Plasma levels of atrial natriuretic peptide in hypertrophic cardiomyopathy

Plasma Levels of Atrial Natriuretic Peptide in Hypertrophic Cardiomyopathy Giorgio Derchi, MD, Pietro Bellone, MD, Franc0 Chiarella, MD, Matilde Randazzo, BS, Vera Zino, BS, and Carlo Vecchio, MD he most typical physiopathologicabnormality in hypertrophic cardiomyopathy (HC) is diastolic dysT function, characterized by abnormal stiffnessof the left ventricle during diastole,with resultant impaired ventricular filling. This abnormality in diastolic relaxation results in elevationof left ventricular end-diastolicpressure. Impaired early diastolic filling as well as abnormal distensibility leadsto a compensatoryincreasein the contribution of atria1 systole to left ventricular fdling.1 Atria1 natriuretic peptide (ANP) is a cardiac polypeptideexerting potent diuretic, natriuretic and vasodilatory activities, and is producedand secretedpredominantly by the atria in responseto volwne or pressureoverload.2SThe mechanism of ANP releasehas been attributed to increasesin either atria1pressuresor atria1distension.4*5 PlasmaANP levelsare increasedin patients with congestiveheart failure and correlate well with left ventricular end-diastolic pressure and atria1 pressure in patients with thii disease.671 Experimental data provideevidenceof ventricular activation of the ANP gene in ventricular overload. A recent report8indicated that ventricular ANP expression occurs as a responseto disease-specificchangessuch as myocardial fiber disarray, hypertrophy of myocytesand fibrosis in HC.8 Plasma ANP levels have not yet been investigatedand related to the clinical status in HC. The purposeof this study was to verify whether an increasein plasma ANP levels in patients with HC exists and to establish a possiblecorrelation betweenANP levels and clinical anatomic status of patients with HC. The study group consistedof 30 patients (21 men, 9 womenaged 13 to 74 years, mean 43 f 18) with HC in ambulatory follow-up at the Cardiology Division, E.O. Ospedali Galliera, Genoa,Italy. Thirteen patients were receiving antiarrhythmic drugs. The control group consisted of 50 normal subjects (30 men, 20 womenaged 8 to 70 years, mean 42 f 19). All normal subjects had a normal rest electrocardiogram, chestx-rays, ventricular diameters and wall motion by 2-dimensional echocardiography. Each patient was classified according to the criteria of New York Heart Associationfunctional class. Of the 30 patients with HC, 20 were designated New York Heart Association class I, 5 were class II, 4 were class III and 1 was class IV. Body surface area ranged from 1.3 to 2.05 m2. After echocardiographicexamination (30 minutes in the supine position), blood samples were collected and analyzedfor ANP concentration.Blood wasdrawnfrom all patients in the morning via an antecubital vein, after From the Cardiology Division and Nuclear Medicine Service, E.O. Ospedali Galliera, Via Volta 8, 16128Genova, Italy. Manuscript re ccived April 13, 1992;revisedmanuscript receivedand acceptedJune 15, 1992.

1M)2

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70

30 minutes in the supineposition and after an overnight fat. Blood samples were collected in pre-chilled test tubes containing ethylenediaminetetraacetic acid-2Na and 500 kIU of aprotine. Plasma isolated by low-temperature centrtfugation was stored at -70°C and ANP levelswerelater determinedby a commercially available kit from Eiken Chemical Co., Tokyo, Japan. Reference values in our laboratory are: 50 f 12 pglml (range 20 to 77). Values are expressed as mean f SD. Differences betweenmeanswerecomparedusing unpaired Student’s t test. Upper and lower 95% normal confidencelimits for the echocardiographic data were calculated from a 2tailed Student’s t test distribution by using thefollowing formulas: mean + (2.042 X SD) and mean - (2.042 X SD). Regression analysis was applied to examine the relation between2 variables as appropriate. A p value x0.05 was consideredsignificant. Echocardiographic data revealed significantly hypertrophic ventricles and increasedatria1 dimension in patients with HC comparedwith normal subjects. Table I summarizes the echocardiographic data for all patients. No differencesoccurred in left ventricular internal diameters.Left ventricular outjlow tract obtruction was presentin 11 of the 30patients with HC (mild in 4, severe in 7). Mild mitral regurgitation waspresent in 10 of the 30patients with HC. New York Heart Association class rangedfrom I to IVwith a median value in classI. Mean plasma ANP concentrationof the group of patients with HC was significantly higher than that of the control group (101 f 88 us 53 f 18 pglml; p
Patients with HCM

Control Subjects

LVlDd (mm) LA (mm) VS thickness (mm) PW thickness (mm) LVlSd(mm)

48 2 6 40 k 6 18 + 5

46 + 5 33 + 6 821 a+2 29 f 4

10 + 3 31 + 5

p Value NS

0.001 0.001 0.05 NS

95% Confidence Limits 35-60 27-54 8-28 4-16 21-41

HCM = hypertrophic cardiomyopathy; LA = left atrium; LVlDd = left ventricular internal diastolic diameter; LVlSd = left ventricular internal systolic diameter; NS = not significant; PW = posteriorwall; VS = ventricular septum.

