The spectrum of left ventricular size in dilated cardiomyopathy: Clinical correlates and prognostic implications

The spectrum of left ventricular size in dilated cardiomyopathy: Clinical correlates and prognostic implications To address the issues of variability and prognostic role of left ventricular dimensions in dilated cardiomyopathy (DCM), 144 patients with DCM were studied. They were arbitrarily assigned to two groups according to an echocardiographic left ventricular end-diastolic diameter index ~15% (45 patients with mildly dilated cardiomyopathy) and above 15% (99 patients with typically dilated cardiomyopathy) of the upper normality range. Among the patients with mildly dilated cardiomyopathy, there were more men (89% vs 88%; p < 0.01). This group of patients also had a greater prevalence of atrial fibrillation (22% vs 3%; p < 0.001) higher left ventricular fractional shortening (15 F 8% vs 13 t 5%; p < 0.05), higher ejection fraction (28 k 8% vs 24 f 8%; p < O.Ol), and a lower exercise tolerance (5 _+ 2 MET vs 6 t 2 MET; p < 0.05). At the time of follow-up examination (30 + 15 months), event-free survival was not significantly different between patients with mildly dilated cardiomyopathy and those with typically dilated cardiomyopathy. Pulmonary capillary wedge pressure (p < 0.001) and left atrial dimension index (p < 0.01) were significant predictors of prognosis as determined by Cox multivariate analysis. Minimal or mild ventricular dilatation is not uncommon in DCM, and it identifies a heterogenous group of patients-some who are in the early stages of disease and others with severe pump dysfunction and persistently small hearts. Ventricular dilatation is not an independent predictor of prognosis. (AM HEART J 1993;125:410.)

Antonello Gavazzi, MD, Renata De Maria, MD, Giuliano Renosto, MD, Agnese Moro, MD, Massimo Borgia, MD, Angelo Caroli, BS, Gabriele Castelli, Mauro Ciaccheri, MD, Daniela Pavan, MD, Claudio De Vita, MD, Giorgio Baroldi, MD, and Fulvio Camerini, MD on behalf of the SPIC (Italian Multicenter Cardiomyopathy Study) Group (see appendix) Italy

Ventricular dilatation is traditionally considered one of the hallmarks of dilated cardiomyopathy; however, the role of ventricular dimensions among the diagnostic criteria for dilated cardiomyopathy has not yet been clarified, and the clinical relevance of left ventricular enlargement has not been systematically investigated. Moreover, whether or not ventricular dilatation represents an important prognostic factor remains controversial. Although some studies showed a positive correlation between the degree From Divisione di Cardiologia, entifico Policlinico San Matteo, Supported “Prevention diovascular Received Reprint Policlinico

Instituto Pavia,

Ricovezo Italy.

e Cuzie

e Caralteze

in part by National Research Council (CNR)-Targeted and Control of Disease Factors,” Subproject “Control Disease,” grant no. 104299/41/9103611. for publication

Mar.

24, 1992;

accepted

SciProject of Car-

Aug. 20, 1992.

requests: Antonello Gavazzi, MD, Divisione di Cardiologia, San Matteo, Piazzale Golgi, 27100 Pavia, Italy.

IRCCS

MD,

of ventricular dilatation and an unfavorable outcome,le4 two recent reports by Keren et a1.5,6 described a group of patients with “dilated” cardiomyopathy who, despite mild or absent ventricular dilatation, presented in end-stage heart failure and had poor prognosis. The aim of the present prospective study was to analyze the spectrum of left ventricular size in dilated cardiomyopathy and to establish the clinical and prognostic significance of ventricular dimensions. METHODS Between January 1986 and January 1990 a total of 238 consecutive patients with dilated cardiomyopathy from 15 different centers were prospectively enrolled in a multicenter registry. One of the aims of this registry is the study of the natural history of dilated cardiomyopathy, with particular attention to early manifestations of disease. Patients who were referred to the participating centers

Copyright

410

’ 1993

by Mosby-Year

UOO2-8703/93/$1.00

+ .lO

Book, 4/l/42647

Inc.

Volume Number

125 2, Part

1

becauseof heart failure and/or high-grade ventricular arrhythmias and/or severedepressionof ventricular function (echocardiographic left ventricular fractional shortening <20 %) of unknown causeunderwent a noninvasive evaluation including physical examination, 12-lead ECG, M-mode and two-dimensional echocardiography, 24-hour dynamic ECG monitoring, exercise stress testing, and a complete biochemical evaluation including thyroid function tests. Patients with systemic hypertension, car pulmonale, valvular heart disease,thyroid dysfunction, or systemicdiseaseswere excluded from the study. Excessive alcohol consumption was recorded and analyzed as a potential risk factor. The clinical suspicion of dilated cardiomyopathy was confirmed invasively in every patient by demonstrating: (1) absence of significant coronary artery disease (>50% luminal diameter reduction of a major coronary artery branch) as determined by coronary angiography, (2) absenceof specific heart musclediseaseor active myocarditis asdetermined by endomyocardial biopsy, and (3) reduced left ventricular ejection fraction (<55 %) asdetermined by cineangiography. In two centers with an establishedcardiac transplantation program, patients with end-stagecardiomyopathy who had been specifically referred for heart replacement and whose nameswere added to the transplant waiting list were not included in this series. All patients underwent noninvasive and invasive evaluation within 1 month. Functional status was classifiedaccording to New York Heart Association (NYHA) criteria. Echocardiographicmeasurementswere obtained according to previously published standards7 and normalized for body surfacearea.M-mode echocardiographicimageswere recorded under two-dimensional guidance, which was selected for measurements.Mean myocardial thickness was calculated as [interventricular septum + posterior wall end-diastolic thickness] + 2. Left ventricular volumeswere obtained from the apical four-chamber view; left ventricular ejection fraction was calculated with the single-plane area-length method.s Left and right heart catheterization wasperformed with fluid-filled cathethers and a low volume displacement transducer. Mean right atrial, right ventricular end-diastolic, pulmonary artery, capillary wedge, left ventricular end-diastolic, and aortic pressureswererecorded. Patients with restrictive patterns of ventricular pressurerecordings were excluded from the study. Cardiac output was measured with the thermodilution method; the mean of three measurementswas given and corrected for body surface area to obtain cardiac index. Left ventricular angiography was accomplishedin the 30-degreeright anterior oblique projection; meannormal values for left ventricular ejection fraction in the participating hemodynamic laboratories were 72$(, t 8% ; thus, 56% (meannormal value - 2 SDS) waschosenasthe lower normality range of left ventricular ejection fraction. Mitral regurgitation wassemiquantitated as mild or moderate; patients with severe regurgitation were not included in the study. Selective coronary angiography was performed according to Judkins’ technique.

