votume 109

Number 3, Part 1 Lidocaine-increased ventricular refractoriness

17. Handel F, Luzzi FA, Wenger TL, Barchowsky A, Shand DG, Strauss HC: Lidocaine and its metabolites in canine plasma and myocardium. J Cardiovasc Pharmacol5:44, 1983.

18. Scherlag BJ, El-Sherif N, Hope R, Lazzara R: Characteriza- tion and localization of ventricular arrhythmias resulting from myocardial ischemia and infarction. Circ Res 35:372, 1974.

19. El-Sherif N, Scherlag BJ, Lazzara R, Hope RR: Re-entrant ventricular arrhythmias in the late myocardial infarction period. Circulation 56:395, 1977.

20. Allen JD, Bremen FJ, Wit AL: Actions of lidocaine on transmembrane potentiate of subendocardial Purkinje fibers surviving in infarcted canine hearts. Circ Res 43:470, 1978.

Asymmetric septal hypertrophy and sympathetic overactivity in normotensive hemodialyzed

patients

Sympathetic activity has been evaluated in 23 chronic uremic normotensive patients on long-term hemodialysis. M-mode and bidimensional echocardiographic finding of asymmetric septal hypertrophy (ASH) was shown in seven (30.4%). Sympathetic function was assessed by determining arterial plasma norepinephrine (plasma NE) and epinephrine (plasma E) in supine and upright positions, both before and after dialysis. After dialysis standing caused a significant increase in plasma NE levels in the patients with ASH in comparison to the patients without ASH and the control group. A significant decrease in mean blood pressure (mBP) and a sharp heart rate (HR) increase were detected in the patients without ASH, whereas mBP and HR were unchanged in the patients with ASH. Predialysis serum creatinine and fasting triglycerides were found to be significantly higher in the group with ASH. These results suggest that sympathetic overactivity may play a role in the development of interventricular septum hypertrophy. This increased neurosympathetic responsiveness is probably related to the counteraction of the

postural dialysis-induced hypotension. (AM HEART J 109539, 1985.)

Daniele Bernardi, M.D., Luigi Bernini, M.D., Giuseppe Cini, M.D.,

Sergio Ghione, M.D., and Igino Bonechi, M.D. Pl’sa, Italy

Asymmetric septal hypertrophy (ASH) is a well- known echocardiographic finding reported in several types of cardiovascular disease.’ Chronic renal fail- ure in dialysis treatment is also a condition associ- ated with ASH in hypertensive and/or cardiomyop- athy patients.2-5 In our previous study performed on normotensive hemodialyzed patients, we discovered an incidence of ASH of 36.4% .6 Recent findings suggest that the chronic catecholamine excess may be related to ASH in borderline hypertension7 and

From the Division of Medicine, Ospedale S. Miniato; Clinica Medica Generale II, University of Pisa; and CNR Clinical Physiology Institute, University of Pisa.

This study was supported in part by the Accademia degli Euteleti of San Miniato.

Received for publication May 7, 1984; revision received Aug. 2, 1984;

accepted Sept. 4,1984.

Reprint requests: Daniele Bernardi M.D., Ospedale di San Miniato, Piazza XX Settembre, 56027 San Mini&o, Pisa, Italy.

in hypertrophic cardiomyopathy.* To assess the neurosympathetic function in normotensive chronic uremic patients with and without ASH, we have determined arterial plasma catecholamines, both at rest in the supine position and after postural activa- tion, just before and after a regular hemodialysis session.

METHODS

Patients. The study was performed on 23 normotensive patients (12 women and 11 men) aged 25 to 69 years, with chronic renal failure undergoing long-term hemodialysis treatment for more than 6 months. These patients were maintained on chronic intermittent hemodialysis for 12 to 15 hours weekly for 7 to 110 months. The causes of renal failure were: glomerulonephritis in 10, polycystic kidney disease in eight, pyelonephritis in two, nephropathy of unknown origin in two, and bilateral nephrectomy for renal abscesses in one. Patients with valvular heart dis- eases, past history of arterial hypertension or of coronary

