determinants of ventricular ectopy in hypertensive cardiac hypertrophy

Volume 123

Number 1 Sotalol for VT in CAD

16. Kuchar DL, Garan H, Venditti FJ, et al. Usefulness of sotalol in suppressing ventricular tachycardia or ventricular fibrillation in patients with healed myocardial infarcts. Am J Cardiol 1989;64:33-6.

17. Kus T, Costi P, Dubuc M, Shenasa M. Prolongation of ventricular refractoriness by class Ia antiarrhythmic drugs in the prevention of ventricular tachycardia induction. AM HEART J 1990;120:855-63.

18. Furukawa T, Rozanski JJ, Moroe J, Gosselin AJ, Lister JW. Efficacy of procainamide on ventricular tachycardia: relation to prolongation of refractoriness and slowing of conduction. AM HEART J 1989;118:702-8.

19. Gillis AM, Wyse DG, Duff HG, Mitchell LB. Drug response at electropharmacologic study in patients with ventricular tachyarrhythmias: the importance of ventricular refractoriness. J Am doll Cardiol 199$7:914-20.

20. Kus T. Dubuc M. Lambert C. Shenasa M. Efficacv of nro- pafenone against ventricular tachycardia: inverse correla’tion with prolongation of conduction time. J Am Co11 Cardiol 1990;16:1229-37.

21. Funck-Brentano C, Kibleur Y, LeCoz F, Poirier JM, Mallet A, Jaillon P. Rate dependence of sotalol-induced prolongation of

ventricular repolarization during exercise in humans. Circula- tion 1991;83:536-45.

22. Giorgi C, Nadeau R, Agha A, Primeau R, de Champlain J. Ef- ficacy of oral sotalol in suppression of premature ventricular complexes and analysis of its beta-adrenergic blocking activity. Can J Cardiol 1990;6:191-7.

23. Anastasiou-Nana MI, Anderson JL, Askins JC, Gilbert EM, Nanas JN, Menlove RL. Long-term experience with sotalol in the treatment of complex ventricular arrhythmias. AM HEART J 1987;114:288-95.

24. Kienzle MG, Martins JB, Wendt DJ, Constantin L, Hopson R, McCue ML. Enhanced efficacy of oral sotalol for sustained ventricular tachycardia refractory to Type I antiarrhythmic drugs. Am J Cardiol 1988;61:1012-7.

25. Marchlinski FE, Buxton AE, Josephson ME, Schmitt C. Pre- dicting ventricular tachycardia cycle length after procainamide by assessing cycle length-dependent changes-in paced QRS duration. Circulation 1989:79:39-46.

26. dohbe SM, Hoffman E, Ritzenhoff A, Brachmann J, Kubler W, Senges J. Action of sotalol on potential reentrant pathways and ventricular tachyarrhythmias in conscious dogs in the late postmyocardial infarction phase. Circulation 1983;68:865-71.

Determinants of ventricular ectopy in hypertensive cardiac hypertrophy

Left ventricular hypertrophy in arterial hypertension has repeatedly been documented to trigger or aggravate ventricular ectopy. To determine cardiovascular mechanisms underlying ventricular ectopy, we examined 53 hypertensive patients with mild to moderate nondilated left ventricular hypertrophy by P&hour echocardiographic monitoring and two-dimensional (P-D)-guided M-mode echocardiography. Patients with more severe ectopy (Lown’s class II to IV) were older and had greater increases In left ventricular mass, ejection fraction, velocity of circumferential fiber shortening, end-diastolic volume index, and left ventricular stroke work than patients with less severe ectopy (Lown’s class 0 to I). Left ventricular mass, end-diastolic diameter, stroke volume, stroke work, ejection rate, velocity of circumferential fiber shortening, and fractional fiber shortening were enhanced in a subgroup with complex ventricular ectopy (multiform or paired premature ventricular beats or runs of ventricular tachycardia) when compared with a subgroup matched with respect to age, sex, body surface area, and mean arterial pressure, which had uniform monofocal ventricular beats occurring with a frequency of less than lO/hr only. Our data indicate that the frequency and severity of ventricular ectopy in patients with essential hypertension is determined by age, severity of left ventricular hypertrophy, chamber volume, and indices of contractility and pump function. Whether or not the pattern of ventricular ectopy will identify hypertensive patients with left ventricular hypertrophy who are at increased risk of sudden death remains to be determined. (AM HEART J lgg2;123:89.)

