscript received October 14, 1999;
revised manuscript received June 5, 2000,
accepted July 14, 2000.
Reprint requests and correspondence: Dr. G. Pons-Lladó, Secció de Imatge Cardiaca, Servei de Cardiologia, Hospital de la Santa Creu i Sant Pau, Sant Antoni M. Claret 167, 08025-Barcelona, Spain
gponsl{at}meditex.es
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Abstract
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OBJECTIVES
The goal of this study was to investigate the presence of myocardial cell damage in patients with systemic hypertension and its relationship with left ventricular hypertrophy (LVH).
BACKGROUND
Although initially compensatory, LVH adversely affects myocellular integrity and contributes to congestive heart failure in hypertensive patients. Noninvasive detection of myocardial damage can be of value.
METHODS
We performed imaging studies with 111In-labeled monoclonal antimyosin antibodies to identify myocardial damage in 39 patients with systemic hypertension and variable degrees of LVH. Three groups were considered: 16 asymptomatic patients with normal echocardiographic left ventricular mass (LVM) (group I); 14 asymptomatic patients with LVH (group II) and 9 patients with symptomatic hypertensive heart disease and advanced LVH (group III). The severity of myocardial damage was represented as heart-to-lung (target-to-background) antibody uptake ratio (normal: <1.55).
RESULTS
Mean LVM index was 105 ± 14 g/m2 in group I, 124 ± 24 in group II and 174 ± 29 in group III. Heart-to-lung ratios of antimyosin uptake were: 1.45 ± 0.14 in group I, 4 of the 16 (25%) patients showing an abnormal scan; 1.50 ± 0.07 in group II with abnormal scans in 2 of the 14 (16%) patients and 1.77 ± 0.16 (p < 0.001) in group III, all 9 patients presenting with abnormal antimyosin scans. On multivariate regression analysis LVM index was the main variable that independently correlated with the degree of myocardial uptake of antimyosin (r = 0.815; p = 0.001).
CONCLUSIONS
This study provides the first in vivo evidence of myocyte damage in patients with hypertension. The severity of myocardial damage can be related to the magnitude of LVH.
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Abbreviations and Acronyms
| | ACE | = angiotensin-converting enzyme | | HLR | = heart-to-lung ratio (of antimyosin uptake) | | LVH | = left ventricular hypertrophy | | LVM | = left ventricular mass |
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Hypertension is one of the most important risk factors for left ventricular hypertrophy (LVH) and congestive heart failure (1–3). Increasing levels of systolic blood pressure have been reported to be associated with progressively increasing echocardiographic left ventricular mass (LVM) (4,5). Although LVH may be associated with supernormal ventricular ejection phase indexes (6), both exercise-induced depression in systolic function (7,8) and a depressed midwall fractional shortening/end-systolic stress relationship (9) in a large proportion of patients with hypertension suggest that LVH may actually result in systolic dysfunction. It is logical to assume that a loss of cardiomyocytes should precede deterioration in myocardial systolic function. Myocyte loss occurs late in the natural history of hypertension and has been demonstrated to correlate with the degree of LVH in necropsy specimens (10,11).
The role of myocardial damage in the progression of LVH to heart failure in hypertensive patients has not been specifically evaluated. This study was designed to determine the prevalence and severity of myocardial damage of patients with hypertension by means of noninvasive imaging with antimyosin antibody radiolabeled with indium-111. The antimyosin antibody directed specifically against cardiac myosin only accumulates in the necrotic myocytes that have lost the sarcolemmal integrity, thereby exposing intracellular myosin to extracellular milieu (12–14). This method has been extensively used in the detection of diffuse myocardial damage in several cardiac conditions (15–22).
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Methods
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Patients.
Thirty-nine patients, 14 men and 25 women, mean age of 55 ± 11 years, with varying degrees of systemic hypertension were included in this study. Of them, 30 consecutive asymptomatic patients were recruited from the outpatient clinic of the Hypertension Unit. All patients had documented primary hypertension of variable degrees and were being followed-up and treated by the Hypertension Unit staff for at least one year. While 16 of these 30 patients (group I) had normal echocardiograms, 14 patients (group II) demonstrated echocardiographic evidence of LVH. The diagnosis of LVH was entertained when the indexed LVM exceeded the upper normal limits in our laboratory (>123 g/m2 in men and >109 g/m2 in women), applying the echocardiographic methods detailed below. None of the patients had any clinical or investigative evidence of secondary hypertension. Regarding other coronary risk factors, 6 of 30 were past smokers, 8 had high total cholesterol blood levels under treatment, and none were diabetics. Coronary artery disease was deemed unlikely in these 30 patients due to a lack of history of chest pain in 24 and in 6 who related symptoms consistent with angina because either coronary angiography (2 cases) or myocardial perfusion scintigraphy (4 cases) was normal. Hypertension was adequately controlled in all patients at the time of the study: 6 were receiving a beta-adrenergic blocking agent alone, 11 were on calcium channel blockers, and the remaining 13 patients received a combined therapy including these drugs and, in some cases, thiazide diuretics.