539

540 Bernardi et al. March, 1995

American Heart Journal

Table I. Clinical data and serum biochemistry in groups I and II compared using unpaired Student’s t test

Group I (n = 16) mean + SD

Group II (n = 7) mean t SD t P

Age (yr) 52.9 t_ 11.9 57.8 -+ 6.1 1.023 NS L.D. (ma) 49.0 2 30.7 69.3 f 28.7 1.487 NS I.W.C. (kg) 1.91 r 0.60 2.03 2 0.84 0.391 NS Urea bvddl) 32.7 + 6.6 32.2 f 4.:JJ 0.18:Jl NS Creat. (mmol/L) 1064.0 + 158.2 1222.4 i 104.3 2.415 <0.026 Ur. AC. (mmol/L) 476.0 + 54.3 487.6 i .55.5 0.469 NS Trigl. (mmol/L) 1.95 z!I 0.70 2.81 + 0.78 2.6”” -I <I).02 LDL Chol. (mmol/L) 3.13 t 0.93 3.10 t_ 0.81 0.074 NS HDL Chol. (mmol/L) 1.02 i 0.30 0.94 f 0.42 0.531 c -L NS Ca (mmol/L) 2.3 It 0.13 2.38 i 0.19 I .250 NS P (mmol/L) 1.41 f 0.34 1.32 * 0.29 0.608 Nd K (mmol/L) 5.77 rt 0.70 5.50 T 0.74 0.838 NS Na (mmol/L) 139.1 i 3.0 140.0 + :x2 0.650 NS Tot. Prot. (gm/dl) 6.69 + 0.41 6.40 it 0.38 1.593 NS Ht ( (I( 1 34.6 i- 15 34.9 i 10.9 0.047 NS

___-. _-~ L.D. = length of dialysis; I.W.C. = interdialysis weight changes; Great. = creatinine; Ur. Ac. -= uric acid; Trigl. = triglycerides: I,DL Chol. = LDL cholesterol; HDL Chol. = HDL cholesterol; Tot. Prot. = total protein; Ht = hematocrit.

Table II. M-mode echocardiographic data (mean values + SD) related to the thickness of ventricular septum and left ventricular posterior wall in the two groups of patients, compared using unpaired Student’s t test

IVST PWT IVSTI

(cm) (cm) PWT

Group I (n = 16) Without ASH Group II (n = 7) With ASH

M 1.1 0.95 1.1 SD 0.1 0.1 0.1 M 1.7 0.9 1.5 SD 0.25 0.5 0.1 t 8.333 0.394 8.889

P <O.OOl NS <O.OOl ____-

ASH = asymmetric septal hypertrophy; IVST = interventricular septal thickness; PWT = posterior wall thickness.

artery disease, significant pericardial effusion, signs of cardiac failure, cardiothoracic ratio greater than 0.50, diabetes mellitus, or neoplasms were excluded. In all patients the ECG was normal.

Serum biochemistry. The reported values of urea, creatinine, uric acid, electrolytes (K, Na, Ca, P), total protein concentration, hematocrit (Ht.%), and serum lip- ids (cholesterol, triglycerides) are the mean values of six determinations over the previous 4 to 6 months. Predialy- sis blood samples were obtained after an overnight fast.

Experimental procedures. None of the patients was taking sedative or stimulant drugs during the study. No edema or symptomatic arterial hypotension in the upright position or clinical evidence of peripheral neuropathy were present. All patients were taking a normal dietary regimen with free protein and salt intake. No coffee, tea, or smoking were allowed for at least 12 hours prior to testing. The experimental procedure was carried out in the morning, between I and 8 A.M., in a quiet room at a constant temperature (24 -t 2’ C). The sequence of events

and timing were as follows: (1) an indwelling silicone rubber catheter was placed in the arm arteriovenous fistula towards the arterial side; (2) there were 20 minutes of resting in the supine position; (3) arterial blood samples were drawn for supine catecholamine determination; (4) there were 7 minutes of rest in the upright position; and (5) arterial blood samples were drawn for upright cate- cholamine determination. The blood pressure (BP) by indirect method and heart rate (HR) were measured before and at the end of the standing period. This procedure was repeated both before the start and after the end of a regular dialysis treatment. Hemodialysis lasting 4 hours was carried out with patients in the fully supine position by using a dialysis bath with the following chemical composition: Na+, 138 mmol/L; K’, 1.5 mmol/L; Ca++; 2.0 mmol/L; and Na acetate, 37.1 mmol/L. A graded rate-constant fluid loss was obtained until the “ideal dry body weight” was achieved.

