Left ventricular diastolic function predicts outcome in uncomplicated hypertension

AJH

2001; 14:504 –508

Original Contributions

Left Ventricular Diastolic Function Predicts Outcome in Uncomplicated Hypertension Robert Fagard and Karel Pardaens Whereas left ventricular systolic function has been shown to predict outcome in hypertensive patients without clinical evidence of heart failure, the prognostic power of diastolic function has not been examined. We assessed the relation of mean pulmonary capillary wedge pressure as an index of left ventricular diastolic function to mortality and the incidence of cardiovascular events in patients with uncomplicated hypertension at baseline. Invasive hemodynamic measurements were performed in the period 1972 to 1982 in 172 hypertensive patients without evidence of cardiovascular disease, cardiomegaly or heart failure, and their outcome was ascertained in 1994. Age at baseline averaged 37 ⫾ 12 years, brachial artery pressure was 162 ⫾ 30/88 ⫾ 18 mm Hg, and mean pulmonary wedge pressure 6.3 ⫾ 3.0 mm Hg. During 2675 patient-years of follow-up, 15 patients died and 34 suffered at least one fatal or nonfatal cardiovascular event. Cox regression analysis showed that pulmonary wedge pressure was a

R

significant predictor of total mortality and of cardiovascular events, after control for age and gender (P ⬍ .05). Each 1 mm Hg increase in wedge pressure was associated with a 23% increase in the risk of all-cause mortality and a 13% increase in the risk of a cardiovascular event. The prognostic power was independent of mean brachial artery pressure, body mass index, serum cholesterol, electrocardiographic left ventricular hypertrophy, and smoking at baseline. We conclude that mean pulmonary wedge pressure, which is likely to reflect left ventricular diastolic function in the selected patients of the current study, is a significant and independent predictor of mortality and of cardiovascular events in uncomplicated hypertension. Am J Hypertens 2001;14:504 –508 © 2001 American Journal of Hypertension, Ltd. Key Words: Cardiovascular events, hypertension, left ventricular diastolic function, mortality, pulmonary wedge pressure.

ecently, it has been shown that depressed midwall left ventricular shortening, an index of impaired left ventricular systolic function, is a predictor of adverse outcome in hypertensive patients without clinical evidence of heart failure.1,2 However, there are no data on the prognostic power of diastolic function in asymptomatic hypertensive patients. Diastolic dysfunction is common in hypertension and may precede any reduction in systolic function,3–5 even when measured at the midwall level.6 Diastolic dysfunction results from both impaired relaxation and altered passive elastic properties of the left ventricle7 and a number of measurements have been proposed to assess various aspects of diastolic function.8 Among these mean pulmonary wedge pressure and left ventricular end-diastolic pressure are considered indexes of left ventricular diastolic stiffness or reduced distensibility, at least in the presence of a normal left ventricular chamber size. In the current study we analyzed the prognostic power of mean pulmonary wedge pressure as an

index of left ventricular filling pressure in hypertensive patients without history, signs, or symptoms of heart failure, without evidence of cardiac enlargement on chest x-ray and with normal cardiac performance. In these patients pulmonary wedge pressure is likely to reflect left ventricular diastolic function, more specifically diastolic stiffness.

Received April 14, 2000. Accepted August 21, 2000. From the Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, Faculty of Medicine, University of Leuven KU Leuven, Leuven, Belgium. This work was partially supported by the Belgian National Research

Council (NFWO, Brussels, Belgium).

0895-7061/01/$20.00 PII S0895-7061(00)01272-3

Methods Study Population The present analysis includes patients who were referred to the Hypertension Unit of the University Hospitals of Leuven between 1972 and 1982, and who underwent a hemodynamic study. In that period routine investigations included history, clinical examination, appropriate laboratory tests, eye–fundus examination, chest x-ray, electrocardiography at rest, exercise testing, pulmonary function tests, intravenous urography, and renal arteriography when

Address correspondence and reprint requests to R. Fagard, MD, PhD, U.Z. Gasthuisberg-Hypertensie, Herestraat 49, B-3000 Leuven, Belgium; e-mail: [email protected] © 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.

