Diastolic function and creatine phosphate: An echocardiographic study

CURRENT THERAPEUTIC RESEARCH VOL. 54, NO. 5, NOVEMBER 1993

DIASTOLIC FUNCTION AND CREATINE PHOSPHATE: AN ECHOCARDIOGRAPHIC STUDY G. SCATTOLIN, A. GABELLINI, A. DESIDERI, M. FORMICHI, F. CANEVE, AND F. CORBARA Department of Cardiology, Este Hospital, Padova, Italy

ABSTRACT I n p r i m a r y i s c h e m i a or s i t u a t i o n s in w h i c h t h e h e a r t is forced to ope r a t e in a s t a t e o f relative a n a e r o b i o s i s , d i a s t o l i c d y s f u n c t i o n m a y be t h e f i r s t a l t e r a t i o n to appear. A c u t e i n f u s i o n o f c r e a t i n e p h o s p h a t e (5 gm i n t r a v e n o u s l y ) in 20 men s u f f e r i n g f r o m c h r o n i c ischemic cardio p a t h y induced a g e n e r a l i m p r o v e m e n t in t h e echo-Doppler d i a s t o l i c f u n c t i o n p a r a m e t e r s . A s t a t i s t i c a l l y s i g n i f i c a n t m o d i f i c a t i o n was observed in t h e p a r a m e t e r s t h a t r e p r e s e n t t h e p r o g r e s s o f t h e first p a r t of t h e d i a s t o l i c phase: t h e isovolumetric r e l a x a t i o n t i m e and t h e protod i a s t o l i c d e c e l e r a t i o n slope r a t e . These d a t a suggest t h a t c r e a t i n e p h o s p h a t e can be usefully employed in cases o f serious a c u t e c o r o n a r y i n s u f f i c i e n c y o r in c o n d i t i o n s in w h i c h t h e r e is a c l e a r but reversible a l t e r a t i o n in diastolic function, w h i c h i f n o t corrected, t h r e a t e n s to j e o p a r d i z e t h e a l r e a d y defective m y o c a r d i a l blood supply as well as the pump function. INTRODUCTION

In primary ischemia (acute myocardial infarction, preinfarction angina) or situations in which the heart is forced to operate in a state of relative anaerobiosis (left ventricular hypertrophy secondary to arterial or postischemic hypertension, cardiomyopathies), diastolic dysfunction may be the first alteration to appear. 1-6 Alterations in myocardial elasticity may significantly influence the adaptation of the left ventricle to pathologic conditions and are potentially present in almost all cases of adult cardiopathy. The fact that the left ventricular diastolic phase is often altered, even at rest, in patients with a normal systolic performance1 is particularly interesting. This phase in the cardiac cycle, long considered a passive phenomenon, is now recognized, at least in its initial stages, to be an active event whose activation may demand a greater energy expenditure than the activation of the systolic phase, v The initial isovolumetric rapid filling phase of the diastole involves the activation of biochemical processes requiring energy, while the middle and terminal diastole is dominated by the viscoelastic properties of Address correspondenceand reprint requests to: Prof. E. Strumia, Direttore MedicoScientifico, Schiapparelli Searle, Corso Belgio 86, 10153 Torine, Italy. Received for publication on May 13, 1993. Printed in the U.S.A. Reproduction in whole or part is not permitted. 562

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the ventricle itself. The energy produced by the activation of membrane adenosine triphosphatase (ATPase) is required to repump calcium ions into the storage cells of the sarcoplasmic reticulum and beyond, through the cell membrane, s'9 This prevents the interaction of actin and myosin filaments. Clinical and experimental data 1°-13 have clarified the relationship between the drop in high-energy phosphates and alterations in ventricular relaxation in the decompensation phase. Some recent studies 14-17 have shown that the rate of transmitralic flow revealed by Doppler ultrasound represents a noninvasive and clinically reliable indicator of left ventricular diastolic function. The diastolic function indices obtained by this technique correlate well with data obtained by invasive techniques (cardiac catheterization and angioscintigraphy).14'1s In the present study, we used the Doppler ultrasound technique for the noninvasive assessment of left ventricular diastolic function in a group of 20 patients with chronic ischemic cardiopathy. We also tested the effects of creatine phosphate (CP) therapy on left ventricular diastolic function, considering CP to be a metabolic drug capable of delivering high-energy phosphates to the myocardial cells and regulating their utilization by the cell. PATIENTS AND METHODS