Roland E. Schmieder, MD,a and Franz H. Messerli, MD. New Orleans, La., and

Nurnberg, Germany

From the Department of Internal Medicine, Section on Hypertensive Dis- eases, Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans; anda the Department. of Medicine, University of Erlangen Nurnberg. This research was supported in part by a grant from Deutsche Forschungs- gemeinschaft, Germany.

Received for publication May 17, 1991; accepted June 24, 1991. Reprint requests: Dr. F. H. Messerli, Ochsner Clinic, 1514 Jefferson High- way, New Orleans, LA 70121. 4/l/33649

RO

January 1992

90 Schmieder and Messerli American Heart Journal

In modern cardiology textbooks, hypertensive heart disease is not listed as a potential cause of ventricular arrhythmias and cardiac sudden death. Ever since the first report in 1984,l numerous studies have shown that detection of left ventricular hypertrophy in arterial hypertension is related to more prevalent and more severe ventricular arrhythmias.l-I* Thus nonsustained ventricular tachycardia occurred more frequently in patients with electrocardiographic evidence of left ventricular hypertrophy than in those without left ventricular hypertrophy or in con- trol subjects.2 A subanalysis of the Framingham heart study3 showed that left ventricular hypertrophy was more common in each of six ventricular arrhythmia grades in men and in four of six grades in women. Also, obese hypertensive patients with ec- centric left ventricular hypertrophy had a 30 times higher prevalence of premature ventricular contractions and scored higher in the classification of Lown and Wolf than lean subjects without left ventricular hypertrophy, although all subjects had the same level of arterial pressure. lo These observations have to be interpreted in light of the Framingham study, in which both obesity per se and left ventricular hypertrophy increased the risk of dying suddenly, independent of arterial pressure.11-*3

Ventricular arrhythmias seem to be predictive of subsequent sudden death in patients with hypertrophic cardiomyopathy and ischemic heart disease.14,‘” In hypertensive patients with left ventricular hypertrophy, however, the clinical importance of ventricular arrythmias has not been delineated pro- spectively. Nevertheless, the higher prevalence of ventricular arrhythmias observed in hypertensive patients with left ventricular hypertrophy supports the hypothesis that because of ventricular ectopy, these patients are at least to some extent at high risk for catastrophic cardiac events. Left ventricular hypertrophy appeared to be the echocardiographic hallmark for the increased risk of ventricular ectopy. However, hypertensive patients at high risk for cardiac arrythmias and perhaps for sudden death are only insufficiently characterized. The current study was designed to identify those clinical and echocardiographic determinants that put hypertensive patients with left ventricular hypertrophy at high risk for severe ventricular ectopy.

METHODS Study population. Fifty-three patients with uncompli-

cated essential hypertension (World Health Organization stage I or II) but echocardiographic evidence of left ventricular hypertrophy were enrolled in the study. Estab- lished essential hypertension was said to be present if diastolic pressure registered in the outpatient clinic was con- sistently higher than SO mm Hg. All patients had appro-

priate clinical and laboratory evaluations to exclude secondary forms of hypertension. Left ventricular hypertrophy by echocardiography was said to be evident if posterior wall thickness was ~12 mm and/or septal wall thickness was ~13 mm. Thirty-one patients had left ventricular hypertrophy on electrocardiograms, as described by Sokolow and Lyon.“j Patients were excluded who had any clinical evidence of coronary artery disease or other organic heart diseases, as evidenced by clinical examinations, standard 12-lead electrocardiograms at rest, or two- dimensional (Z-D) echocardiography. Exercise treadmill testing, thallium scintigraphy, or both were performed when clinically indicated. Patients with a dilated left ventricle (end-diastolic diameter >32 mm/m2 for men and 31 mm/m2 for women17) were also excluded, since this group of hypertensive patients is known to be predisposed to ventricular arrythmias. lo All patients had stopped antihy- pertensive medication for at least 4 weeks prior to the electrocardiographic and echocardiographic examinations.