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indicated, but not echocardiography. The hemodynamic investigations were performed for research purposes, without specific clinical indication. Patients were excluded when World Health Organization stage III organ damage,9,10 more recently termed associated clinical conditions,11 was present at the time of the investigation. Patients with evidence of ischemic heart disease, heart failure, cerebrovascular accident, claudication, retinal exsudates or hemorrhages, or renal insufficiency were thus excluded. All patients were in sinus rhythm and none had evidence of valvular heart disease, pulmonary disease, or diabetes. Patients had never been treated for high blood pressure or had their antihypertensive medication stopped for at least 2 weeks. Hemodynamic Study All hemodynamic measurements were performed by the same investigators, always in the morning and in the same laboratory, where room temperature was 18° to 22°C, a few days after hospital admission. Patients gave informed consent after the nature of the procedures had been explained. The brachial artery was cannulated to measure intraarterial pressure and to sample arterial blood. A venous catheter (Swan-Ganz, 93.110.5F, Edwards Laboratories, United Kingdom) was introduced in the antecubital vein and positioned in the pulmonary artery to sample mixed venous blood; the catheter was positioned so that pulmonary capillary wedge pressure was measured when the balloon near the tip of the catheter was inflated and pulmonary artery pressure was measured when it was deflated. Pressures were registered on a Mingograph 81 recorder (Siemens Medical, Germany). Uptake of oxygen and carbon dioxide output were measured by the opencircuit method (standard temperature, pressure dry). Minute volume (body temperature, pressure saturated) was determined by a pneumotachograph, and oxygen and carbon dioxide concentrations by a paramagnetic and an infrared gas analyzer, respectively. Cardiac output (in liters per minute) was determined by the direct oxygen Fick method and divided by body surface area (cardiac index in liters per minute per meter square). Heart rate (in beats per minute) was recorded from the electrocardiogram. Stroke volume (in milliliters) and stroke index (in milliliter per meter square) were calculated from cardiac output or index and heart rate. Hemodynamic measurements were performed at supine rest, 30 min after introduction of the catheters. Follow-up After the baseline examination, the patients were referred to their usual source of care. Follow-up was performed in 1989 and 1994.12 Their vital status was determined through contacts with municipal authorities. Causes of death were ascertained from contacts with physicians or family members and from hospital files and autopsy reports if available. The health status of living patients was

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determined through a standardized questionnaire filled in by physicians or, in the absence of a response, through a shorter questionnaire, which could be filled in by the patients; if necessary, patients were contacted by telephone. In addition, the charts of patients followed at the University Hospitals in Leuven were checked for possible cardiovascular events. When such events had occurred, the responsible physicians were contacted and all available documents concerning the events were checked. Events were coded according to the Ninth Revision of the International Classification of Diseases. The following cardiovascular events, known to be associated with hypertension,13 were considered: sudden death, myocardial infarction, cerebrovascular accident, heart failure, newonset angina pectoris, transient ischemic attack, and peripheral vascular disease. Objective evidence was required for acceptance. The vital status of all patients could be determined in 1994. However, two living patients could not be traced, therefore their data from the 1989 survey were used in the present analysis. Statistical Analysis Database management and statistical analysis were performed with the SAS software (SAS Institute Inc., Cary, NC). Data are reported as mean ⫾ SD or median and range. Two categories of end points were considered: 1) all-cause mortality and 2) fatal and nonfatal cardiovascular events combined. In patients with more than one cardiovascular event, only the first event was considered. The Cox proportional hazards regression model was used for survival analysis.14,15 The prognostic value of a variable is given by its relative hazard rate, which estimates how much the incidence of the event changes when the independent variable increases with one unit. Two-sided P values ofⱕ.05 were considered statistically significant.

Results Patient Characteristics Age of the 172 patients averaged 36.7 ⫾ 11.6 years, and body mass index 26.0 ⫾ 3.9 kg/m2; 69% were men. Blood pressure on admission to the hospital averaged 179 ⫾ 31/111 ⫾ 21 mm Hg. Antihypertensive treatment had been interrupted for at least 2 weeks in 71% of the patients, whereas the others had never been treated. Left ventricular hypertrophy, based on electrocardiographic voltages (SV1 ⫹ RV5 ⱖ 3.5 mV or RaVL ⱖ 1.2 mV) was present in 37% of the patients. Serum cholesterol averaged 5.57 ⫾ 1.04 mmol/L and serum creatinine 94 ⫾ 18 ␮mol/L. Most patients did not smoke (63%) at the time of the hemodynamic study. Hemodynamic Data Systolic/diastolic brachial intraarterial pressure averaged 162 ⫾ 30/88 ⫾ 18 mm Hg, mean brachial artery pressure