Ventricular

size in dilated

cardiomyopathy

411

Right ventricular endomyocardialbiopsy wasaccomplished through the right femoral vein or through the right internal jugular vein; in a minority of patients left ventricular endomyocardial biopsy was performed. In each biopsy procedureat least four tissuespecimenswereobtained and processedfor histologic diagnosis; Dallas criteria9 were usedto rule out myocarditis. Dynamic ECG wasrecordedfor at least 24 hoursand the number of ventricular premature beats and of ventricular tachycardia episodesin a 24-hour period were calculated. Ventricular arrhythmias were graded according to Lown classificationas modified by Ryan et al.” When clinically feasible, a symptom-limited exercise stresstest was performed in the upright position with a bicycle ergometerin 25 W increments every 3 minutes or in 10 W increments every minute. Clinical examination and noninvasive tests were repeated yearly during follow-up. Among 238 patients with dilated cardiomyopathy who were consecutively enrolled in the study until January 1990,there were 144 with an angiographicleft ventricular ejection fraction <40%, who were observedfor at least 12 months. On the basisof echocardiographicleft ventricular dimensionstwo groups were arbitrarily distinguished, in accordancewith previously publishedcriteria5*? (1) mildly dilated cardiomyopathy (MDCM) or (2) typically dilated cardiomyopathy (DCM). A left ventricular end-diastolic diameter index value no more than 15% above the upper normality range (32 mm/m2)waschosenasthe upper limit for mild dilatation. On December31,199Othe 144patients were classifiedas survivors or transplant recipients (for deteriorating cardiac function and for a life expectancy shorter than 6 months) or deceased.Deceasedpatients and transplant recipients formed the “negative outcome” group. Classificationof the type of death wasbasedon evaluation of circulatory conditions immediately before death.” The latter wasdistinguished as sudden, if it occurred instantaneously within minutes or during sleepand was not precededby deteriorating cardiac failure, or secondaryto heart failure, when it resulted from ongoing deterioration of heart performance. Statistical analysis. For comparison between groups, two-tailed unpaired Student’s t test wasusedfor continuous variables, and chi square test was used for discrete variables. Product limit survival for MDCM and typical DCM groups was calculated with Kaplan-Meier curves, and differencesbetween curves were assessed by the Mantel-Cox test. The Cox Proportional Hazards model was used to analyze the relationship between survival and prognosticindices.Each variable wasanalyzed individually to calculate a chi square statistic, which was a measureof the relationship between that variable and outcome (Cox univariate analysis). Significant variables were suhsequently entered into a multivariate model to select major independent variables that were predictive of outcome. Discriminant analysiswas usedto select threshold values for adverseoutcome for significant prognostic predictors. The Statistical Packagefor the Social Sciences(SPSS Inc.,

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- .;.... ..:.,: ; : ..;. : ,:, ; :;,:.;. I

0 DCM

20.

0 MDCM

15. 10. 5.

-20

0

15

20 LVEDDIX

40

60

in the 144 patients with

Table I. Clinical characteristicsaccording to left ventricular dilatation

RESULTS

Left ventricular dimensions in the 144 patients (Fig. 1) were distributed according to a bell-shaped curve. The mean value for left ventricular end-diastolic diameter index was 40.2 + 5.9 mm/m’, and the confidence interval was 95%. Forty-five patients (31% ) with left ventricular end-diastolic diameter index less than 15% above upper normality range and 99 patients (69%) with left ventricular enddiastolic diameter index greater than 15% from the upper normality range formed the MDCM and DCM groups, respectively. Of the 45 patients with MDCM, 13 had normal ventricular size (left ventricular enddiastolic diameter index 132 mm/m2), and 32 showed mild dilatation. Clinical and laboratory findings. Clinical characteristics and laboratory findings of the two groups are given in Tables I, II, and III. Medical treatment was not significantly different in the two groups. There were more men in the group with MDCM (p < 0.01). Alcohol abuse (p < 0.05) and atria1 fibrillation (p < 0.001) were observed more often in patients with MDCM. Palpitations at presentation (p < 0.05) were significantly more frequent in patients with MDCM, whereas there were no differences in the prevalence of intraventricular conduction defects. Left atria1 dimension index was larger in DCM than in MDCM (p < 0.05). Right ventricular end-diastolic diameter index could be measured in 122 cases and was similar in both groups. Two-dimensional echocardiography confirmed that left ventricular volumes were significantly smaller in patients with MDCM

100

from normal

Fig. 1. Distribution of left ventricular end-diastolic diameter index (LVEDDI) DCM.