Study design. Fifty-three patients seen by the authors were consecutively enrolled if they qualified for the study. Before the echocardiographic evaluation, electrocardiographic tracings were recorded continuously during one 24-hour period starting and ending in the morning. Each type was initially scanned at high speed and was subsequently reviewed for detailed analysis by two independent investigators. According to the severity of ventricular arrhythmias, the patients were divided into two groups. The criterion for the stratification was based on the grading system proposed by Lown and Wolf,ls which was developed in patients with coronary artery disease, and implied that higher grades of arrhythmias carry a higher risk for the occurrence of cardiac sudden death. Hyperten- sive patients with left ventricular hypertrophy classified as Lown’s class 0 to I were compared with patients scored as Lown’s class II to IV. No patients examined exhibited Lown’s class V (early cycle ventricular premature beats [R-on-T phenomenon]). Since the classification suggested by Lown and Wolf combines prevalence with morphology of ventricular ectopy, in a second analysis we compared hypertensive patients with compIex ventricular ectopy (multiform or paired ventricular premature beats or ventricular tachycardia) with those without complex ventricular ectopy and total premature ventricular beats of <lo/ hr.‘” Both arrhythmia groups were matched with respect to age, sex, race, body surface area, and mean arterial pressure, in descending order of priority.

Echocardiography. 2-D-guided M-mode echocardio- grams were recorded with the subject in the supine position after 30 minutes of rest. All electrocardiograms were inde- pendently evaluated according to t,he recommendations of the American Society of EchocardiographyzO by two physicians who were blinded with regard to the results of the 24-hour electrocardiographic monitorings. Only patients for whom a good echocardiographic tracing was obtained were included.” Patients with increased end-diastolic diameter were excluded.17 Left ventricular hypertrophy was said to be present if posterior wall thickness was ~1.2 cm and/or septal wall thickness was ~1.3 cm. Measurements were made over three consecutive cardiac cycles, and all

“olume 123

Number 1

values determined by the physicians were averaged. Left ventricular mass was calculated according to the formula of Troy et a1.22 Since such values for left ventricular mass systematically overestimate anatomic left ventricular mass, appropriate correction was made by using the automati- cally validated regression equation of Devereux et a1.s3 Cross-sectional area was chosen as a second parameter for the degree of left ventricular hypertrophy,‘” and relative wall t,hickness as a parameter for concentric left ventricular hypertrophy’” was calculated by dividing end-diastolic posterior wall thickness by end-diastolic radius.

End-systolic and peak systolic meridionial wall stresses were calculated according to the formula evaluated by Reichek et al.,2s and were taken as parameters for afterload. Preload was estimated by end-diastolic volume index computed according to the formula of Teichholz et a1.27 Fractional fiber shortening, ejection fraction, and velocity of circumferential fiber shortening were calculated in standard fashion.‘s+ sg Stroke volume, cardiac output, and left ventricular stroke work were also calculated from echocardiographic data.

Statistical analysis. All data (age, body surface area, blood pressure, heart rate, and all echocardiographic measurements) were obtained by a comparison of hypertensive patients with Lown’s class 0 to I, and those with Lown’s class II to IV were compared by analysis of variance. Dif- ferences in race, sex, prevalence of ectopic beats, and complex ventricular arrythmias were evaluated by chi square analysis. The analysis of matched pairs was done by paired t tests. Values are given as the mean + 1 standard deviation in the tables and as mean & 1 standard error of the mean in the figures. Statistical tests were carried out on an IBM 308-l computer (IBM Corp., Atlanta, Ga.) using SAS pro- grams (SAS Institute, Cary, N.C.).“”

RESULTS

Of the 53 hypertensive patients with echocardiographic evidence of left ventricular hypertrophy, 38 patients had Lown’s classification 0 (n = 11) or I (n = 27), and 15 patients were scored Lown class II (n = 6), III (n = 7), or IV (n = 2) (Table I). Systolic and diastolic pressure as well as heart rate, body surface area, and racial distribution were not significantly different in the two groups.