Catecholamine assay. The blood samples were pro- cessed by the techniques of separation and determination required for the high-pressure liquid chromatography electrochemical method for catecholamines.g The mean value of two determinations from each sample is reported; the samples were always analyzed by the same technician. In eight healthy subjects similar in sex (four women and four men) and age (26 to 64 years) to the selected uremic patients, plasma catecholamines were also measured.

Echocardiographic study. An Aloka Sect Scan SSD- 710 instrument with a 3 MHz transducer was used to perform the echocardiographic study. The patients were assessed just after the dialysis treatment. On M-mode echocardiograms the thickness of ventricular septum and posterior left ventricular free wall were measured just before atria1 systole, with the ultrasonic beam directed slightly below the mitral leaflets, according to the recom- mendations of the American Society of Echocardiogra- phy.“’ To verify ventricular septal thickness, M-mode

volume 109

Number 3, Part 1 Development of asymmetric septal hypertrophy 541

Fig. 1. Two-dimensional echocardiograms of a uremic hemodialyzed patient with asymmetric septal hypertro- phy shown in the parasternal long-axis (A) and apical two-chamber (B) views.

echocardiograms were also obtained simultaneously with direct visualization of the cardiac anatomy using a bidi- mensional image. Moreover, the two-dimensional echocar- diographic examination included the imaging of a number of cross-sectional planes through the heart, as previously described.” The diagnosis of ASH was made when the ventricular septal thickness and posterior wall thickness ratio (IVST/PWT) was greater than 1.3.” According to this parameter the patients were divided into two groups: group I = patients without ASH, and group II = patients with ASH.

Statistical analyses. The statistical methods used were the paired and unpaired Student’s t test for comparison of two means and the one-way analysis of variance (ANOVA) for more than two means. ANOVA was followed by multiple comparisons according to the Scheffe method,13 whenever significant F values arose. Differences for p values <0.05 were assumed to be significant.

RESULTS

Table I summarizes the clinical parameters and the serum biochemistry for the two groups of uremic

Fig. 2. Two-dimensional echocardiograms of another uremic hemodialyzed patient with ASH shown in the parasternal long-axis (A) and short-axis (B) views.

patients. Serum triglycerides and creatinine were significantly higher in the patients in group II. No significant differences were found in the other data. There was no prevalence of any specific type of nephropathy in either of the two groups.

incidence of ASH (Table II). Echocardiographic study showed ASH in 7 of the 23 patients (30.4%) (Figs. 1 and 2). In these cases the IVST/F’WT ratio was respectively: 1.6, 1.7, 1.4, 1.4, 1.5, 1.6, and 1.4. None of the patients presented systolic anterior motion of the anterior mitral valve leaflet or other findings specific of hypertrophic cardiomyopathy.’ In the cases without ASH, concentric left ventricular hypertrophy was not present.

Plasma catecholamines (Table Ill). Before dialysis the uremic patients showed a trend, although not statistically significant, to higher values of plasma norepinephrine (NE) in comparison with those of the control group. This behavior was more evident in group II in the upright position. After dialysis both the upright plasma NE concentration and the

542 Bernardi et al. March, 1985

PImerican Heart Journal

Table III. Mean values (k SD) of plasma catecholamines and statistical results of comparison among controls and uremic patients of group I and group II, before and after dialysis

Supine NE (rxlmli

Standing NE (pglmll

ANE (pglmli

Supine E ipglml,

Standing E fmlml)

AE bdmlj

Controls (n = 8) 248 k 28

Before dialysis G I (n = 16) G II Cn = 7)

