Cardiac performance after reduction of myocardial hypertrophy

Cardiac Performance after Reduction of Myocardial Hypertrophy ROLAND E. SCHMIEDER, M.D., FRANZ H. MESSERLI, M.D., DAWN STURGILL, B.S., GUILLERMO E. GARAVAGLIA, M.D., BORIS D. NUNEZ, M.D. Newor/eans, Louisiana

PURPOSE: The current study was performed to assessthe functional sequelae of reducing left ventricular hypertrophy in patients with essential hypertension. PATIENTSANDhfEXHODS: Toanalyzeleftventricular function and contractility in patients with essential hypertension after reduction of left ventricular hypertrophy, 14 patients with essential hypertension and left ventricular hypertrophy were studied prospectively by echocardiogram (1) before, (2) during, and (3) after left ventricular masshad been reduced by antihypertensive therapy of 19 f 3 months’ duration. All drugs were discontinued four weeks before the first and the third study. RESULTS: At the time of the third study, arterial pressure had returned to pretreatment values, and mean, peak, and isovolumetric (but not end-systolic) wall stress increased, whereas left ventricular massremained diminished. Despite the increased pressure load to the heart, myocardial contractility was maintained or improved after reduction of left ventricular hypertrophy, as indicated by the ratio of end-systolic wall stress to end-systolic volume index (p CO.02)and by the relation of fractional shortening to end-systolic wall stress (p <0.06). End-diastolic volume, an indicator of preload, remained reduced after therapy (p <0.05). As a result, pump function of the left ventricle improved as shown by an increase in the ejection fraction (p <0.05), fractional fiber shortening (p <0.05), and velocity of circumferential fiber shortening (p
From the Department of Internal Medicine, Section on Hypertensive Diseases. Ochsner Clinic and Alton Ochsner Medical Foundation. New Orleans, Louisiana. This research was supported in part by a grant from Deutsche Jefferson

22

Highway,

New Orleans,

Louisiana

70121.

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n the initial stage, cardiac structural adaptation to Iprocess arterial hypertension is regarded asa compensatory for offsetting increased wall stress of the left ventricle [la]. With a progressive increase in afterload, this compensatory processno longer suffices and cardiac pump function becomesimpaired, ultimately resulting in congestive heart failure [5-71. Data from the Framingham cohort showed that left ventricular hypertrophy as established by electrocardiographic evidence cannot be considered a compensatory processonly, but should be viewed asa powerful independent risk factor for congestive heart failure, coronary artery disease,and sudden death [B-lo]. Subsequent investigations revealed that early stages of left ventricular hypertrophy evaluated by echocardiographic criteria also increased the risk for cardiovascular morbid events [11,12]. Although a variety of studies have documented that left ventricular hypertrophy can be reduced by specific antihypertensive therapy [13-X], it is not clearly established whether such a reduction of myocardial hypertrophy is indeed beneficial or detrimental [1,2,4,6]. Reduction of left ventricular mass refers to both myocytes and to non-contractile components. If contractile elements of the myocardium are reduced without a proportional reduction of non-contractile components, latent cardiac dysfunction may result, which might be unmasked by any sudden increase in afterload. A decreasein arterial pressure by antihypertensive therapy does not always parallel a reduction of left ventricular hypertrophy. Of note, reduction of cardiac hypertrophy has been documented even in the absenceof effective blood pressure control (16,171.However, a significantly greater reduction of myocardial mass than of arterial pressure might be hazardous since increased wall stressmay result, thereby leading to impaired left ventricular function [3]. Clinical studies demonstrated that left ventricular function was preserved after reduction of left ventricular hypertrophy aslong as arterial pressure wascontrolled by antihypytensive therapy [B-23]. To our knowledge, all studies examining the heart’s pump efficiency after reduction of hypertrophy were performed in hypertensive patients who were still receiving medication. However, since antihypertensive agents affect cardiac loading conditions and the inotropic state of the left ventricle, these trials do not assessmyocardial function independently of pharmacologic effects. In the current study, therefore, we discontinued antihypertensive medication after long-term therapy to re-examine left ventricular function and contractility after reduction of left ventricular hypertrophy.