Patients with Lown’s class II to IV ventricular ectopy had an increased cardiac index, stroke volume, stroke work, and mean left ventricular ejection rate, as well as a slightly lower total peripheral resistance than patients scoring Lown’s class 0 to I (Fig. 1 and Table I). Further, left ventricular mass and cross- sectional area (degree of left ventricular hypertrophy), diastolic diameter, and diastolic volume index (preload) were increased in patients with more severe ventricular ectopy compared with those classified as Lown’s 0 to I (Fig. 2 and Table II), whereas no differ- ence was seen with respect to end-systolic wall stress and peak systolic wall stress (afterload). Fractional fiber shortening and velocity of circumferential fiber

Ventricular ectopy in hypertension 9 1

LVSW (mmHg x ml/m *)

100

80

60

40

20

0 I

MLVER (ml/set/m 2 ) 160

120

80

40

0 1 1 Lown’s Lown’s

Class O-I Class II-IV

Fig. 1. Left ventricular stroke work (LVSW) and mean left ventricular ejection rate (MLVER) in hypertensive patients with Lown’s class II to IV coronary heart disease, compared with those with Lown’s class 0 to I.

shortening were enhanced in those hypertensive patients who had a higher Lown grading (Table II). The pattern of left ventricular hypertrophy (asymmetric versus concentric) was similar in the two groups, since both relative wall thickness and the ratio of septal-to-posterior wall thickness were similar (Fig. 2).

In a subanalysis, nine patients with complex ventricular ectopy were matched with respect to clinical characteristics (such as age, sex, race, body surface area) and level of mean arterial pressure with nine patients with uniform ventricular beats (<lO/hr) (Table III). Patients with complex ectopy revealed a higher cross-sectional area, left ventricular mass, end-diastolic diameter, and end-diastolic volume, as well as enhanced indices of left ventricular pump function (velocity of circumferential fiber shortening, fractional fiber shortening, left ventricular ejection rate, and stroke volume), than patients with monofocal premature ventricular beats only.

DISCUSSION

The present study documents that age, severity of left ventricular hypertrophy, chamber volume, and indices of left ventricular pump function are the ma-

92 Schmieder and Messerli January 1992

American Heart Journal

Table I. Clinical and hemodynamic characteristics of hypertensive patients with left ventricular hypertrophy divided according to Lawn’s classification

Lown O-I Lown II-IV (n = 38) (n = 15) p Value

Age (~4 Body surface area (m’) Sex (male:female ratio) Race (white:black ratio) Systolic pressure (mm Hg) Diastolic pressure (mm Hg) Heart rate (beats/min) Cardiac index (L/min/m2) Stroke index (ml/min/m2) Total peripheral resistance (U/m2)

54 f 11 1.95 k 0.16

27:ll 32:6

157 + 14 98 zk 5 78 -t 8

2.45 + 0.75 32 k 9 52 + 14

60 f 6 1.97 + 0.21

13:2 12:3

154 +- 21 98 f 10 74 i. 8

2.94 + 0.90 38 f 11 44 * 14

p < 0.05 ns ns ns ns ns ns

p < 0.05 p < 0.01 p < 0.07

ns, Not statistically significant.

Table II. Echocardiographic characteristics of hypertensive patients with left ventricular hypertrophy divided according to Lawn’s classification

Lown O-I (n = 38)

Lown II-IV (n = 15) p Value

Left ventricular mass (gm/m2) Cross-sectional area (cm2) End-diastolic diameter (cm/m2) End-diastolic volume index (ml/m2) Velocity of circumferential fiber shortening

(circ/sec) Fractional fiber shortening ( 7% ) End-systolic wall stress (lo3 dyne/cm2) Peak systolic wall stress (lo3 dyne/cm2)

125 f 23 21.8 + 2.3 2.23 + 0.02 48.0 -c 10.0 1.29 f 0.3

37 + 8 55 t 20

174 f 30

Abbreviation as in Table I.

jor determinants of prevalence and severity of ventricular ectopy in hypertensive patients with left ventricular hypertrophy. Since left ventricular mass increases with age even in the normotensive population (but of course more steeply in hypertensive patients), it should not be surprising that both age and left ventricular hypertrophy are powerful determinants of ventricular ectopy. A variety of studies has shown that normotensive elderly subjects who are free of heart disease often exhibit impressive ventricular ectopy.31