Chicago,Ill.) and Biomedical Computer Programs(BMPD Statistical Software Inc., Los Angeles, Calif.) software was used.A p value of lessthan 0.05wasconsideredsignificant.

80

DCM

MDCM group (n = 45)

group (n = 99)

P Value

44 t 9 89

41 + 13 66

NS
32 2 40

24 i 39

NS

Patients

Age (yr) Gender (% male) Duration of disease (mo) Family history of cardiomyopathy Alcohol intake 280 gmfday NYHA class III-IV Palpitations as presenting symptom Follow-up (mo) Medical treatment None Digitalis Diuretics Nitrates ACE inhibitors Oral anticoagulants Antiarrhythmics p-blockers ECG Atria1 fibrillation LBBB Left anterior hemiblock RBBB

9 ‘:

3 1’;

NS

42 p,.

20 5

-co.05

53 “i

32 5

<0.05

30 + 17

30 f 16

NS

22°C

I C’c 66 “;I 86% 9s; 58?, 18?

NS NS NS NS NS NS

31cr 13r;

32% 6 ?i,

NS NS

13°C

62 “c, 80 5 11:; 56i’r

22% 24 5 7’;


-

NS

MDCM, mild dilated cardiomyopathy; NS, not significant; sin-converting enzyme; LEEB, left bundle branch block; dle branch block.

ACE, angiotenRBBB, right bun-

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Table II. Laboratory findings according to left ventricular dilatation MDCM Echocardiography LA1 (mm/m2) LVEDDI (mm/m2) LVESDI (mm/m2) RVEDDI (mm/m2) MMThI (mm/m2) LVFS (%) LVEDVI (ml/m2) LVESVI (ml/m?) Radius/posterior wall Catheterization mRAP (mm Hg) RVEDP (mm Hg) mPAP (mm Hg) mCWP (mm Hg) mAP (mm Hg) CI (L/min/m2) SVI (ml/min/m2) LVEDP (mm Hg) LVEF (%)

MR (?I)

22 34 28 12 5.2 15 112 79 3.45

(n = 45)

-t 5 f 3 + 3 Y!z4 f 0.9 + 6 + 55 +- 50 + 1.1

6+-5 6-t4 23 + 16 + 91 & 3.11 -t 39 f 18 + 28 t 22

13 10 16 1.28 20 13 8

DCM

25 43 37 13 5.3 13 158 118 4.34

p Value

in = 99)

k k k + t t + L i

5*4 71t5 23 k 16 f 88 -+ 2.95 +37 r 20 k 24 + 31

5 4 6 5 1.2 5 62 53 1.1


NS NS <0.05
9 9 16 0.8 17 11 8

LAI, Left atria1 dimension index; LVEDDI, left ventricular end-diastolic diameter index; LVESDI, left ventricular end-systolic diameter index; RVEDDI, right ventricular end-diastolic diameter index; MMThI, mean myocardial thickness index; LVFS, left ventricular fractional shortening; LVEDVI, left ventricular end-diastolic volume index; LVESVI, left ventricular end-systolic volume index; m&W, mean right atrial pressure; RVEDP, right ventricular enddiastolic pressure; mPAP, mean pulmonary artery pressure; mC WP, mean capillary wedge pressure; mAP, mean aortic pressure; CI, cardiac index; SVI, stroke volume index; LVEDP, left ventricular end-diastolic pressure: LVEF. left ventricular ejection fraction; MR, percent of patients with mitral regurgitation at cineangiography; other abbreviations as in Table I.

(p < 0.001). The mitral valve was structurally normal in all patients. Mitral regurgitation as determined by cineangiography was mild in 18% of patients with MDCM and 17% of those with DCM and moderate in 4% and 14%) respectively (NS). No differences were observed in the hemodynamic profile between the two groups, except for a slightly higher left ventricular ejection fraction as determined by cineangiography in patients with MDCM (28 + 8% vs 24 + 8%; p < 0.01). Dynamic ECG monitoring, which was performed in 141 patients, showed similar average heart rates; no difference in the latter index was observed according to rhythm (normal sinus vs atria1 fibrillation) either in the whole series or in the two groups separately. Prevalence of ventricular premature beats and of ventricular tachycardia episodes was greater in patients with mild DCM, but this value did not reach statistical significance 0, = 0.08). Exercise stress testing was performed in 106 patients (36 with MDCM and 70 with DCM). Twentyfive patients did not undergo the test because of severe symptoms and 13 because of technical problems. Exercise tolerance, as indicated by estimated metabolic equivalents (MET), was significantly lower in patients with MDCM (5 -+ 2 MET vs 6 _+ 2 MET;

Table Ill. Laboratory findings according to left ventricular dilatation MDCM (n = 45) Dynamic ECG (n = 141) Average heart rate 81.4 + 15 (beats/min) VPBs (no.) 4542 + 8537 VT episodes (no.) 3.68 + 15 Modified Lown 70% class 24 Exercise stress test (n = 108) MET 5*2 Rate-pressure 21743 i: 6222 product Exercise duration 8+4 bin)

DCM (n = 99)

P Value

81.5 f 13

NS

2347 f 5086 1.37 + 3.8 64 5

NS NS NS

22161

6?2 + 6484 9zk3

CO.05 NS NS

VP&, Ventricular premature beats/24 hours; VT, ventricular tachycardia/24 hours; MET, estimated metabolic equivalents; other abbreviations as in Table I.

p < 0.05). Patients with a lower exercise tolerance

(15 MET) had, on average, a longer duration of disease than patients who reached higher (>5 MET) exercise tolerance values (36 f 44 months vs 18 + 25 months; p < 0.05); the difference was confirmed, al-