The remaining 9 of the 39 patients (group III) had a history of long-term hypertension and were admitted to the hospital either for evaluation of chest pain (3 patients) or heart failure (6 patients); coronary arteries were angiographically normal in these 9 patients, and none had valvular or congenital heart disease to account for the clinical manifestations. None of the patients had a history of alcohol abuse or consumed potentially cardiotoxic drugs. Hypertension was found to be poorly controlled in all nine patients at the time of hospital admission. All of these nine patients were receiving a combination therapy including two or more of the following: diuretics, digoxin, calcium channel blockers, nitrates and vasodilators other than angiotensin-converting enzyme (ACE) inhibitors.
Antimyosin imaging was performed in all patients for the detection and assessment of the severity of myocardial damage. The protocol of this study was approved by the institutional ethics committee and research review board. All patients voluntarily agreed to participate in the study and signed a consent form before antimyosin imaging.
Echocardiography and cardiac catheterization.
Two-dimensional echocardiography guided M-mode tracings were obtained, and left ventricular chamber dimensions (both systolic and diastolic) and wall thickness (septal and posterior) were measured with a pair of electronic calipers in accordance with the recommendations of the American Society of Echocardiography (23). From these measurements, LVM and ejection fraction were calculated as described elsewhere (24,25). Coronary angiography was performed for patients who were admitted to the hospital (group III) in order to rule out coronary artery disease as the cause of chest pain or congestive heart failure.
Antimyosin imaging and quantitative analysis of antibody uptake.
Commercially available antimyosin antibody, R11D10-Fab-DTPA (500 µg) (Centocor, Leiden, Netherlands) was labeled with 2 mCi of indium-111 before intravenous administration to all patients. Planar images were obtained 48 h later with a large field-of-view gamma camera equipped with a medium energy collimator. Pulse height analyzers were set at the center lines of 173 and 247 keV with a 20% window for each peak. The images were obtained in the anterior and 60 to 70° left anterior oblique views for a minimum of 500,000 counts between 5 to 10 min and stored in a dedicated computer for subsequent analysis. Interpretation of antimyosin studies was performed by an independent observer who was blinded to the clinical and echocardiographic findings. Quantitative uptake was determined by calculating heart-to-lung count density ratio (HLR) of antimyosin uptake obtained from dividing average counts per pixel in the cardiac region of interest by average counts per pixel in area of interest set at right lung. Heart-to-lung count density ratio of antimyosin uptake up to 1.55 was considered to be normal; this limit was established as 2 standard deviations higher than the mean HLR observed in a series of normal individuals studied at our laboratory and as reported previously (15).
Statistical analysis.
All results were expressed in mean ± standard deviation. Analysis of variance was performed for the comparison of continuous clinical, echocardiographic and scintigraphic variables, followed by Newman Keul’s multiple range test for the assessment of pairwise significance. Correlation coefficient was estimated between antimyosin uptake and all continuous variables and between LVH and potential confounders of the former relationship. Of the variables that correlated because they intervened in equations leading to third calculated variables, those with the best correlation coefficient were used. Changes in correlation coefficients were assessed by 95% confidence interval. Multiple linear regression analysis was performed to assess the effect of LVH on the degree of antimyosin uptake adjusting for potentially confounding factors. Confounding variables were selected from the table of bivariate correlation coefficients between antimyosin uptake and continuous variables, which showed a p value lower than 0.10. Variables necessary to calculate LVM index and ejection fraction were disregarded. Chi-square or Fisher exact test, as appropriate, was applied for categorical variables.
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Results
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Clinical and echocardiographic characteristics (Table 1).
The mean age and body surface area of patients in the three groups were similar. Patients in groups I (hypertensive patients without LVH) and II (hypertensive patients with LVH) showed adequately controlled systolic and diastolic blood pressure levels; hypertension was poorly controlled in group III patients (hypertensive patients with LVH). Patients in groups I and II were asymptomatic. Of the nine patients of group III, three were in New York Heart Association functional class II, two in functional class III, and the remaining four were in New York Heart Association class IV.