PATIENTS AND METHODS Study Design Fourteen patients (11 men and three women, 12 whites and two blacks) with mild to moderate essential

MYOCARDIAL

hypertension were followed for 20 f 3 months. Mean age of the study population was 46 f 10 years. Average body weight at study entry was 91 f 14 kg and did not change during the study period (90 f 13 kg at the end). Secondary causes of arterial hypertension, a clinical history or evidence of congestive heart failure (New York Heart Association class II, III, or IV), myocardial infarction within the last six months, cardiac arrhyth‘miss affecting cardiac pump function, and valvular and congenital cardiac lesions were ruled out by routine clinical examinations (including screening twodimensional echocardiography) [24]. Arterial blood pressure was determined by cuff and mercury manometry with patients at rest on at least three visits in the outpatient clinic and at the time of the echocardiographic recordings. Before being included in the protocol, each patient had to have diastolic pressure equal to or greater than 90 mm Hg during the last three outpatient visits. Four weeks after withdrawal of all cardiovascular drugs, left ventricular structure and function were assessed by the first echocardiogram (“before therapy”). Patients were subsequently treated for high blood pressure and routinely followed in our outpatient clinic. The therapeutic goals were to reduce both diastolic pressure (below 90 mm Hg) and the degree of left ventricular hypertrophy. Consequently, agents that have been proven to reduce myocaritial hypertrophy such as sympatholytic agents, calcium entry blockers, and converting enzyme inhibitors were used as the first step of the regimen [13,14,20-231. Diuretics were avoided because it is not yet clear whether they reduce left ventricular hypertrophy [21,25]; they were only added if diastolic pressure failed to drop below 90 mm Hg. Finally, five patients were treated by beta blockers (atenolol, propranolol), four by converting enzyme inhibitors (captopril), two by calcium entry blockers (diltiazem), and three by combining beta blockers and diuretics (hydrochlorothiazide). The level of arterial pressure was checked once every month. After 7 f 1 months, M-mode echocardiography was repeated to evaluate the impact of the antihypertensive drug regimen on left ventricle structure (“during therapy”). Antihypertensive therapy was maintained for an average of 19 f 3 months. Thereafter, all antihypertensive medication was withdrawn, and blood pressure values were monitored weekly. After four weeks of discontinued therapy (i.e., 20 f 3 months since study entry), echocardiographic evaluation of left ventricular structure and function was repeated (“after therapy”). Echocardiography Patients were included in the current study only if during the first examination an echocardiogram of good quality could be obtained. M-mode echocardiographic studies were conducted by standard methods, as previously outlined 118,261. Briefly, an ultrasonoscope (Smith-Kline Ecoline 28; Andover, Massachusetts) interfaced with a strip chart recorder (Honeywell; Andover, Massachusetts) and a probe measuring 1.27 cm in diameter were used. Ultrasonic emission characteristics were as follows: frequency, f ,OOO/second; wavelength, 2.25 MHz; and focal length, 10 cm. All echocardiograms were recorded in the third or fourth left interspace with the patient recumbent in the half left-sided position. All traced echocardiograms were independently interpreted by two investi-

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gators according to the standard measurement convention of the American Society of Echocardiography [27]. The two readers were unaware as to when in the study period the echocardiograms were obtained and as to the patients’ names. The coefficient of variation for intra- and inter-observer reproducibility in our laboratory was less than 5% for left ventricular dimensions and below 10% for left ventricular wall thickness. LEFTVENTRICULARSTRUCTURE: Septal and posterior wall thicknesses and systolic and diastolic diameters were measured at the onset of the QRS complex. Two formulas were used to calculate left ventricular mass. Based on our measurements according to the American Society of Echocardiography (ASE), left ventricular (LV) mass (ASE cube LV mass) and its index were calculated according to the standard formula of Troy et al [28], which takes both septal and posterior wall thicknessesinto account. Since this formula appeared to systematically overestimate left ventricular mass, the value based on the ASE cube formula of Troy et al [28] was corrected by the regression [29] PENN cube LV mass= 0.80 (ASE cube LV mass)+ 0.6 g. In contrast, Woythaler et al [30] reported that PENN cube LV masswas lessaccurate than the ASE cube LV massin some patients. PRELOAD: Using the measurements of end-diastolic diameter at the onset of the QRS complex, intraventricular end-diastolic volumes were calculated by the classicformula utilizing the Teichholz correction [31]; end-diastolic volume normalized for body surface area was taken as the most valid parameter for preload. AFTERLOAD: Left ventricular meridional wall stress was used as a parameter for afterload measurement [32-371 and was estimated using the angiographically validated method of Grossmann and co-workers [36]: 0.334 + P/LVID/PWT + [l + PWT/LVID] where P = LV pressure,LVID = LV internal diameter, and PWT = LV posterior wall thickness. The average systolic pressure at the time of echocardiography was used to compute end-systolic and peak-systolic meridional wall stressby noninvasive means[33]. In addition, end-isovolumetric systolic wall stresswasderived from measurementsobtained at the end of isovolumetric contraction, when intraventricular pressure reachesthe aortic diastolic pressure level and left ventricular wall thickness has not yet been changed from end-diastolic diameters [37]. Mean systolic wall stress was estimated as an average of end-isovolumetric and end-systolic wall stress [35]. LEFT VENTRICULAR FUNCTION: Myocardial pump function, a product of myocardial contractility and hemodynamic load, was estimated by calculating ejection fraction, fractional fiber shortening, and velocity of circumferential fiber shortening in standard fashion [37,38]. MYOCARDIAL CONTRACTILITY: Since all three parameters for cardiac performance are highly dependent on cardiac loading conditions, they do not accurately reflect myocardial contractility. The end-systolic wall stress-volume relationship appeared to be linear and sensitive to the inotropic state of the myocardium ]33,39,40]. It was reported to be less affected by changesin preload and afterload [35,41-45]. The ratio of end-systolic wall stress to end-systolic volume index was calculated to quantify the inotropic cardiac state [42,46-48]. As a second parameter for myocardial contractility, we calculated left ventricular July