ANOVA c “9 I vs II

420.5 i 230 485 f 394

NS

After dialysis G I (n = 16) G II (n = 7)

ANOVA c vs I vs II

360 + 208 424 IL 257

NS

Significance of multiple comparisons: c “S I c “S II I “S II

475 i 182

526 + 186 785 t 385

NS

679 ? 384 998 -t 230

*

NS t

NS

233 2 162 85 i 39 143 k 81 58 f 64

106 i 231 145 t 304 182 * 344 36 + 64 300 + 215 74 + 77 66 k 64 8 + 40

NS NS NS NS

319 + 206 110 + 84 111 k 95 1 2 102 575 i 215 79 I 58 117 i 82 37 f 43

1 NS NS NS

NS

i *

G I = group I; G II = group II; C = controls; NE = norepinephrine; E = epinephrine; ANE = postural change of plasma NE levels; JE = postural change of plasma E levels. *p < 0.05. tp < 0.02. tp < 0.01.

postural change of plasma NE (A plasma NE) levels were significantly higher in the uremic patients of group II compared to the normal subjects (p < 0.02 and (p < 0.01, respectively). Plasma NE levels were not statistically different between the patients of group I and the controls. While the patients of group II responded to orthostasis by a significant increase of plasma NE levels both before (p < 0.01) and after dialysis (p < O.OOl), the patients of group I showed such a behavior only after dialysis (p < 0.001). How- ever, A plasma NE after dialysis was significantly higher in group II than in group I (p < 0.05).

Plasma epinephrine (E) did not differ significant- ly between the three groups in all examined condi- tions. Plasma E concentrations were not different in lying and upright positions before and after dialysis, both in group I and in group II.

Mean BP and HR (Fig. 3). Mean blood pressure (mBP) was obtained from the following formula: % diastolic pressure + % systolic pressure. In the patients of group I standing caused a significant decrease in mBP after dialysis (88.4 ? 16.2 vs 79.5 f 18.4 mm Hg; t = 3.506, p < 0.01) and a marked HR increase both before (79 + 12 vs 87 + 13 bpm; t = 3.670, p < 0.01) and after dialysis (88 + 13 vs 103 f 19 bpm; t = 5.934, p < 0.001). These changes in mBP and HR were not observed in the patients of group II.

DISCUSSION

ASH. Current dataI show that NE is a growth hormone for myocytes; this is a direct hormonal effect unrelated to imposed afterload. Other recent clinical7 and experimentall findings suggest the presence of a link between the development of ventricular septum hypertrophy and chronic cate- cholamine excess. Our results in chronic uremic normotensive patients on hemodialysis seem to con- firm this relationship. In the present study the incidence of ASH was 30.4 % .

Sympathetic activity. The assessment of plasma catecholamines in arterial blood allows an accurate estimation of sympathetic tone,16 particularly of cardiac adrenergic activity.” In addition, the assumption of the upright posture, leading to an increase of plasma NE concentrations, is a reliable index of the adrenergic neuronal activity.18 A signif- icant increase of plasma NE during both activelg and passivezO postural tests in uremic hemodialyzed patients has been demonstrated. In our patients the mean values of plasma NE also tended to be higher in uremic patients than in the normal subjects, although such an increment was statistically signifi- cant only in group II, after dialysis following postur- al stimulation.

Previous investigators have demonstrated that plasma NE is only slightly elevated in chronic renal

Volume 109

Number 3, Part 1 Development of asymmetric septal hypertrophy 543

MEAN B.l? H. R.

GI GII GI GII BEFORE DIALYSIS

SUPINE ns ns

I ns ns

STANDING A’

b I33

$*** b

ns 0 l **

AFTER DIALYSIS

SUPINE ns

ns

STANDING

EB

ns

@... @..a!.

ns

I: f?