For the study we selected 20 men, with a mean age of 62 +_ 12 years (range, 52 to 75 years), all suffering from chronic ischemic cardiopathy. None of the patients selected had a history of myocardial infarction. In all patients, Doppler ultrasound revealed baseline alterations in the main diastolic function indices. The control group for normal diastolic indices consisted of male volunteers, with a mean age of 55 -+ 8 years (range, 30 to 59 years), all with no history of cardiopathy, cardiovascular pathology, or electrocardiogram (ECG) abnormalities (Table I). The patients were subdivided according to the New York Heart Association (NYHA) classification (class I, 18; class II, 2). We also noted the Table I. Normal controls: Diastolic function Doppler ultrasound parameters. Peak A (cm/sec) Peak E (cm/sec) NE AHT (msec) DHT (msec)_ DR (cm/sec ~) IRT (msec)

58.1 78.5 0.71 62 95.3 485 48.5

_+ 6.82 + 11.96 _+ 0.2 _ 6.58 _ 12.05 _+ 19 _+ 7.27

Peak A = presystolic peak; peak E = protodiastolic peak rate; AHT = acceleration half time; DHT = deceleration half time; DR = deceleration rate; IRT = isovolumetric relaxation time. 563

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presence and type of arrhythmias, blood pressure, heart rate, and ECG alterations. We eliminated patients with heart rates greater than 90 beats/ min in order not to compromise the reliability of the examination. The sample was homogeneous, presenting no significant differences at baseline. Doppler ultrasound scans were performed using a Hewlett-Packard Model 77020 AC Rev Imaging System (Hewlett-Packard, Andover, Massachusetts), with a 2.5 mHz transducer. Patients were positioned on their left sides in slight lateral decubitus to allow for the "sample volume" to be positioned at the mitral anulus level. An ECG tracing and a phonocardiographic recording (aortic focus) were obtained simultaneously (Figure 1). The following parameters were measured: protodiastolic peak rate (peak E); presystolic peak (peak A); the A/E ratio; the time required to reach the maximum protodiastolic rate starting from 50% of that rate (acceleration half time, AHT); the time required to reach 50% of deceleration rate (deceleration half time [DHT]); the slope of the first half of deceleration rate (DR); and isovolumetric relaxation time (IRT) measured from the second aortic tonus to the start of the transmitralic flow wave. The figures for each parameter represent the mean of 5 consecutive beats in order to minimize the effect of respiration on ventricular filling. All tests were performed by the same operator. The Doppler ultrasound scan was repeated as described above after the infusion of 5 gm of CP diluted in 100 cc physiologic solution. Immediately after this first acute test, the patients were given 1 gm of CP intravenously per day during the

.

'!11 Figure 1. Method of m e a s u r e m e n t of peak velocity of diastolic early inflow (E), atrial contraction (A), deceleration rate (DR), acceleration h a l f time (AHT), deceleration h a l f time (DHT), and isovolumetrie relaxation time (IRT). 564

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following 5 days. On the sixth day, the initial protocol was repeated (base and after infusion of 5 gm of CP) in order to ascertain the effect of prolonged t r e a t m e n t and the reproducibility of data obtained on the first day. Means and standard deviations were calculated for all data; Student's t test for paired d a t a was used for statistical analysis. RESULTS