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MYOCARDIAL CONTRACTILITY / SCHMIEDER ET AL

r TABLE

1 Arterial Pressure, Heart Rate, and Left Ventricular

Structure

before, during, and after Therapy

Before Therapy

l

Systolic pressure (mm Hg) Diastolic pressure (mm Hg) Heart rate (beats/minute) Septal wall thickness (cm) Posterior wall thickness (cm) Left ventricular mass(g) (ASE)tt Left ventricular mass(g) (PENN)rt .^ ^^. (aefore , p
148f3 97f 63f2 1.20f 1.04 f 274 f 227 f

During Therapy

After Therapy

132 f 4’ 85 f 2’ 62f3 1.16f0.04* 0.99 f 0.02* 239 f 18s 197 f 16*

2 0.05 0.03 24 23

‘g,‘;: 67 zt 1.20 f 0.99 f 240 f 193 f

2 0.035 0.02” 15” 15”

t p
TABLE II Preload (I), Afterload (II), Myocardial Therapy

Contractility

(Ill), and Left Ventricular

Function (IV) before, during, and after

Before Therapy

During Therapy

After Therapy

I End-diastolic diameter (cm) End-drastolic volume index (mL/me)

4.9 f 0.6 56f3

4.7 f 0.5’ 51 f 3’

4.7 f 0.6t 50*3t

II Wall stress (103 dynes/cma) End-isovolumetric Peak-systolic End-systolic Mean-systolic

130f6 199f8 65f4 98% 5

113f 176~k 54 f 83 f

130 f 5t 195 f 75 56f 3 94f4§

Ill ESWS/ESVI %FFS

2.4 f 0.15 97 f 3

2.3 f 0.14 -

2.6 f 0.16t 103 f 4’3

IV Velocity of circumferential fiber shortening (cir/s) Fracbonal fiber shortening (%) Ejection fraction (%)

1.09 f 0.06

1.17 f 0.09’

1.28 f 0.07t

34& 1.6 62f 2

36 f 2.0’ 65 f 3’

37 f 1.6t 66 f 2t

ESWS/ESVI = end-systolic wall stress/end-systolrc volume index (lo6 relation to end-systolic wall stress (% predicted); cir/s = circumference l p -CO.05 (before therapy versus during therapy). t p <0.05 (before therapy versus after therapy). * p
dynes . ma/cm2 per second.

fractional fiber shortening as a percent of predicted in relation to end-systolic wall stress(from the regression line of normotensive subjects, as suggestedby Devereux) [45,49]. The relation of fractional fiber shortening to end-systolic wall stress is also regarded to assess myocardial contractility of the left ventricle [45].