Group I patients had normal echocardiograms with normal septal and posterior left ventricular wall thickness, end-diastolic and end-systolic diameter, ejection fraction and LVM index. Group II patients had normal left ventricular size and ejection fraction but showed significantly increased septal and posterior wall thickness and, consequently, increased LVM index. Group III patients showed significantly increased left ventricular cavity dimensions and septal and posterior wall thickness as well as LVM index; ejection fraction was lower compared with groups I and II (p < 0.0001).
Evaluation of myocardial damage (Table 1).
Abnormal antimyosin scans were observed in 4 of the 16 patients of group I (25%) and in 2 of the 14 patients (15%) of group II. All nine patients (100%) of group III demonstrated an abnormal antimyosin scan. The HLR in group III (1.77 ± 0.16) was significantly higher than it was in groups I and II (1.45 ± 0.14 and 1.50 ± 0.07, respectively). The abnormal antimyosin scans always demonstrated a diffuse pattern of myocardial uptake of antimyosin antibody.
Correlation coefficients were calculated to evaluate possible clinical and echocardiographic variables associated with myocardial uptake of antimyosin (Table 2). Left ventricular cavity dimensions and posterior wall thickness showed correlation coefficients higher than 0.5, while an inverse correlation with ejection fraction was found (r = –0.68) (Fig. 1); the indexed LVM demonstrated the highest correlation coefficient (r = 0.72), which increased to 0.81 when only patients with left ventricular hypertrophy (groups II and III) were considered. The relationship between LVM index and HLR of antimyosin uptake is shown in Figure 2.
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Figure 1 The correlation between left ventricular ejection fraction and the severity of myocardial damage detected by antimyosin antibody heart-to-lung uptake ratio in those 36 patients in whom reliable measures of ejection fraction by echocardiography were obtained. The area below the horizontal line represents normal range of antimyosin antibody heart-to-lung uptake ratio (<1.55). LV = left ventricular.
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Figure 2 The correlation between the indexed LVM and the severity of myocardial damage detected by antimyosin antibody heart-to-lung uptake ratio in the 39 hypertensive patients. The area below the horizontal line represents the normal range of antimyosin antibody heart-to-lung uptake ratio (<1.55). There was a significant positive correlation between LVM index and the HLR (r = 0.72). Open squares = patients in group I (no LVH), solid squares = patients in group II (asymptomatic patients with LVH) and solid circles = patients in group III (symptomatic patients). HLR = heart-to-lung ratio; LV = left ventricle; LVH = left ventricular hypertrophy; LVM = left ventricular mass.
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The adjusted correlation coefficient obtained in multiple linear regression analysis was 0.81, predominantly due to LVM index. Residual correlation coefficients of left ventricular ejection fraction, age and systolic blood pressure were not statistically significant in the stepwise analysis and made minor contributions to the equation (Table 3).
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Discussion
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Antimyosin studies in the assessment of myocardial cell damage.
This study constitutes the first in vivo evidence of diffuse myocardial damage in hypertensive patients. The method employed, the myocardial uptake of indium-111 labeled monoclonal antimyosin antibodies, provides the only available means to detect noninvasive myocardial cell necrosis (12–14). Conceptually, uptake of antimyosin antibodies implies that, at the time of the study, an ongoing myocardial necrosis is taking place (18). In clinical studies myocardial uptake has been equated with the presence of biopsy-proven myocardial damage (17,21); the intensity of such uptake correlates with the degree of damage (26), and patients with very intense uptake show adverse clinical outcomes, as reported in myocarditis (15,16), cardiac rejection after transplantation (17), chronic dilated cardiomyopathy (18,19), alcohol induced heart disease (20) and cardiotoxicity associated with anthracycline (21) or tricyclic antidepressant drugs (22).
Cardiomyopathy of overload.
The loss of cardiomyocytes herein reported in patients with hypertension is consistent with the elegant observations made by Meerson (27) who showed in an experimental model of pressure overload the induction of a process of compensatory myocardial hypertrophy associated with myocyte damage. Loss of myocytes further enhances the overload leading to progressive heart failure (28), recent evidence suggesting that the transition from a state of compensation to myocardial failure is related to both cardiomyocyte loss (29) and alterations in the metabolism of extracellular matrix (30). Occurrence of myocardial cell death with long-standing myocardial hypertrophy has been termed cardiomyopathy of overload (31–33).
LVH and myocardial cell damage.