The exact electrophysiologic mechanisms by which left ventricular hypertrophy triggers or aggravates ectopic impulse generation remain speculative. It was found that left ventricular hypertrophy increases the risk of coronary heart disease in an elderly cohort.32 Conceivably, small vessel disease leading to electri- cally silent (that is, fibrotic) areas and thereby disturbing intercellular current flow and impulse propagation could give rise to reentry mechanisms.33 It is of note, however, that left ventricular hypertrophy per se results in relative myocardial ischemia that is most pronounced in subendocardial tissue.34-36

139 f 25 23.3 s 2.9 2.41 k 0.17 54.0 f 10.0 1.47 -t- 0.3

43 * 9 59 r 18

172 k 32

p < 0.05 p < 0.05 p < 0.02 p < 0.05 p < 0.05

p < 0.05 ns ns

Recently, elevated coronary resistance at the mi- crovascular level was observed in a subset of hypertensive patients without left ventricular hypertrophy.37 Thus experimental and clinical data indicate that progressive underperfusion of the myocardium increases ectopic impulse generation.

Myocardial ischemia could also account for the fact that indices of a hypercirculatory state, such as stroke volume, stroke work, velocity of circumferential fiber shortening, and ejection fraction, were determinants of ventricular ectopy. Clearly, myocardial oxygen consumption is prone to increase in parallel with these hemodynamic parameters. Increased activity of the sympathetic nervous system may well be one common denominator of left ventricular hypertrophy, increased ventricular pump function, and ectopic impulse generation. Indeed, several studies have documented that increased activity of the sympathetic nervous system may provoke premature ventricular contractions.38-40 A recent preliminary report4i suggested a connection between ventricular ectopy in patients with left ventricular hypertrophy and activity of the sympathetic nervous system.

Volume 123

Number I

LVM (g/m ‘) pco.05 CSA (cm 2,

160

120 25

20

SO

30 1

15

10 40

5 n n

Y

LOWl’S LOWil’S Class O-I Class II-IV

RWT ns. STIPWT 1.01 201

Ventricular ectopy in hypertension 93

pco.05

u LOWrI’S LOvm’S x3ss O-I Class II-IV

IlS.

0.4 -

02-

0 Lawn’s LOWfl’S Lovds Low’s

Class O-I Class II-IV Class O-I Class II-IV

Fig. 2. Degree of pattern of left ventricular hypertrophy in hypertensive patients with Lown’s class II to IV coronary heart disease and in those scored as Lown’s class 0 to I. LVM, Left ventricular mass; CSA, cross-sectional area; R WT, relative wall thickness; STIPWT, ratio of septal-to-posterior wall thickness of the left ventricle.

Table III. Characteristics of hypertensive patients with multiform or paired ventricular beats of ventricular tachycardia (group A) matched with those without complex ventricular ectopy and with premature ventricular beats slO/hr (group B)

Group A Group B (n = 9) (n = 9) p Value

Age (~4 58 k 6 55 f 5 ns Sex (male:female ratio) 712 7:2 - Race (white:black ratio) 7:2 7.2 Body surface area (m2) 2.04 + 0.22 1.94 t 0.23 IlS Mean arterial pressure (mm Hg) 120 f 16 117 f 8 ns

Heart rate (beats/min) 79 k 8 75 _t 7 Cardiac index (L/min/m? 3.01 + 0.76 2.36 + 0.66 On:6 Stroke index (ml/min/ms) 39 k 8 34 t 9 0.02

Total peripheral resistance (U/m’) 44 +- 13 46 k 17 Left ventricular stroke work (mm Hg . mL/m? 85 + 21 63 f 20 oni2 Left ventricular ejection rate (ml/sec/m2) 140 + 39 107 k 35 0.02 Left ventricular mass (gm/m? 142 + 20 124 + 20 0.08 Cross-sectional area (cm2) 24.1 f 3.0 21.0 + 2.3 0.04 End-diastolic diameter (cm/ms) 2.42 f 0.1 2.23 k 0.2 0.02 End-diastolic volume index (ml/m? 54 i 8 48 2 7 0.05 Velocity of circumferential fiber shortening (circ/sec) 1.49 * 0.2 1.34 * 0.3 0.05 Fractional fiber shortening ( %) 42 k 7 37 + 7 0.05

Abbreviations as in Table I.