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-DC&i -

0

12

24

36

February 1993 Heart Journai

MDCM

48

Fig. 2. Survival curves in mildly dilated cardiomyopathy (MDCM) and typically dilated cardiomyopathy

(DCM) groups.

though not significantly, in MDCM and DCM groups separately. The test was stopped because of dyspnea or blood pressure drop in 25% of patients with MDCM and in 30% of patients with DCM; because of arrhythmias in 6 % and 3 % , respectively; because of ECG abnormalities or chest pain in 0 % and 7 % , respectively; and because of muscular exhaustion in 63 % and 57 % , respectively. Six percent of patients with MDCM and 3 % of patients with DCM achieved 85% of the maximal age-adjusted predicted heart rate. Differences were not significant. All variables described (Tables I, II, and III) were also tested within the MDCM group between patients with normal left ventricular size (n = 13) and those with mild left ventricular dilatation (n = 32). Only left bundle branch block was significantly more frequent in patients with mild dilatation (0% vs 34.4%; p < 0.05). Follow-up study. During a mean follow-up period of 30 + 16 months (range, 15 days to 69 months) 25 patients died of cardiac causesand 15 underwent heart transplantation. One patient committed suicide and was not included in this outcome analysis. Cardiac deaths (8 patients with MDCM and 17 with DCM) and transplants (4 patients with MDCM and 11 with DCM), all of whom were referred because of refractory heart failure) were equally distributed in the two groups. Death was sudden in three patients with MDCM versus seven patients with DCM and was due

to heart failure in five and nine patients, respectively; one patient with DCM died of pulmonary embolism (confirmed at autopsy). Survival curves are shown in Fig. 2; 88 % ,76 % , and 68% of patients with MDCM and 83 % , 74%) and 68% of those with DCM were alive and had not undergone transplantation at 1, 2, and 3 years, respectively (p = NS). Time to death or transplantation was 16 +- 11 months in patients with MDCM and 14 + 13 months in patients with DCM (p = NS). The mean interval between entry into the study and outcome classification for survivors who did not undergo transplantation was 36 2 13 months (range, 12 to 69 months). The latest follow-up data available, at a mean interval of 23 -t 14 months from the time of baseline evaluation, showed a similar evolution of NYHA class in both groups (Fig. 3). Although left ventricular dimensions were stable in a similar percentage of both groups, an increase of more than 10% in left ventricular end-diastolic diameter index was observed in 19% of patients with MDCM and 4% of those with DCM; conversely, a decrease greater than 10% in left ventricular dimensions occurred in 16% of patients with MDCM and in 31% of those with DCM (p < 0.05) (Fig. 3). A follow-up echocardiogram was available before death or transplantation at a mean interval of 15 + 13 months from baseline in 19 of 40 patients with a negative outcome (6 with

Volume Number

125 2, Part 1

Ventricular

size in dilated

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415

100

80

MDCM DCM

increased

improved

LVEDDI

NYHA class

decreased

stable

mm/m *

Fig. 3. Evolution of functional classand left ventricular end-diastolic diameter index (L VEDDI) during follow-up in mildly dilated cardiomyopathy (MDCM) and typically dilated cardiomyopathy (DCM) groups. Table IV. Clinical characteristics according to outcome MDCM Survivors

Patients (n) Age (yr) Gender (% male) Duration of disease (mo) Family history of cardiomyopathy Alcohol intake 280 gm/day NYHA class III-IV Medical treatment Digitalis Diuretics Nitrates ACE-inhibitors Oral anticoagulants Antiarrhythmics p-blockers ECG Atria1 fibrillation LBBB Left anterior hemiblock RBBB

DCM

Negative

outcome

Survivors

Negative

outcome

33 44 t 8 88 27 k 37 9% 39% 48%

12 45 * 13 92 47 YZ46 8% 50% 58%

70 43 2 12* 64 26 f 41 1% 41%

28 35 i- 14 71 22 ?I 36 75 25% 61%

58 % 73% 9% 51% 2770 33% 18%

92% 100% 17% 67% 25% 33% -

69% 84 % 10% 61% 14% 33% 7%

64% 89 % 7% 50 %> 29% 32% 4%

21% 27% 6% -

33% 17% 8%

4% 33% 9% 1%

7% 29% 15% 7 7;

18%

Abbreviations as in Table I. *p < 0.01 (survivors

vs patients

with

negative

outcomes).

MDCM and 13 with DCM): only in two patients with DCM was a further (greater than 10$6) increase in left ventricular end-diastolic diameter index observed. Findings in patients with MDCM and DCM according to outcome. Clinical and laboratory findings in patients with MDCM and DCM are presented according to outcome in Tables IV, V, and VI. Patients with DCM

who had a negative outcome were younger (p < 0.05) than survivors. Left atria1 dimension index was significantly larger in patients with MDCM and DCM who had a negative outcome compared with survivors of both groups. Left ventricular diameters and volumes were larger in patients with DCM who had a negative outcome compared with survivors (p < 0.001 and p < 0.01); in contrast, the right ventricle was

416

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Table

V. Laboratory

February 1993 Heart Journal

American

findings

according

to outcome MDCM

Sui-viuors

Patients (n) Echocardiography LA1 (mm/m”) LVEDDI (mm/m”) LVESDI (mm/m”) RVEDDI (mm/m’) MMThI (mm/m2) LVFS (5 ) LVEDVI (ml/m”) LVESVI (ml/m2) Radius/posterior wall Catheterization mRAP (mm Hg) RVEDP (mm Hg) mPAP (mm Hg) mCWP (mm Hg) mAP (mm Hg) CI (L/min/m2) SVI (ml/min/m’) LVEDP (mm Hg) LVEF (“4 1 MR ( “6 )