0 l **

Fig. 3. Effects of standing on mean BP and HR in the two groups of uremic patients before and after dialysis. Mean B.P. = mean blood pressure; H.R. = heart rate; G I = group I; G II = group II; Arrows = dif- ferences between stimulated and basal values (paired t test); solid circles = differences between means of the two groups at a given time (unpaired t t.est). @ = significant increase; 0 = significant decrease. Asterisks represent the significance of differences: *** = p < 0.01; **** = p < 0.001; ns = not signifi-

failure before the onset of dialysis and tends to further increase during chronic dialysis treatment,2l while it can be lowered by renal transplantationzO Long-term hemodialysis, therefore, might cause enhancement of plasma NE levels, either by a chronic hypotensive stimulationz2 or by impaired central dopaminergic control of sympathetic activi- ty.23

Relation between sympathetic activity and ASH. The relationship between sympathetic nervous function and ASH has been recently assessed in patients with hypertrophic cardiomyopathy24 and in patients with borderline hypertension7; however, in these condi- tions plasma NE levels, although increased, remained within the normal range. Our results seem to support the hypothesis of a close relationship between the chronic excess of plasma NE and ASH, since the patients with ASH showed a higher sympa- thetic responsiveness to postural activation after dialysis than the patients without ASH and the controls. In group II the lack of plasma NE enhance- ment before dialysis may be explained by concomi- tant fluid overload preventing adrenergic overactivi- ty induced by the postural change.25

Noteworthy is the impressive prevalence of hyper- trophic cardiomyopathy detected by Drukker et a1.5 in a series of uremic hypertensive children main-

tained on chronic dialysis. Their report also sup- ports the attractive hypothesis that NE may play an important role in septal hypertrophy development; the presence of ASH may relate to the maturity of the myocardium at the time of exposure to NE.

As shown in Fig. 4, in the patients without ASH at the end of dialysis treatment when “dry body weight” was achieved, the assumption of upright position caused a significant decrease in mBP and a sharp HR increment, according to a previous report.22 On the other hand the patients with ASH did not have such changes in mBP and HR. Proba- bly this behavior in group II reflects more powerful adrenergic responsiveness resulting in arteriolar constriction; hyposensitivity of sinus node receptors to chronic increased sympathetic activity2” may be the cause of reduced HR response to standing. These results suggest that sympathetic nervous overactivity is probably related to impeding postural dialysis-induced hypotension. The biochemical find- ings of elevated levels of serum triglycerides and creatinine in patients with ASH may represent indirect support for the central role of plasma catecholamines. Indeed, adrenergic activity might induce these changes by an increase of lipolysis27 and protein synthesis of myocytes.14,2s Because of the possible role of sympathetic overactivity in the

544 Bernardi et al.

AFTER DIALYSIS

GI GII

SUPINE- STANDING SUPlNE---DSTANDING

PLASMA 900. N.E.

Pg/l-!ll 700 _

600.

300 _

100.

100

MEAN B.P. SO t

mmtfg 80

70

60

t

HR.

b/m

110.

100.

so _

80.

70 _

60-

r------- . r/; ti ; 2. -- ,.**

T ti

--- ..** ! i-------

I+

Fig. 4. Effects of standing on plasma NE, mean BP, and HR in the uremic patients of group I and of group II after dialysis compared by paired and unpaired Student’s t test. G I(0) = group I; G II (M) = group II; Plasma NE = plas- ma norepinephrine. ** = p < 0.02. Values are means 2 SD. For further explanation, see legend to Fig. 3.

development of ASH, long-term follow-up is needed in order to determine the clinical course of this echocardiographic finding and to evaluate the possi- ble therapeutic implications of using drugs which interfere with sympathetic activity.23s 2g

REFERENCES

1. Maron BJ, Epstein SE: Hypertrophic cardiomyopathy. Recent observations regarding the specificity of three hall- marks of the disease: Asymmetric septal hypertrophy, septal disorganization and systolic anterior motion of the anterior mitral leaflet. Am J Cardiol 45:141, 1980.

2. Abbasi AS, Slaughter JC, Allen MW: Asymmetric septal hypertrophy in patients on long-term hemodialysis. Chest 74:548, 1978.

3. Kuroda M, Murakami K: Variety of cardiomegaly showing asymmetric septal hypertrophy or dilatation in long-term hemodialyzed patients. Nephron 24:155, 1979.

4.

3.

6.

7.

8.

9.