Evidence of myocyte damage in this study was observed in a small proportion of ambulatory patients (groups I and II) who had either none or only mild degrees of LVH. On the other hand, all patients with advanced hypertensive heart disease (group III) showed evidence of such damage. Although LVM strongly correlated with the severity of myocardial damage (Fig. 2), the role of hypertrophy in relation to myocardial damage must be considered with caution. First, there was no difference in the prevalence of antimyosin uptake between asymptomatic ambulatory patients without (group I) and with (group II) left ventricular hypertrophy (25% vs. 15%). Second, the presence of myocardial damage in 4 of 16 patients without hypertrophy (group I) raises the issue of the relationship of such damage with the mere presence of hypertrophy. For patients in group III admitted to the hospital as a result of advanced hypertensive heart disease, very high left ventricular mass values were detected, and myocardial damage was 100% prevalent. The unstable clinical situation of these patients as a group could raise the argument that positive antimyosin scans are due to a persistence of high blood activity of antimyosin in those patients with markedly reduced left ventricular function, as data from Figure 1 could suggest. We did not measure blood clearance of 111In-labeled antimyosin antibodies from serial blood samples in our patients. Pharmacokinetics of antimyosin antibodies was investigated in early studies (34), showing that mean half-life of antimyosin was 5 h and that a negligible proportion of the initial blood activity was present in samples drawn at 48 h, a time when imaging could be done without risk of a false positive—or negative—myocardial scan. In addition, observations from our own group (15) indicate that in images obtained at 48 h from the injection, the intensity of uptake is not higher than that observed for imaging at 72 h, both in normal individuals and in patients with depressed left ventricular function. This result suggests that a plateau of minimal blood pool activity had already been reached at 48 h. Our previous observation that heart failure per se does not lead to abnormally high antimyosin uptake provided that a process of ongoing myocardial cell loss is not present (18) also speaks against the occurrence of false positive studies in patients with heart failure. Finally, it has to be considered that some of the patients in group III (three out of nine) who also exhibited abnormally high HLR, were not hemodynamically unstable.
Mechanisms of myocardial cell death.
The mechanisms leading to the death of myocytes in LVH are not well understood. Augmented LVM and systolic pressure significantly increase intramyocardial tension and myocardial oxygen demand, which are not accompanied by a proportional increase in vascular density per unit area of hypertrophied myocardium. The discordance between oxygen demand and supply is likely to result in relative myocardial ischemia and myocellular death by necrosis (35–37). Recently, it has been proposed that apoptosis, or programmed cell death, may also contribute to myocardial damage in hypertrophic hearts (29,32,38,39). Apoptosis is a form of cell death distinct from myocyte necrosis that does not result in an inflammatory response (40). Apoptosis in terminally differentiated cells such as cardiomyocytes may result from an unnatural growth response where protein synthesis is augmented but the cell division cannot be induced (32). In hypertension, hemodynamic load to myocytes via stretch receptors (41) or integrin-mediated (42) mechanisms and paracrine or autocrine stimulation of various neurohumoral receptors (43–45) including angiotensin are likely to initiate the cascade of compensatory ventricular hypertrophy. It is also possible that repetitive ischemia not sufficient to result in necrosis may induce apoptosis (39). However, despite the established evidence of the role of apoptosis in the transition from stable compensation to failure in the animal model (46), this mechanism has not been shown in humans to date (47). Although apparently contradictory, the finding of positive antimyosine scans (which require a disrupted sarcolemma) in hearts with apoptosis, a process in which membrane integrity is preserved, has been observed by our group in a series of patients with heart transplant and allograft rejection (48).
Clinical implications.
The clinical implications of the observations presented here are important. First, our study suggests that, at a certain stage or in certain individuals with hypertensive heart disease, ongoing myocellular loss is present. This could explain the progressive nature of the disease and the clinical and epidemiological observations that hypertension is an important cause of heart failure (1–3). Second, the evidence of myocardial damage for patients with apparently well controlled blood pressure raises the issue of adequacy of management of hypertension guided by the mere control of blood pressure. If progressive loss of myocytes determines the development of cardiomyopathy, then the optimum treatment of hypertension should consider the alleviation or suppression of myocyte damage in addition to the control of blood pressure.
In spontaneously hypertensive rats ACE tissue levels correlate with the presence and degree of myocyte apoptosis, which can be prevented by treatment with ACE inhibitors (49). In the clinical context it remains to be seen whether pharmacologic agents such as ACE inhibitors (50,51) or newer generations of beta-blockers (52,53) could interfere with the mechanisms leading to myocardial cell death.
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Footnotes
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Supported by a grant from the Fondo de Investigación Sanitaria (92/0706), Ministerio de Sanidad y Consumo, Spain.
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Abstract
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