DCM Negative

33 21 + 34 + 28 k 11 2 6i3 16 f 102 + 70 k 3.28 + 4+5 5 + 19 k 14 ir 92 f 3.37 i 43 t 17 + 28 k 18”;)

outcome

6$ 45 33 1.1

27 34 30 15 5 13 138 107 3.62

3$ 12* 9t 15 1.2$ 19$ 14 9 t

2 + i + 2 -t + _t +

Negative

7rJ

12 4* 2 3 4t

Survivors

5* 3 3 4T 1 4$ 76 80 1.4

7+5 9 IL 6$ 32 i- 9* 24 F 7t 88 -e 13 2.4 t 1.04$ 27 + 15$ 22 + 8 26 i 7 50 On t

24 + 42 i 36 t 12 + 5+1 14 -t 143 * 107 I 3.7 z

4+ 3* 4* 5t

4 2 5 i 21 x 15 ri 89 t 3.06 + 40 + 19 + 26 -+ P8”,

3+ 3t 8* 8t 16$ 0.8$ 15 10 7*

6 51* 43t 1.8

outcomr -____

..-

28 28 k 45 t 40 I 15 + 6_+1 12 It 195 zk 146 I 4.07 3. 7 i 9 iz 28 -i21 i 82 t 2.6 fr 33 i23 + 20 i 50’;

6* 6* 6* 6t 4 72* 64t 1.6 6t 6t lO* lot 14$ 0.84 20 13 9*

Abbreviations as in Tables I and II. *p < 0.001 (survivors vs patients with negative outcomes) tp < 0.01 (survivors vs patients with negative outcomes). Sp < 0.05 (survivors vs patients with negative outcomes).

more dilated in both negative outcome groups (p < 0.01). Patients with MDCM and DCM who had a negative outcome had a significantly worse hemodynamic profile than survivors. Left ventricular ejection fraction, however, was not significantly different according to outcome in the MDCM group, whereas it was higher in survivors in the DCM group (p < 0.001). None of the dynamic ECG variables that were tested was significantly different in the four groups, except for the mean number of ventricular premature beats, which was higher in patients with MDCM compared with those with DCM who had a negative outcome (6787 4 7548 vs 1477 _+ 2480, p < 0.01). The former also showed a higher but not significant percentage of complex ventricular arrhythmias with respect to survivors (modified Lown class 1 4a in 92 % vs 62 ‘% ; p = 0.056). Antiarrhythmic treatment was similar in the four groups (Table IV). Exercise stress testing variables did not differ in both patients with MDCM and those with DCM according to outcome. Multivariate analysis of outcome. To determine variables that were predictive of prognosis a Cox proportional hazard model was applied to the 143 patients in the series (one patient with DCM who committed significantly

suicide was excluded from this analysis) and separately to 45 patients with MDCM and 98 patients with DCM. The end point was a negative outcome (cardiac death or heart transplantation). Variables that were significant as determined by Cox univariate analysis are shown in Table VII; the following variables were included in Cox’s Proportional Hazards model: mean pulmonary capillary wedge pressure, left atria1 dimension index, left ventricular ejection fraction, mean right atria1 pressure, left ventricular end-diastolic diameter index, cardiac index, NYHA class, and modified Lown class. The latter variable was not. selected for univariate analysis; however, because Lown class is usually considered an expression of arrhythmic risk, we included it in the multivariate model, since in our series 43 ‘% of deaths were sudden. Among the above variables, multivariate analysis selected the following as major independent determinants of negative outcome in the 143 patients: mean pulmonary capillary wedge pressure (p < 0.001) and left atria1 dimension index (p < O.Ol), whereas left ventricular ejection fraction was just below statistical significance (p = 0.056). At discriminant analysis, the following threshold values for adverse outcome were selected for the

Volume Number

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Table Vi. Laboratory findings according to outcome DCM

MDCM

Patients (n) Dynamic ECG (n = 141) VPBs (no.) VT episodes (no.) Modified Lown class ~4 Exercise stress test (n = 108) MET Rate-pressure product Exercise duration (min) Abbreviations

as in Tables

I and

Suruiuors

Negative outcome

Survivors

Negative outcome

33

12

70

28

4276 k 9049 4 f 16 62%

6187 +- 7548 1.9 k 2 92s

2637 + 5142 1.4 i- 3.6 6358

1477 + 2480 1.2 k 4 68%

5t2 22442 t 6255 8f4

4+1 19297 + 5818 6+3

6k2 22648 + 5829 9+3

6~2 21432 + 7812 8t4

III.

above significant prognostic predictors: mean pulmonary capillary wedge pressure 515 (n = 72) and >15 mm Hg (n = 71); left atria1 dimension index <25 (n = 76) and 225 mm/m2 (n = 65); and left ventricular ejection fraction 125 (n = 71) and >25% (n = 72). Survival curves that were constructed according to these dichotomized variables are shown in Fig. 4. MDCM and DCM groups were subsequently analyzed separately. Left atria1 diameter index (p < 0.0001) was found to be a significant predictor of prognosis for MDCM, whereas left ventricular ejection fraction (p < O.OOl), mean right atria1 pressure (p < 0.05), and left ventricular end-diastolic diameter index (p < 0.05) were selected for DCM.