10

11

12

13

14

15

16

17

18

19

20

21

2%

23

24

25

March. 1985

American Heart Journal

Mehta BR, Ireland MA, Shiu MF, Robinson BHB: Echocar- diographic detection of cardiac involvement in uraemia. Proc Em Dial Transplant ASSOC 17:707. 1980. Drukker A, Urbach J, Glaser J: Hyperthrophic cardiomyopa- thy in children with end-stage renal disease and hyperten- sion. Proc Eur Dial Transplant Assoc 18:542, 1981. Bernardi D, Bernini L, Cini G, Brandinelli Geri A, Urti DA, Bonechi I: Asymmetric septal hypertrophy in uremic-normo- tensive patients on regular hemodialysis. Nephron 39:30. 1985. Corea L, Bentivoglio M. Verdicchia I’. Motolese M: L,eft ventricular wall thickness and plasma catecholamines in borderline and stable essential hypertension. Eur Heart ,J 3:164. 1982. Dargie HJ, Goodwin JF: Catecholamines. cardiomyopathies, and cardiac function. In Yu PN, Goodwin JF, editors: Progress in cardiology. Philadelphia. 1982, Lea & Febiger, p 93. LCEC application. West Lafayette. lnd.. 1981, Bioanalytical Systems Inc., Note No. 14. Sahn DJ, DeMaria A. Kisslo .J, Weyman A: Recommenda- tions regarding quantitation in M-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation 58:1072, 1978. Tajik AJ. Seward JB, Hagler Dd, Mair DD, Lie .J’I’: ‘I’wo- dimensional real time ultrasonic imaging of the heart and great vessels. Technique, imaging orientation, structure iden- tification and validation. Mayo Clin Proc 53:271, 1978. Feigenbaum H: Echocardiography. Philadelphia, 1981, Lea & Febiger, p 456. Dixon WJ, Massey FJ: Introduction to statistical analysis. New York, 1969, McGraw-Hill Book Company, Inc, p 162. Simpson P. McGrath A, Savion S: Myocyte hypertrophy in neonatal rat heart. cultures and its regulation by serum and by catecholamines. Circ Res 51:787, 1982. Raum WJ, Laks MM, Garner D, Swerdloff KS: +adrenergic receptor and cyclic-AMP alterations in the canine ventricular septum during long-term norepinephrine infusion: Implica- tions for hypertrophic cardiomyopathy. Circulation 68:693, 1983. Kjeldsen SE, Eide I, Aakesson I, Leren P: Elevated arterial adrenaline and noradrenaline in essential hypertension. Milan, 1983, First European Meeting on Hypertension. abstr. No. 210. Braunwald E: Mechanisms of contraction of the normal and failing heart. Boston, 1976, Little Brown & Company. Kopin IJ, Lake CR, Ziegler M: Plasma levels of norepineph- rine. Ann Intern Med 88:671, 1978. Brecht HM. Ernst W, Koch KM: Plasma noradrenaline levels in regular haemodialysis patients. Proc Eur Dial Transplant Assoc 12:281, 1976. McGrath BP, Ledingham .JGG, Benedict CR: Catechoiam- ines in peripheral venous plasma in patients on chronic haemodialysis. Clin Sci Mol Med 55:89, 1978. Ksiazek A: Dopamine-beta-hydroxylase activity and cate- cholamine levels in the plasma of patients with renal failure. Nephron 24:170, 1979. Cannella G. Picotti GB, Movilli E. Cancarini G, De Marinis S. Calva MD, Maiorca R: Plasma catecholamine response to postural stimulation in normotensive and dialysis hypoten- sion-prone uremic patients. Nephron 27:285. 1981. Sturani A, Degli Esposti E, De March A, Santoro A, Fuschini G, Zuccala’ A, Chiarini C, Flamigni C, Zucchelli P: Dopamin- ergic control of sympathetic activity and blood pressure in haemodialysis patients. Proc Eur Dial Transplant Assoc 20:156, 1983. Dargie H. Boschetti E. Reid J. Goodwin d: Autonomic function in hypertrophic cardiomyopathy (abstr). Circulation 62fsuppl III):;IOl, 1980. Wehle B, Asaba H, Castenfors J, Gunnarsson B, Bergstrom J: Influence of dialysate composition on cardiovascular function

Volume 109

Number 3, Part 1 Development of asymmetric septal hypertrophy

in isovolaemic haemodialysis. Proc Eur Dial Transplant Assoc 16153, 1981.