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Table 1. events

All fatal events and first cardiovascular

Cardiovascular events Sudden death Myocardial infarction Heart failure Cerebral stroke Angina pectoris Peripheral arterial disease Noncardiovascular death

First Cardiovascular Events (n ⴝ 34)

All Fatal Events (n ⴝ 15)

Fatal

Nonfatal

13 5

9 3

25 —

3 1 4 —

2 1 3 —

2 2 5 11

—

—

5

2

116 ⫾ 22 mm Hg, heart rate 80 ⫾ 13 beats/min, stroke volume 93 ⫾ 28 mL, stroke index 50 ⫾ 14 mL/m2, cardiac output 7.33 ⫾ 2.00 L/min, and cardiac index 3.97 ⫾ 1.03 L/min/m2. Mean pulmonary artery pressure averaged 13.3 ⫾ 4.0 mm Hg and mean pulmonary wedge pressure 6.3 ⫾ 3.0 mm Hg; the highest value amounted to 16 mm Hg. Events During Follow-up The follow-up time in individual patients until death or until the date of the last available information on their vital status in 1994 ranged from 0.7 to 21.1 years (median, 16.3 years); the total follow-up time was 2675 patient-years. Thirteen men and 2 women died between 0.7 and 14.6 years (median, 4.7 years) after the hemodynamic study, 13 from cardiovascular causes and 2 from a noncardiovascular cause (Table 1). Mean age at the time of death was 49 years (range, 32 to 76 years). Thirty-four patients (26 men) experienced at least one cardiovascular event, of which 9 were fatal and 25 nonfatal (Table 1). Mean age at the time

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of the first cardiovascular event was 50 years (range, 32 to 70 years); the events occurred between 0.6 and 19.1 years (median, 7.3 years) after the hemodynamic evaluation. Prognostic Value of Pulmonary Wedge Pressure Age at baseline was curvilinearly correlated with the incidence of cardiovascular events; the model required both the linear (P ⬍ .05) and quadratic (P ⬍ .05) terms of age. All-cause mortality was related to only the linear term of age (P ⬍ .05). Mortality (P ⬍ .05) and the incidence of cardiovascular events (P ⬍ .01) were lower in women than in men, after control for age, and for age and age squared, respectively. Mean pulmonary wedge pressure was a significant predictor of death after adjustment for age and gender (P ⬍ .05). The relative hazard rate amounted to 1.23 (95% confidence limit: 1.03–1.47). When mean brachial artery pressure, body mass index, serum cholesterol, electrocardiographic left ventricular hypertrophy, and smoking at baseline were offered to the model, only mean brachial artery pressure contributed significantly to the prediction of all-cause mortality in addition to wedge pressure, age, and gender (Table 2). Mean pulmonary wedge pressure also significantly predicted the incidence of cardiovascular events after control for age, age squared, and gender (P ⬍ .05). A 1 mm Hg higher wedge pressure was independently associated with a 13% higher risk (Table 2).

Discussion Prognostic Power of Pulmonary Wedge Pressure The present study shows that mean pulmonary capillary wedge pressure is a significant predictor of mortality and of cardiovascular events in patients with hypertension, in whom target organ damage was limited to World Health Organization stage II9,10 or who had no associated clinical conditions.11 The prognostic power was independent of

Table 2. Relative hazard rates of mean pulmonary capillary wedge pressure, age, gender, and mean brachial artery pressure for all-cause mortality and for the first occurring fatal or nonfatal cardiovascular event All-cause Mortality [RHR (95% CL)] MPCWP (mm Hg) Age (yr) Age2 (yr2) Gender‡ MBAP (mm Hg)

1.22 (1.02–1.45)* 1.07 (1.02–1.12)† NS 0.07 (0.01–0.38)† 1.03 (1.00–1.06)*

First Cardiovascular Event [RHR (95% CL)] 1.13 1.52 0.996 0.24

(1.01–1.27)* (1.15–2.01)† (0.992–0.999)† (0.10–0.59)† NS

MPCWP ⫽ mean pulmonary capillary wedge pressure; MBAP ⫽ mean brachial artery pressure; NS ⫽ not significant. Values are relative hazard rates (RHR) and 95% confidence limits (CL) from stepwise Cox regression analysis. Body mass index, serum cholesterol, electrocardiographic left ventricular hypertrophy, and smoking at baseline were also offered to the models but did not reach statistical significance (P ⱕ .05). * P ⱕ .05; † P ⱕ .01. ‡ Coded 1 for women and 0 for men.