Table VII. Significant variables according to Cox univariate

analysis

DISCUSSION Ventricular size in DCM. The present study reflects

the experience of a multicenter prospective registry, which was designed to outline the natural history of DCM in the late 1980s. This registry specifically focuses on early manifestations of disease, with close attention to minor symptoms and initial changes. The purpose of this report was to evaluate the spectrum of left ventricular enlargement in this multicenter population of patients with DCM and to assess its clinical significance and its impact on outcome. In the present study among patients with a uniformly severe depression of ventricular function of unknown cause, a continuous pattern of various degrees of ventricular dilatation was observed, with a relatively high prevalence (31% ) of cases with absent or mild increase in left ventricular size. Although previous clinical and autopsy series included some patients with normal or mildly dilated ventricles,4T l2 to our knowledge there is no published report that specifically examines the distribution of ventricular size in a large population of patient’s with DCM. Dilatation is in fact the well-accepted pathologic hallmark of DCM,i2* l3 whereas the definition of unani-

Abbreviations

Variable

p Value

RVEDP mCWP mPAP LA1 LVEF mRAP RVEDDI MR Heart failure signs LVESDI CI SVI LVEDDI NYHA class LVEDP Duration of exercise

0.0001 0.0001 0.0001 0.0002 0.0003 0.0005 0.0008 0.003 0.004 0.004 0.004 0.005 0.006 0.01 0.03 0.03

as in Table

II.

mous clinical criteria regarding ventricular dilatation specific to this disease is still open to question. According to some authors increased ventricular dimensions, expressed by roentgenographic cardiomegaly or angiographic left ventricular enlargement, must be present,2$ r4-16 whereas other investigator& 3*4 consider dilatation to be just one possible diagnostic criterion. Other reports17 do not, as in our study, include an index of ventricular dimensions to diagnose DCM. On the contrary, in all clinical studieslp 5, 6, l5 pump dysfunction is an essential finding in DCM. The high prevalence of mild dilatation in this series may suggest that preserved ventricular size represents an early phase of DCM. Actually referral to a multicenter registry, which is specifically focused on early manifestations of DCM, might have implied a predominant enrollment of patients who were in

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100 -

80 MPCWPd5 MPCWP>l5

mmHg mmHg

60 -

months

----t

12

0

24

36

LAId5mm LAI z25mm

48

Fig. 4b

80 LVEF ~25% LVEF >25% 60

0

12

24

36

48

months Fig. 4c

Fig. 4. Survival curves according to threshold values for significant prognostic predictors: mean pulmonary capillary wedge pressure (MPCWP, 4a), left atria1 dimension index (LAI, 4b), left ventricular ejection fraction (LVEF, 4c)

Volume Number

125 2, Part 1

the initial stages of the disease. This suggestion seemed to be supported by the relatively low prevalence of patients with severe symptoms (48% in NYHA classes III and IV) in comparison with previously published series of the early 1980s.2T is20 Does mild or absent left ventricular dilatation represent an early phase of DCM? Examination of clinical

and laboratory findings according to the degree of left ventricular enlargement revealed surprisingly few apparent differences in our population. In fact, severity of symptoms, as expressed by NYHA class, and hemodynamic impairment largely overlapped in the two groups. A family history of definite DCM was elicited from 9 % of patients with MDCM compared with 3% of those with DCM; the difference is not significant, but the finding of a higher prevalence of a positive family history is in accordance with the data reported by Keren et a1.6 and may suggest a predisposing genetic factor at least in a subset of patients with MDCM. Significant systolic dysfunction with mild dilatation and a restrictive pattern has previously been related to alcohol abuse.21 Although significant differences were observed in alcohol consumption between MDCM and DCM groups, in the present series no patient showed a restrictive pattern at the time of catheterization. Chronic atria1 fibrillation was significantly more frequent in the MDCM group (22 % ) compared with the DCM group (3%). This is probably the first report that relates prevalence of atria1 fibrillation to ventricular size in DCM. Atria1 fibrillation in this disease is reported to range from 14% to 21% ,lm4 whereas its prevalence was 9% in the present study and was consistently lower in the DCM group; this relationship was not examined in other series. The higher prevalence of atria1 fibrillation in the MDCM group may be partially accounted for by a higher incidence of alcohol abuse and a longer duration of disease, since patients with atria1 fibrillation had experienced symptoms, on average, for a longer period than patients in sinus rhythm (53 +- 52 months vs 24 f 36 months; p < 0.01). Moreover, ventricular dysfunction with preserved ventricular size in patients with MDCM might be secondary to chronic tachycardia, particularly in the subgroup with atria1 fibrillation. However, average heart rate during Holter monitoring was similar in patients with MDCM and those with DCM, regardless of rhythm. Usually the frequency of atria1 fibrillation correlates to left atria1 size, and progressive left atria1 dilatation has in turn been reported to occur in chronic atria1 fibrillation in the absence of structural and functional cardiac abnormalities.22 Although the left atrium was on the average smaller in cases of MDCM, within the MDCM group, patients with persistent