Mechanical factors, such as stretching of isolated myocardial cells, have been documented to reduce the electrical threshhold and thereby increase auto- maticity.42-44 Although patients with chamber dilatation were excluded by design of the study, mechanical stretching may still have been a contributing electrophysiologic factor, as is shown by the fact that diastolic diameter and chamber volume evolved as determinants of ventricular ectopy. We’O previously

reported that patients with the largest hearts had the highest prevalence of left ventricular ectopy and the second highest prevalence with respect to Lawn’s classification. Thus chamber dilatation, even within normal limits, seemed to trigger or facilitate ventricular ectopy.

In conclusion, the present study identifies several determinants of ventricular ectopy in hypertensive patients with nondilated left ventricular hypertro-

94 Sehmieder and Messerli

phy, such as age, degree of left ventricular hypertrophy, chamber volume, and indices of left ventricular pump function. An increased sympathetic drive to the heart could be a common denominator linking hypertension, left ventricular hypertrophy, increased ventricular pump function, and ectopic impulse generation. A prospective study is needed to more firmly establish the connection between ventricular ectopy in hypertensive patients with left ventricular hypertrophy and their well-documented risk of sudden cardiac death.

REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

Messerli FH, Ventura HO, Elizardi DJ, Dunn FG, Frohlich ED. Hypertension and sudden death: increased ventricular ectopy activity in left ventricular hypertrophy. Am J Med 1984;77:18-22. McLenachan JM, Henderson E, Morris KI, Dargie HJ. Ven- tricular arrhythmias in patients with hypertensive left ventricular hvnertroohv. N Enel J Med 1987:317:‘787-92. Levy D, Anderson KM, Sav”+ge DD, Balk& SA, Kannel WB, Castelli WP. Risk of ventricular arrhythmias in left ventricular hypertrophy. The Framingham Heart Study. Am J Cardiol 1987;60:560-5. Luque-Otero M, Casar-Perez F, Alcazar J. Increased ventricular arrhythmias in hypertensives with left ventricular hypertrophy. J Hypertens 1986;4(suppl6):66-7. Guazzi MD. Relationship between the rhythm and the hemodynamic load in the hypertensive heart. In: Messerli FH, ed. The heart and hypertension. New York Yorke Medical Books, 1987:241-8. Le Henzey JY, Guize L. Cardiac prognosis in hypertensive patients. Incidence of sudden death and ventricular arrhythmias. Am J Med 1988$4(suppl lB3:65-8. Loaldi A, Pepi M, Agostoni PG, Fiorentini C, Grazi S, Bella PD, Guazzi MD. Cardiac rhythm in hypertension assessed through 24-hour ambulatory electocardiographic monitoring effects of lead manipulation with atenolol, verapamil, and nifedipine. Br Heart J 1983;50:118-26. Nunez BD, Messerli FH, Garavaglia GE, Schmieder RE. Ex- aggerated atrial and ventricular excitability in hypertensive patients with isolated septal hypertrophy (ISH) [Abstract]. J Am Co11 Cardiol 1987;9:225A. James MA, Jones JV. Ventricular arrhythmias in untreated hypertensive patients compared with a matched normal population. J Hypertens 1989;7:409-15. Messerli FH, Nunez BD, Ventura HO, Snyder DW. Over- weight and sudden death: increased ventricular ectopy in car- diopathy of obesity. Arch Intern Med 1987;147:1725-8. Kannel WB, Gordon T, Offut D. Left ventricular hypertrophy by electrocardiogram: prevalence, incidence and mortality in the Framingham study. Ann Intern Med 1969;71:89-105. Kannel WB. Doyle JT, McNamara PM, Quinchenton P, Gor- don T. Precursor of sudden death: factors related to the incidence of sudden death. Circulation 1975:51:606-13. Hubert HB, Feinleib M, Menamacre PM, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26 year follow-up of participants in the Framingham Heart Study. Circulation 1983;67:968-77. Maron BJ, Savage DD, Wolfson JK, Epstein SE. Prognostic significance of 24-hour ambulatory electocardiographic monitoring in patients with hypertrophic cardiomyopathy: a prospective study. Am J Cardiol 1981;48:252-7. Ruberman W, Weinblatt E, Goldberg JD, Frank CW, Shapiro S. Ventricular premature beats and mortality after myocardial infarction. N Engl J Med 1977;297:750-7. Sokolow M, Lyon TP. The ventricular complex in left ven-

tricular hypertrophy as obtained by unipolar precordial and limb leads-AM HEART J 1949;37:161-86..