The data of Doppler ultrasound parameters, both at baseline and after the infusion of 5 gm of CP, of the two acute tests at the first and the sixth day of the study are summarized in Table II. Baseline values at the first and sixth day are compared in Table III. No statistically significant variations (baseline values and after CP infusion, respectively, on days 1 and 6) were observed in the following parameters: peak E (52.6 -+ 25.8 versus 55.4 +- 30 and 54.0 -+ 23.7 versus 57.6 -+ 28.6); peak A (54.8 -+ 18.5 versus 52.6 +- 19.3 and 55.8 -+ 18.5 versus 54.2 - 16.7); A/E (1.17 -+ 0.42 versus 1.12 -+ 0.37 and 1.09 -+ 0.23 versus 1.05 -+ 0.34); AHT (40.5 -+ 5.2 versus 41.8 -+ 10.11 and 40.7 +- 2.7 versus 41.4 -+ 4.6); DHT (80.4 -+ 13.9 versus 76.3 +- 14.3 and 85.3 -+ 17.4 versus 79.3 -+ 19.5). On the other hand, statistically significant variations were observed for the parameters associated with the first diastolic phase: DR (301.6 +154.4 versus 337 -+ 216.7, P < 0.05, day 1 and 285 +- 150 versus 338.4 -+

Table II. Diastolic function Doppler ultrasound parameters. Acute tests: Baseline values and after creatine phosphate (CP) 5 gm IV.

Day I Parameter E (cm/sec) A(cm/sec)

A/E

DR (cm/sec 2) AHT (msec) DHT (msec) IRT (msec)

Baseline

After CP

52.6 54.8 1.17 301 40.5 80,4 75,6

+-- 25 +- 18 -+ 0.4 _+ 154 _+ 5 _+ 13 -+ 26

55.4 52.6 1.12 337 41.8 76.3 68.7

54 55.8 1.09 285 40.7 85.3 68.3

_+ 23 -+ 18 -+ 0.2 +_ 150 _+ 2 _+ 17 +- 31

57.6 54.2 1.05 338 41.4 79.3 60.7

_+ 30 +_ 19 -+ 0.3 -+ 216 _+ 10 _+ 14 _+ 25

P NS NS NS <0.05 NS NS <0.05

Day 6 E (cm/sec) A(cm/sec)

A/E

DR (cm/sec 2) AHT (msec) DHT (msec) IRT (msec)

_+ 28 -+ 16 -+ 0.3 -- 213 -- 4 _+ 19 _+ 26

NS NS NS <0.05 NS NS <0.01

peak rate; A = presystolic peak; DR = deceleration rate; AHT = acceleration half time; EH• protodiastolic = deceleration half time; IRT = ~sovolumetric relaxation time; NS = not significant.

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Table III. Diastolic function Doppler ultrasound parameters. Comparison of baseline values of t h e two acute tests on day 1 and after 6 days of t r e a t m e n t with creatine phosphate, 1 gm IV daily,

Parameter E (cm/sec) A(cm/sec)

NE

DR (cm/sec 2) AHT (msec) DHT (msec) IRT (msec)

P Value

Baseline, Day I

0.301 0.37 0.240 0.180 0.439 0.807 0.123

52.6 -+ 25 54.8-+ 18 1.17 -- 0.4 301 -+ 154 40.5 - 5 80.4 -- 13 75.6 +- 26

Baseline, Day 6 54 55.8 1.09 285 40.7 85.3 68.3

-+ 23 +-18 -- 0.2 +- 150 ___2 _+ 13 -- 31

peak rate; A = presystolic peak; DR = deceleration rate; AHT = acceleration half time; EH• protodiastolic = deceleration half time; IRT = ~sovolumetric relaxation time.

213.4, P < 0.05, day 6) and IRT (75.6 -+ 26.8 versus 68.7 -+ 25.9, P < 0.05, day 1 and 68.31 +- 31.2 versus 60 -+ 26.7, P < 0.01, day 6) (Figures 2 and 3). No patient complained of discomfort or side effects after the infusion of 5 gm of CP and no significant variations in blood pressure or heart rate were noted. DISCUSSION

For some time, cardiac function has been identified with pump function as well as with the systolic phase of the myocardium, whereas the diastole is considered to be a passive and inevitable event. Soufer et al 1 were among cm/sec 2 P < 0.05

350

P < 0.05 337

338.4

iiiiiiiiiiiiiii!iiiiiiiiil

o

iiiiiiiiiiiii

270 ~ ..... 250 _L Day 1 ~]]]Baseline~After

DR

Day 6

CP, 5 gm IV ~ B a s e l i n e ~

After CP, 5 gm IV

Figure 2. The slope of the first h a l f of deceleration r a t e (DR) on days 1 and 6. CP = creatine phosphate; DR = deceleration rate. 566

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msec 80 P < 0.05

P < 0.01

75.6 75

.....