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size in dilated

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419

atria1 fibrillation showed significantly larger left atria1 dimensions than patients in sinus rhythm (26 k 5 mm/m2 vs 21 -+ 5 mm/m2; p < 0.05). Alternatively, the high prevalence of atria1 fibrillation in patients with mild ventricular dilatation might reflect a peculiar alteration of myocardial diastolic properties and, consequently, reduced left ventricular compliance; this might in turn facilitate atria1 damage; no precise measurement of diastolic function was obtained in this multicenter series, but the role of left ventricular compliance should probably be more accurately assessed. Palpitations as the presenting symptom were significantly more frequent in patients with MDCM. Furthermore, in this group the total number of ventricular premature beats and ventricular tachycardia episodes during dynamic ECG monitoring and the prevalence of complex ventricular arrhythmias were higher in comparison with patients who had DCM; however, differences between groups were not significant. It is well known that ventricular arrhythmias represent a common finding in DCM*; their higher prevalence in patients with mild dilatation again supports the concept of a lack of relationship between arrhythmias and ventricular enlargement. Exercise tolerance as indicated by estimated metabolic equivalents was slightly yet significantly reduced in patients with MDCM compared with those with DCM, which suggests defective mechanisms of pathophysiologic adaptation to effort in small cardiomyopathic ventricles, which may be related to increased stiffness of the left ventricular chamber. On the other hand, it may be supposed that in the same range of left ventricular ejection fraction small ventricles produce a lower stroke volume. Thus the above findings did not confirm the hypothesis that mild dilatation of the left ventricle represents just an initial phase of DCM or a more favorable physiopathologic and clinical condition. These conclusions are in fact supported by results of follow-up and outcome assessment. Correlation of left ventricular dimensions, follow-up evaluation, and prognosis. At medium-term follow-up

a similar evolution of functional state in patients with MDCM, as well as in those with DCM, was observed. Furthermore, over 60% of patients in both groups had stable left ventricular size. However, a group that represented less than 20% of patients with MDCM showed an echocardiographic progression to overt ventricular dilatation. Probably this subset may actually be classified as having an initial phase of DCM. The overall event-free survival at medium- and long-term follow-up appeared to be substantially the same in patients with MDCM and those with DCM. *References

16, 20-21.

23, and

24.

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Gavazzi et al.

Moreover, sudden death or heart failure that resulted in death, transplantation, and time to death 01 transplantation did not differ between the two groups. Among patients with MDCM, survivors and nonsurvivors differed only in the degree of ventricular dysfunction. Patients with MDCM and an unfavorable outcome, who showed severe ventricular impairment., had a longer symptomatic period before enrollment than patients with DCM who died, which suggests long-lasting mild dilatation in the former group. Thus the suggestion that most of the patients with absent or mild ventricular dilatation have an early, less severe stage of the disease seems unlikely. As a matter of fact, a relatively preserved left ventricular size in DCM does not appear to be a distinctive feature of a homogeneous subset of patients with respect to clinical condition, ventricular function, and outcome: within the same range of left ventricular dimensions, patients with differing degrees of ventricular impairment and different prognoses were observed. Keren et al.” reported on the clinical evolution in a highly selected group of 20 patients with mild ventricular dilatation, heart failure, and severe systolic dysfunction (left ventricular ejection fraction <30%) without a restrictive pattern. The authors identified a subset of patients with MDCM who had poor medium-term prognosis. In the present series severe heart failure was not a requirement for inclusion, but left ventricular ejection fraction had to be less than 400,. The criteria of Keren et al.6 were applied to our series, and 11 patients with MDCM and 23 patients with DCM who had heart failure and left ventricular ejection fraction <30% were compared. Patients with MDCM in this group were older (49 + 8 years vs 38 + 12 years; p < 0.05) and had a longer symptomatic period (62 +- 56 months vs 21 f 32 months; p < 0.05) than those with DCM. Laboratory findings were once again similar, except for mean aortic pressure at catheterization (98 + 15 mm Hg vs 85 * 12 mm Hg; p < 0.01) and presence of persistent atria1 fibrillation (45 % vs 9 % ; p < 0.05). The mortality rate for this subgroup was higher than that for the whole series: four patients with MDCM (36 “0) and six with DCM (26% ) died. One patient with MDCM and three with DCM died suddenly, and five patients with DCM underwent transplantation. These findings further confirm that patients in the advanced stages of idiopathic ventricular dysfunction may still not have significant ventricular enlargement. We have no explanation for a better understanding of the underlying physiopathologic mechanisms for mild dilatation. The paucity of myofibrillar loss that has been reported by others57 6 seems to suggest functional rather than anatomic

American

February 1993 Hearf Journal

causes. The prognostic impact of left ventricular df mensions is controversial. Among the most, recent reports in which Cox’s model was used to predict prognosis in patients with DCM,i4, I6 I7 only one’ 1 retrospective study showed that dilatation-related indexes (left ventricular end-systolic volume and left ventricular end-diastolic diameter) had a predict,ive value. In the present prospective series multivariate analysis selected an index of ventricular dysfunction (pulmonary capillary wedge pressure) and left atria1 size as determinants of a negative outcome in t,he whole population. No parameter that was related to left ventricular dilatation showed an independent prognostic value. Left atria1 size was found to be a significant prognostic indicator in the MDCM group: although the higher prevalence of atria1 fibrillation, which was observed in approximately one fifth of patients, might partially account for the finding, rhythm had no independent prognostic relevance in this series. On the contrary, hemodynamic changes that, could be considered an expression of reduced ventricular compliance, such as pulmonary capillary wedge pressure and left ventricular end-diastolic pressure, were significant predictors of prognosis according to univariate analysis; their prognostic significance might be indirectly reflected in multivariate analysis by increased left atria1 size. Left ventricular dimension was an independent predictor of prognosis in the DCM group, which may reflect physicians’ tendency t,o award priority for transplantation to patients with more dilated hearts. Both death and transplantation were defined as negative outcomes in this study: as a matter of fact, heart transplantation has now become an established treatment for advanced DCM and will probably contribute significantly to alter the natural history of this disease. This outcome had not been considered in the previously quoted reports, which were largely retrospectivei’s le.‘7 or based on cases excluded from this therapeutic option.‘*’ The choice of including transplantation in negative outcome might have influenced the selection of variables in our multivariate model. In fact one multivariate analysis in which death was considered as the only end point yielded the following different results: the three variables that were selected as major independent predictors of survival were mean right atria1 pressure (p = O.OOa), modified Lown class (p = 0.004) and left atria1 dimension index (p = 0.004). Once again no parameter that was related to left ventricular dilatation was selected. Moreover, in accordance with numerous reports in the literature,16,20. 23-‘L5 an index of the arrhythmic risk was predictive of prognosis.