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possible confounders such as age, gender, mean brachial artery pressure, body mass index, serum cholesterol, electrocardiographic left ventricular hypertrophy, and smoking at baseline. Patients with evidence of heart failure, ischemic heart disease, peripheral arterial occlusive disease, cerebral complications, renal insufficiency, and eyeground grade 3 were excluded, as well as patients with diabetes, valvular heart disease, pulmonary disease, and those with other than sinus rhythm on the electrocardiogram. Although measurements of left ventricular systolic function and chamber size were not included in the baseline examinations of the current study, the normal cardiac output, the absence of cardiomegaly on chest x-ray, and the exclusion of patients with a history, signs, or symptoms of heart failure, suggest that left ventricular systolic function was adequate. It is reasonable to assume that mean pulmonary wedge pressure or left ventricular filling pressure is an index of left ventricular diastolic function in these patients and more specifically reflects left ventricular diastolic stiffness.8 These results were achieved in patients with an average normal pulmonary wedge pressure, and only 6 of the 172 patients exceeded the upper limit of normal of 12 mm Hg.8 Whereas it has been shown before that impaired left ventricular systolic function predicts a worse outcome in asymptomatic hypertensive patients,1,2 there are no data on the prognostic value of diastolic function in hypertension. More generally, Brogan et al16 scrutinized 3107 patients undergoing heart catheterization and identified 53 patients with elevated left ventricular end-diastolic pressure, normal ejection fraction, normal left ventricular volumes, and no coronary artery or valvular heart disease; 83% of them had a history of hypertension. Follow-up revealed that isolated left ventricular diastolic dysfunction was associated with low cardiac mortality, but with substantial morbidity in terms of new onset symptoms of congestive heart failure and recurrent chest pain. It remains, however, uncertain whether diastolic function would predict the development of heart failure in hypertensive patients. In the present study only few cases of heart failure occurred during follow-up, probably related to the fact that, for ethical reasons, patients were treated for hypertension and that lowering of blood pressure is known to reduce the incidence of heart failure.17,18 Details on treatment during the many years of follow-up are, however, not available. When heart failure develops, the prognosis of heart failure with preserved systolic function and presumably impaired diastolic function appears to be better than that of systolic heart failure.19

mitral Doppler velocimetry has gained wide acceptance for the evaluation of hypertensive patients, and most studies agree that abnormalities of diastolic function can be detected early in the development of the disease.3– 6 Doppler echocardiography was, however, not performed in the patients of the present study, and, to the best of our knowledge, no studies are available on the prognostic power of echocardiographic indexes of diastolic function in hypertensive patients. It would be worthwhile to know whether they predict cardiovascular morbidity and mortality, and more specifically heart failure. Such data would be important for the management of hypertension. Whereas left ventricular hypertrophy is readily reversible by currently used antihypertensive agents,20 diastolic dysfunction appears to be more resistant to treatment21,22; therefore, prevention or halting the progression of diastolic function abnormalities may be a worthwhile goal to pursue in the treatment of hypertension. A specifically designed clinical trial would be needed to clarify this issue. Limitations The current study is a retrospective analysis of the outcome of hypertensive patients in whom an invasive hemodynamic investigation was performed between 1972 and 1982. The selection of the patients could have been biased by indication for the hemodynamic study; however, all hemodynamic studies were performed for research purposes without specific clinical indication. The number of patients is relatively small, which may limit the general prognostic inference from the multivariable Cox model. Furthermore, the assumption of normal chamber size and systolic function was not made on solid measurements such as from echocardiography, but on chest x-ray and on clinical and hemodynamic data; therefore, we cannot totally exclude an effect of systolic dysfunction on pulmonary capillary wedge pressure. Finally, the diagnosis of left ventricular hypertrophy was based on electrocardiographic voltages with limited sensitivity.23

Acknowledgments We acknowledge the assistance of N. Ausseloos, J. Delsupehe, and J. Romont. R. Fagard is holder of the Professor A. Amery Chair in Hypertension Research, founded by Merck, Sharp and Dohme (Belgium).

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