5’ 8* 411 411

. mL): %FFS = fractional

fiber

shortenmg

as a percent

of predicted

iI

and diastolic pressuresdropped markedly (p
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function despite the rise in arterial pressure. End-isovolumetric, peak-systolic, mean systolic, and, to a lesser extent, end-systolic wall stress after therapy were similar to their pretreatment values and exceeded values during therapy (p CO.05 and p
COMMENTS The current study was carried out to assess the functional sequelae of reduction of left ventricular hypertrophy. Cardiac function is the product of the interaction of hemodynamic load imposed on the heart and myocardial contractility. In interpreting pump function indices in arterial hypertension, the roles of afterload and pharmacologic milieu must be considered. Antihypertensive agents have been shown to change both the contractile state and hemodynamic load conditions (pressure and volume load) (3,211. Previous studies documented that left ventricular function was not depressed(but seemingly improved) in hypertensive patients who were receiving effective, long-term treatment [16,17,20-231. Those studies, however, did not differentiate the effects caused by a reduction in left ventricular massfrom those causedby a decrease in arterial pressure or from those induced by antihypertensive therapy [32,50]. Therefore, in the current study, antihypertensive medication was discontinued four weeks prior to the first and third evaluations to exclude any pharmacologic interactions. Hence, two similar steady-states were compared; however, due to antihypertensive

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ESWS/ESVI (106dynes

- m2/

cm2.

ml)

p-o.02

BEFORE THERAPY

AFTER THERAPY

Figure 1. End-systolic wall stress/end-systolic volume ratio, an index of myocardial contractility, increased after reduction of left ventricular hypertrophy. FFS

(%)

140 p < 0.06

1

120-

+

100-

80-

--

60 1

I-----

----

,

BEFORE

AFTER

THERAPY

THERAPY

J

Figure 2. Graphic display of left ventricular fractional fiber shortening expressed as a percent of predicted value in relation to end-systolic wall stress (FFS%) before therapy and after therapy. July 1989

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MYOCARDIAL CONTRACTILITY / SCHMIEDER ET AL

Preload

%

Before Therapy

120

Afterload

%

After Therapy

Before Therapy

Myocardlal Contractlllty

%

‘p

Left

< 0.05 1

After Therapy

Ventricular Function

rp

< 0.05 1

100 80

80 Before Therapy

After Therapy

Before Therapy

therapy, left ventricular mass was significantly reduced. Since afterload increased again to pretreatment levels after the drug-free interval, load-insensitive indices were applied to assess myocardial contractility such as the ratio of end-systolic wall stressto end-systolic volume index and fractional fiber shortening given as a percentage of predicted in relation to end-systolic wall stress. Following antihypertensive treatment, left ventricular massdecreasedin each patient and remained reduced for at least four weeks after medication was discontinued. This reduction in left ventricular mass was due to a decrease in posterior wall thickness and diastolic dimension of the left ventricle. Although similar to findings in a previous report [51], a localized increase in septal thickness was observed as early as four weeks after therapy was stopped. Surprisingly, after therapy, at the time of the third study, myocardial contractility of the left ventricle was not found to be depressed, as is often discussed [1,2,6,50]. In contrast, after reduction of left ventricular hypertrophy, the contractile state waspreserved or improved when compared with the pretreatment status and, asa consequence,overall left ventricular function was slightly ameliorated. Of note, systolic pressure rose to pretreatment values and mean systolic wall stress increased without changes in myocardial mass,thereby imposing a new pressureload on the left ventricle. Even more striking was the fact that the myocardium was capable of withstanding the newly imposed pressure load in the absenceof compensatory hypertrophy. Preload may have played an important role in the function after treatment, since end-diastolic dimension remained low, perhaps thereby allowing the smaller ventricle to better tolerate the rise in pressure load. The mildly enhanced myocardial contractility and left ventricular function after reduction of hypertrophy may correspond to the first stage of cardiac adaptive processesto newly imposed afterload on the heart, before structural adaptation or hypertrophy occur [52]. 26

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After Therapy

Figure 3. Average percentage change of preload (end-diastolic volume index), afterload (mean systolic wall stress), myocardial contractility (ratio of endsystolic wall stress to end-systolic volume index), and left ventricular function (velocity of circumferential fiber shortening).

Animal studies examining cardiac function after a reduction of left ventricular hypertrophy yielded conflicting results [53-561. In rats, contractile abnormalities in papillary muscles reverted to normal after reduction of hypertrophy [53], and peak cardiac output due to volume load was not impaired [54,56]. However, when comparable pressure levels were attained, spontaneously hypertensive rats had lower peak cardiac output under conditions of volume loading after reduction of cardiac hypertrophy than normotensive rats at a similar pressure [53]. These results indicate that acute volume and pressure loads may unmask latent dysfunction of the regressed myocardium in rats. In conclusion, myocardial contractility was preserved or enhanced after reduction of left ventricular hypertrophy by antihypertensive therapy despite the fact that arterial pressure was allowed to increase to pretreatment levels. Thus, reduction of myocardial hypertrophy as induced by specific antihypertensive therapy appeared to be beneficial rather than detrimental to cardiac pump performance.

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