vcdume Number

125 2, Part 1

Limitations of the study. In two centers of this prospective registry, patients who had been specifically referred to undergo heart transplantation and who were directly added to the waiting list for transplantation were not enrolled in the study; we believed that inclusion of these patients would reflect a selection bias, which would artificially increase the relative proportion of severe cases. The wide range of clinical severity that is reported in this series probably better represents the spectrum of DCM that is observed today in centers that do not perform transplantation, as a consequence of increased attention to the disease and earlier diagnosis; this may partially explain the low mortality rate observed (7 9%at 1 year). Recently introduced changes in medical treatment (vasodilators and in particular angiotensin-converting enzyme inhibitors) may also have modified the natural history of DCM,26 with a substantial decrease in mortality rate that was, at least in the first reports, very high. ‘3 4 The mean follow-up in this study was limited to 30 months; more prolonged observation might yield a greater incidence of progression to overt dilatation. Echocardiographic diameters were chosen instead of volumes in this series to reduce intercenter variability of measurements and allow a comparison through follow-up; the reproducibility of M-mode echocardiographic measurements in heart failure has previously been demonstrated.27 Accurate studies of diastolic function were not routinely included in our multicenter protocol; diastolic dysfunction, however, might actually be a key point in the evolution of mild DCM cases and deserves better assessment. Duration of exercise, although significant as determined by univariate analysis, was not an independent predictor of prognosis as determined by multivariate analysis; more accurate measurements of exercise tolerance that were not routinely included in this multicenter study such as maximum oxygen consumption, which has been shown to be an excellent prognostic indicator in congestive heart failure,2s may prove to be of value in these patients. Conclusions. Minimal or mild ventricular dilatation is found in a substantial proportion of patients with pump failure of unknown cause, who are included in the clinical syndrome of DCM. MDCM represents a heterogeneous group including patients in the early stages of the disease and those with a peculiar syndrome of contractile impairment and persistently small hearts. The currently used definition of DCM, with its emphasis on ventricular dilatation, does not permit an adequate classification of those cases in which the main feature is not ventricular enlargement but contractile dysfunction. Ventricular

Ventricular

dilatation come.

size in dilated

is not an independent

We thank Meri Saida assistance with statistical

cardiomyopathy

predictor

Zaina, BS, and Marina analysis.

Parolini,

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of outBS, for

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APPENDIX: ITALIAN CARDIOMYOPATHY

MULTICENTER STUDY (S. P. I. C.)

Participating Centers Milan, Ospedale Niguarda Ca’ Granda, Dipartimento di Cardiologia “A. De Gasperis”: C. Belli, C. DeVita, M. Ferratini, F. Recalcati, R. Vecchi, E. Bonacina Florence, Ospedale Careggi, Servizio di Cardiologia San Luca: A. Dolara, F. Cecchi, M. Ciaccheri, G. Castelli, V. Troiani, F. Gori, M. Nannini Milan, Ospedale San Carlo, Divisione di Cardiologia: F. Casazza, A. Capozzi, R. Mattioli Monza, Ospedale San Gerardo, Divisione di Cardiologia: F. Valagussa, A. Bozzano Pisa, Istituto di Fisiologia Clinica de1 C.N.R.: A. Biagini, D. Levorato, F. Vernazza, W. Pelosi

February 1993 Heart Journal

Pavia, I.R.C.C.S. Policlinico San Matbeo. Divisione di Cardiologia: A. Gavazzi, C. Campana, G. Graziano, U. Veritti, E. Arbustini, C. Montemartini Trieste, Ospedali Riuniti, Divisione di Cardiologia: F. Camerini, R. Bussani, A. Di Lenarda, G. Lardieri, I,. Mestroni, D. Miani, A. Salvi, F. Silvestri, G. Sinagra, B. Pinamonti, A. Perkan Rho, Ospedale Civile, Divisione di Cardiologia: I,. Preti, F. Ferrari Varese, Ospedale di Circolo, Divisione di Cardiologia: G. Binaghi, M. Luvini Cinisello Balsamo, Ospedale Bassini, Divisione di Medicina: R. Rumolo, L. Carini, S. De Ceglia, E. Montani. Milan, Consorzio Provinciale Antitubercolare, Servizio di Cardiologia: A. Sachero, E. Giagnoni, L. De Cristofaro, Naples, Ospedale Monaldi, Ia Divisione di Medicina: M. Cafiero, M. Borgia, N.F. Costantino, A. De Santis, R. D’Oriano Vicenza, Ospedale Civile, Divisione di Cardiologia: M. Vincenzi, M. Sartori, R. Ometto Treviso, Presidio Ospedaliero Multizonale, Divisione di Cardiologia: V. Cuzzato, G. Renosto, A. Moro Scientific Committee

G. Baroldi, Istituto Fisiologia Clinica-CNR, Sezione di Milan0 F. Camerini, Ospedali Riuniti, Divisione di Cardiologia, Trieste C. De Vita, Ospedale Niguarda CB Granda, Dipartimento di Cardiologia “A. De Gasperis”, Milan0 Coordinating Centre

R. De Maria, Istituto Fisiologia Clinica-CNR, Sezione di Milano, A. Gavazzi, Policlinico San Matteo, Divisione di Cardiologia, Pavia Statistical

Analysis

A. Caroli, M.S. Zaina Istituto CNR, Sezione di Milan0

Fisiologia

Clinica-