70-

68.7

_

68.3

i SSi!i i i i i i i i iti t

65-

iiiiiiiiiiiii

60-

55 Day 1

IRT

Day 6

[ [ l ] ] ] B a s e l i n e ~ A f t e r CP, 5 gm IV ~ B a s e l i n e ~

After CP, 5 gm IV

Figure 3. Isovolumetric relaxation time (IRT) on days 1 and 6. CP = creatine phosphate.

the first to embark on a critical reassessment of myocardial physiopathology. In doing so, t h e y came to view the diastolic phase as the decisive factor in cardiac performance and diastolic alterations as the cause of signs and symptoms of h e a r t failure. Their observations were confirmed by studies conducted by Iskandrian et al, 2 who reported that, in a variety of pathologic situations, the diastolic phase of the left ventricle was often altered even at rest and even in patients with normal systolic performance. Left ventricular hypertrophy resulting from arterial hypertension, aortic stenosis, or hypertrophic cardiomyopathies is one of the most common causes of diastolic alterations. 16,19,2° Furthermore, Snider et al 3 have found constant and early alterations in ventricular filling among children with slight to moderate hypertension. A compromised diastolic phase is also seen as hemodynamically important in coronary pathology. In fact, an altered ventricular filling as well as an increase in left ventricular telediastolic pressure reduces coronary flow, which is mostly diastolic, and in doing so aggravates the ischemic state causing a primary energy deficiency. Transluminal coronary angioplasty has permitted a more accurate analysis of the magnitude and sequence of the myocardial, electrical, and clinical events arising from the ischemia induced by the inflation of the balloon. The ischemic response to a transitory coronary occlusion was studied in 32 patients 4 subjected to plastic transluminal coronaric artery. Both systolic and diastolic functions are involved, the latter at a very early stage, before the onset of alterations in parietal dynamics. Only 15 seconds

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DIASTOLIC FUNCTION AND CREATINE PHOSPHATE

after the inflation of the balloon, all diastolic indices had noticeably deteriorated, whereas angor and systolic alterations appeared only after 30 seconds of ischemia. Araesty et al 5 achieved very similar results when they used atrial pacing to induce myocardial ischemia. The main problem associated with altered diastolic function is one of therapeutic intervention. The use of beta-blockers and especially calcium antagonists with minimal peripheral action (eg, verapamil) appears capable of normalizing the alteration in ventricular filling typical of hypertrophic cardiomyopathy.6 The normalization of the diastole in arterial hypertension is dependent on the eventual reduction of the degree of hypertrophy with hypotensive drugs. 21 Work conducted by Scognamiglio et a122 has shown that it is possible to intervene at the myocardial level with vasodilator drugs in cardiac pathologies that feature volume overload with high stress levels and varying degrees of myocardial hypertrophy (eg, aortic insufficiency, dilatative cardiomyopathy, and mitralic insufficiency). In our study, we evaluated the effects of CP after two acute infusional tests in patients with altered diastolic function. Between the two tests there was a period of 5 days of treatment with CP, 1 gm intravenously daily. This evaluation involved the main echo-Doppler parameters of diastolic function. In both tests, after acute infusion of 5 gm of CP, we observed a general improvement in the echo-Doppler diastolic function parameters. In particular, a statistically significant modification was observed in the parameters that represent the progress of the first part of the diastole: the isovolumetric relaxation time and the protodiastolic deceleration slope rate. Given the recently identified importance of adequate energy supplies for the myocardium for ventricular relaxation and filling, our data might suggest that CP, which as a metabolic drug is not only an energy carrier but also a regulator of the processes of intracellular energy use, might induce an improvement in diastolic function in the active or energydependent phase expressed as isovolumetric relaxation and deceleration rate. The results of the daily administration of 1 gm of CP, evaluated by comparison of the baseline values of the two acute tests, are not so clear; the deceleration rate is not modified, but a trend toward improvement is observed for the isovolumetric relaxation time. The experimental data allow us to make certain conclusions. The infusion of CP permits a modification in a positive sense of the chief echoDoppler diastolic function parameters; in particular, it has a significant effect on the protodiastolic phase (IRT, DR). The acute effect is well preserved and reproducible in following administrations, as well as after 5 days of treatment with a lower dosage. After 5 days of treatment with a lower dosage, a positive trend is