17. Savage DD. Garrison RJ. Kannel WB. Lew D. Anderson SJ. Strokes J III, Feinleib M, Castilli WP. The spectrum of left ventricular hypertrophy in a general population sample: the Framingham Study. Circulation 1987;75(suppl I):I-26-33.

18. Lown B, Wolf M. Approaches to sudden death from coronary heart disease. Circulation 1971;44:130-42.

19. Bigger JT, Weld FM. Shortcomings of the Lown grading system for observational or experimental studies in ischemic heart disease. AM HEART J 1980;100:1081-8.

20. Sahn DJ, de Maria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072-83.

21. Dunn FG, Chandraratna P, de Carvalho JGR, Basta LL, Frohlich ED. Pathophysiologic assessment of hypertensive heart disease with echocardiography. Am J Cardiol 1977; 39789-95.

22. Troy BL, Pombo J, Rackley CE. Measurement of left ventricular wall thickness and mass by echocardiography. Circulation 1972;45:602-10.

23. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57:450-8.

24. Gaash WH, Amorian WC, Levine NJ. Chronic aortic regurgi- tation: the effect of aortic valve replacement on left ventricular volume, mass and function. Circulation 1978;58:825-36.

25. Devereux RB, Savage DD, Sachs I, Laragh JH. Relation of he-

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

modynamic load to left ventricular hypertrophy and performance in hypertension. Am J Cardiol 1983;51:171-6. Reichek N, Wilson J, St John Sutton M, Plappert TA, Gold- berg S, Hirshfeld JW. Non-invasive determination of left ventricular end-systolic stress: validation of the method and ini- tial application. Circulation 1982;65:99-108. Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence or absence of asynergy. Am J Cardiol 1976;37:7-11: Abi-Samra F. Fouad FM. Tarazi RC. Determinants of left ventricular hypertrophy and function in hypertensive patients. An echocardiographic study. Am J Med 1983;75:26-33. McDonald IG, Feigenbaum H, Chang S. Analysis of left ventricular wall motion by reflected ultrasound. Circulation 1972; 46:14-25. SAS Institute Inc. SAS User’s guide. Statistics. version 5th ed. Cary, NC: SAS Institute Inc, 1985. Crow RS, Prineas RJ, Dias V, Taylor HL, Jacobs D, Blackburn D. Ventricular premature beats in a population sample: frequencv and association with coronary risk characteristics. Circulation 1975;51(suppl III):III-211-5: Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Left ventricular mass and incidence of coronary heart disease in an elderly cohort. Ann Intern Med 1989,110:101-7. Toyoshima H, Park Y-D, Ishikawa Y, Nagata S, Hirata Y. Sakakibara H, Shimomura K. Nakavama R. Effects of ventricular hypertrophy on conduction velocity of activation front in the ventricular myocardium. Am J Cardiol 1982; 49: 1938-45. Marcus ML, Muller TM, Eastham CHL. Effects of short- and long-term left ventricular hypertrophy on coronary circulation. Am 3 Physiol 1981;24:H358-62. Marcus ML, Koyanagi DG, Harrison D, Doty DB, Hiratzka LF, Eastham CHL. Abnormalities in the coronarv circulation that occur as a consequence of cardiac hypertrophy. Am J Med 198X7562-5. Strauer BE, Mahmoud MA. Coronary hemodynamics in hypertensive heart disease: basic concepts and clinical consequences. J Cardiovasc Pharmacol 1985;7:S62-9. Brush JE Jr, Cannon RO III, Schenke WH, Bonow RO, Leon MB, Maron BJ, Epstein SE. Angina due to coronary microvas-

Volume 123 Number 1 Ventricular ectopy in hypertension

cular disease in hypertensive patients without left ventricular hypertrophy. N Engl J Med 1988;319:1302-7.

38. Lown B, Verrier R, Rabinowitz SH. Neural and psychologic mechanisms and the problem of sudden cardiac death. Am J Cardiol 1977;39:890-902.