DECEMBER 1. 1992

York Heart Association class Z (n = 20), ANP values exceeding the maximal value for control subjects were present in 3 patients; converselythe meanANP values in the remaining 17 patients werenot different from values in normal subjects (51 f 31 us 53 f 18 pglml; p = not sisnificant). All patients in New York Heart Association ZZZto IV had increased ANP values (188 f 71 pglml) (range 116 to 317). Leji atria1 cavity enlargement (body surface area >20 mm/m3 waspresent in all patients in New York Heart Association class ZZZto IV and in 9 of 24 patients in New York Heart Association class Z to ZZ (26%). Figure 1 showsthe relation betweenthe degreeof left atria1 cavity enlargement and plasma ANP levels (r = 0.64,p
tricular septum thickness and ANP plasma levels (r = 0.43 and r = 0.41, respectively,p <0.05). No significant correlations werefound betweenend-diastolic, end-systolic ventricular diameters, posterior wall thickness, right atria1 dimension, age,presenceof left ventricular outflow obstruction, mitral regurgitation and plasma levels of ANP. Our results show that plasma levels of ANP are increasedin many patients with HC, and ANP levels are markedly elevated in patients with higher functional class, atriomegaly, and more relevant thickness of ventricular septum. Diastolic dysfunction is present in most patients in the early stage of the disease,resulting in higher filling pressuresand an increasein atria1 systole contribution to left ventricular filling.’ ANP is a cardiac peptide with diuretic, natriuretic and vasodilatory activities, and it plays an important role in the regulation of blood pressureand body fluid volume.2y3Under physiologic circumstancesin the mammalian heart, cardiac synthesisof ANP occursalmost exclusively in the atria. The

ANP (pg/ml) 350 1

300 -

250 -

nGuREl.comauomb tweanabid-pepude(Afw)levdsmdlefl --VW.

0 30

t

I

I

I

32

34

36

38

40

42

I

I

44

46

48

I

I

,

50

52

54

56

I

1

58

60

Left atrium (mm)

ANP (PShl)

ANP (Pdd

I VENTRICULAR SEPTUM THICKNESS bud

II

III

IV

NYNA

I

FtGURE2comwOnrbdWONlWidWbiWdk Hedhsoddonflmdold~

m(Awp)-~-=4-n

ulklamsNYHA=NewYak

BRIEF REPORTS

1303

mechanismof ANP releasehas beenattributed to either al activation and suggest the importance of plasma increasesin atria1pressureor atria1distension.4~5 Recent- ANP concentration in clinical evaluation of the patients ly, there was evidence that the ventricular ANP gene with HC. expressionoccurstriggered by physical overstretchof the ventricular wall, thereby contributing to the control of 1. Maron B, Epstein S. Hypertropbic cardiomyopathy. Pathophysiology and blood volume and blood pressure.9J0In these studies, therapy. In: Braunwald E, ed. Heart Disease.A Textbook of Cardiovascular there was also cardiac hypertrophy in the ventricles in Medicine. 4th ed. Philadelphia: WB Saunders,1992:1404-1415. which ANP was present. In a recent report, Takemura 2. de Bold A. Atria1 natriuretic factor: a hormoneproducedby the heart. Science 1985;767-770. et al* showedthat, in a selectedpopulation of hyperten- 3. Ballerman B, BrennerB. Role of atria1peptidesin body fluid homecatasis.(src sive patients and patients with HC, ventricular ANP Res 1986;58:619-630. AndersonJ, Donckier J, McKenna W, Bloom S. The plasmareleaseof atria1 gene expressionoccurs as a responseto disease-specific 4. natriuretic peptide in man. ChinSci 1986;71:151-155. changes:myocardial fiber disarray, hypertrophy of myo- S. Edwards B, Zimmerman R, SchwabT, Heubein D, Burnett J. Atrial stretch, cytes and fibrosis rather than an adaptative responsein not pressure,is the principal determbrantcontrolling the acute releaseof atria1 factor. C&c Res 1988;62:191-195. HC. Higher ANP plasma values occurred in patients natriuretic 6. Raine A, Eme P, BurgisserE, Muller F, Bolli P, Burkart F, Buhler F. Atria1 with HC and ANP geneexpressionin the ventricle than natriuretic peptideand atrial pressurein patientswith congestiveheart failure. N in thosewithout ANP expression.In our population there Engi J Med 1986;315:533-537. 7. TsutamotoT, Bito K, Kinoshita M. Plasmaatria1natriuretic polypeptideas an was a closerelation betweenleft atrium cavity dimension index of left ventricular end-diastolicpressurein patients with chronic left-sided and plasmaANP levels,suggestingan atria1contribution heart failure. Am Heart J 1989;117:599-606. 8. Takemura G, Fujiwara H, Mukoyama M, Saito Y, Nakao K, Kawamura A, to the releaseof peptide in HC. Releaseof ANP in pa- Ishida M, Kida M, Uegaito T, Tanaka M, Matsumori A, Fujiwara T, Imura H, tients with HC is independent of ventricular chamber Kawai C. Bxnression and distribution of atria1 natriuretic Dentide in human dilation, whereasatrial stretch may be an important stim.. . &opath). Circulation 19?1;83:181-190. ulus as well as ventricular hypertrophy and increased 8. EdwardsB, Rodeheffer R, ReederG, Burnett J. Expressionof atria1natriuretic filling pressures.The results of the presentstudy demon- factor in the human ventricle is independentof chamber dilation. J Am Coil strate that ANP levels are altered in patients with HC Cardiol 1990;16:1589-1593. JougasakiM, Yasue H, Mukojama M, Nakao K, Takahashi K. Appearance and functional impairment. Our findings show that ven- of10.atria1 natriuretic peptidein the ventriclesin patientswith myocardial infarction. tricular hypertrophy may play a role in this neurohumor- Am Heart J 1990;119:92-96.

lb04

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70

DECEMBER 1. 1992