26. Goldstein RE, Beiser GD, Stampfer M, Epstein SE: Impair- ment of autonomically mediated heart rate control in patients with cardiac dysfunction. Circ Res 36:571, 1975.

27. Heuck CC, Ritz E: Hyperlipoproteinemia in renal insufficien- cy. Nephron 25:1, 1980.

In Hurst JW, editor: The heart. New York, 1962, McGraw- Hill Book Co, Inc, p 1299.

29. Corea L, Bentivoglio M, Verdicchia P: Echocardiographic left ventricular hypertrophy as related to arterial pressure and plasma norepinephrine concentration in arterial hyperten- sion. Hypertension 6:837, 1983.

28. Goodwin JF, Roberts WC, Kass Wenger N: Cardiomyopathy.

Three autopsy cases of progression to left ventricular dilatation in patients with hypertrophic cardiomyopathy

The hearts of three cases of congestive heart failure with dilated left ventricles developing in patients with symptomatic hypertrophic cardiomyopathy (HCM) were morphologically investigated. The results showed that disproportionate hypertrophy and dilatation of the left ventricles, accompanied by massive fibrosis and myocardial disarray, were present in the three patients. The mean percent area of fibrosis of the left ventricle was 34.7% and 47.4% at the upper third and lower third levels, respectively, and was much more frequently associated with disarray (84.4 i 12.3%). Moreover, the fibrosis was most extensive in the lateral wall of the left ventricle, followed by the posterior, anterior, and interventricular walls. The fibrosis was also diffuse regardless of the subendocardial or subepicardial region of the heart. The findings in the present study suggest that the disarray in this particular series of HCM might be responsible for

the mechanism of the fibrosis leading to dilatation of the left ventricle. (AM HEART J 109:545, 1985.)

Chikao Yutani, M.D., Masami Imakita, M.D., Hatsue Ishibashi-Ueda, M.D.,

Kaoru Hatanaka, M.D., Seiki Nagata, M.D., Hiroshi Sakakibara, M.D., and Yusuharu Nimura, M.D. Osaka, Japan

The course of hypertrophic cardiomyopathy (HCM) is extremely variable and patients who are asymp- tomatic initially tend to remain so, while those who are more disabled generally deteriorate or die sud- denly.“’ Accordingly, it is very rare that the patient with HCM dies with congestive heart failure, char- acterized by cardiac enlargement similar to that of dilated cardiomyopathy (DCM).3,4 Although the fibrosis of DCM is not uncommonly found and is

From the Division of Pathology, the Department of Etiology and Patho- genesis, the Department of Internal Medicine, and the Research Institute, National Cardiovascular Center.

Received for publication June 4, 1984; revision received Sept. 4, 1984;

accepted Oct. 2. 1984.

Reprint requests: Chikao Yutani, M.D., Ph.D., Division of Pathology, National Cardiovascular Center, 5-125 Fujishirodai Suita, Osaka 565, Japan.

occasionally massive,5 the pattern of the fibrosis of HCM is usually a plexiform fibrosis with an area not as large as that, in DCM. 6,7 To clarify the pathogen- esis of the fibrosis occurring in the patient with HCM who subsequently dies with congestive cardiac failure, the following investigations were conducted: (1) a study of the variations in severity, distribution of fibrosis, and myocardial disarray; (2) an investiga- tion of the relationship between the fibrosis and the myocardial disarray; and (3) a verification of trans- mural myocardial infarction as a cause of massive fibrosis of the left ventricle in older patients with HCM, as reported previously by Maron et al.*

METHODS

Case No. 1. The patient was a 14-year-old adolescent

male, who had a cardiac murmur noted at birth and was

found to have HCM at age 4. Systolic anterior motion of

545