39. Lynch JJ, Paskewitz DA, Gimbel KS, Thomas SA. Psycholog- ical aspects of cardiac arrhythmias. AM HEART J 1977;93:645- 57.

40. Lown B, Temte JV, Reich PR, Gaughan G, Regestein Q, Hai H. Basis for recurring ventricular fibrillation in the absence of coronary heart disease and its management. N Engl J Med 1976;294:623-9.

41. Agabiti-Rosei E, Malerba M, Rizzoni D, Zulli R, Muiesan ML, Beschi M, Castellano M, Muiesan G. Ventricular arrhythmias

as related to adrenergic activity in untreated patients with cardiac hypertrophy [Abstract]. Am J Hypertens 1990;3:part 2, No. 1417.

42. Cameron JS, Myerburg RJ, Wong SS, Gaide MS, Epstein K, Alvarez TR, Gelband H, Guse PA, Bassett AL. Electrophys- iologic consequences of chronic experimentally induced left ventricular pressure overload. J Am Co11 Cardiol1983;2:481-7.

43. White CW, Mirro MJ, Lund DD, Skorton DJ, Pandian NG, Kerber RE. Alterations in ventricular excitability in conscious dogs during the development of chronic heart failure. Am J Physiol 1986;250:H1022-9.

44. Janse MJ, Kleber A. Electrophysiological changes and ventricular arrhythmias in the elderly phase of regional myocardial ischemia. Circ Res 1981;49:1069-81.

A multicenter, randomized, double-blind,

placebo-controlled trial of pimobendan, a new

cardiotonic and vasodilator agent, in patients

with severe congestive heart failure

Pimobendan, a new oral cardiotonic and vasodilator agent, increases myocardial contractile force through specific inhibition of phosphodiesterase type III and increased calcium sensitivity of the myocardtal contractile elements. The effects of pimobendan on left ventricular performance and maximal exercise capacity were studied in a multicenter, randomized, double-blind, placebo-controlled trial involving 52 patients with severe congestive heart failure despite diuretics, digoxin, and angiotensin-converting enzyme inhibitors. The acute hemodynamic evaluation included three single doses of 2.5, 5.0, and 10.0 mg of oral pimobendan, which was subsequently administered at a daily dose of 5 or 10 mg for 4 weeks. Acute administration of pimobendan significantly increased the resting cardiac index and lowered pulmonary capillary wedge pressure in a dose-dependent manner, whereas heart rate and systemic arterial pressure were not substantially altered. Patients receiving pimobendan, 5 and 10 mg daily, had a significantly greater increase in maximal exercise duration than those receiving placebo, that is, 144 t 30 and 124 + 33 seconds versus 58 + 25 seconds (p = 0.05). Peak oxygen uptake increased by 1.7 * 0.8 and 2.2 +- 1.3 ml/kg/min in patients receiving pimobendan at a daily dose of 5 and 10 mg, respectively, whereas it decreased by 0.1 + 0.8 ml/kg/min in patients receiving placebo (p = 0.06). Thus pimobendan acutely improves resting left ventricular performance and chronically increases exercise duration and peak oxygen uptake in patients with severe congestive heart failure concomitantly treated with digoxin, diuretics, and angiotensin-converting enzyme inhibitors. (AM HEART J lgg2;123:95.)

Stuart D. Katz, MD, Spencer H. Kubo, MD, Marie11 Jessup, MD, Suzanne Brozena, MD, Janice M. Troha, Janice Wahl, MD, Jay N. Cohn, MD, Edmund H. Sonnenblick, MD, and Thierry H. LeJemtel MD, Bronx, N.Y.,

Minneapolis, Minn., Philadelphia, Pa., and Ridgefield, Conn.

From the Divisions of Cardiology, Departments of Medicine, Albert Einstein College of Medicine, University of Minnesota Medical Center, Presbyterian Medical Center, Temple University, and Boehringer In- gelheim, Ltd.

Received for publication June 17, 1991; accepted June 27, 1991. Reprint requests: Thierry H. LeJemtel, MD, Albert Einstein College of Medicine, 1300 Morris Park Ave., Forchheimer G-42, Bronx, NY 10461.

4/l/33654

95

determinants of ventricular ectopy in hypertensive cardiac hypertrophy

Documents