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shown for some parameters, such as isovolumetric relaxation rate. It is possible that a stronger and clearer effect can be obtained with a higher dosage. Other authors have shown a favorable effect of CP in patients with acute myocardial infarction, 23-25 congestive heart failure, 26-2s and for myocardial protection during heart s u r g e r y . 29-32 In all these conditions, the fact that CP is able to intervene positively at the level of the diastolic function is important. Our data suggest that CP can be usefully employed with other drugs in cases of serious acute coronary insufficiency (unstable angina, preinfarctual angina) or in other conditions (PTCA, coronary thrombolysis), where a clear but reversible alteration in the diastolic function exists, which, if not corrected, further threatens to jeopardize the already defective myocardial blood supply as well as pump function. References:

1. Soufer R, Wolgelernter D, Vita N. Intact systolic left ventricular function in clinical congestive heart failure. A m J Cardiol 1985; 55:1032-1036. 2. Iskandrian AS, Hakki AH. Age-related changes in left ventricular diastolic performance. A m Heart J 1986; 112:75-78. 3. Snider AR, Gidding SS, Rocchini AP. Doppler evaluation of left ventricular diastolic filling in children with systemic hypertension. A m J Cardiol 1985; 56:921-926. 4. Labowitz AJ, Lewen MK, Kerm M, et at. Evaluation of left ventricular systolic and diastolic dysfunction during transient myocardial ischemia produced by angioplasty. J A m Coll Cardiol 1987; 10:748-755. 5. Araesty JM, McKay RG, Heller GV, et al. Simultaneous assessment of left ventricular ischemia. Circulation 1985; 71:889-900. 6. Hess OM, Murakami T, Krayenbyehl MP. Does verapamil improve left ventricular relaxation in patients with myocardial hypertrophy? Circulation 1986; 74:530-543. 7. Kats AM. The myocardium in congestive heart failure. A m J Cardiol 1989; 63:12A- 16A. 8. Tada M, Yamamoto T, Tonomura Y. Molecular mechanism of active calcium transport by sarcoplasmic reticulum. Physiol Rev 1978; 58:1-79. 9. Katz AM. Calcium fluxes across the sarcoptasmic reticulum. In: Opie LH, ed. Calcium antagonist a n d cardiovascular disease. Vol. 9. Perspectives in Cardiovascular Research. New York: Raven Press. 1984:53. 10. Bashore TM, Magorien DJ, Letterio J, et al. Histologic and biochemical correlates of left ventricular chamber dynamics in man. J A m Coll Cardiol 1987; 9:734-742. 11. Furchgott RF, Lee KS. High energy phosphates and force contraction of cardiac muscle. Circulation 1961; 24:416. 12. Pool PE, Spann J F Jr, Buccino RA, et al. Myocardial high energy phosphate stores in cardiac hypertrophy and heart failure. Circ Res 1967; 21:365-373. 13. Katz A. Cellular mechanism in congestive heart failure. A m J Cardiol 1988; 62:3A-8A.

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14. Lin S-L, Tak T, Kawanishi DT, et al. Comparison of doppler echocardiography and hemodynamic indexes of left ventricular diastolic properties in coronary artery disease. Am J Cardiol 1988; 62:882-886. 15. Pearson AC, Labowitz AJ, Mrosek D, et al. Assessment of diastolic function in normal and hypertrophied hearts: Comparison of Doppler echocardiography and M-mode echocardiography. A m Heart J 1987; 113:1417-1425. 16. Gardin JM, Drayer JL, Rohon MK, et al. Doppler evaluation of left ventricular filling in mild and severe hypertension. J A m Coll Cardiol 1986; 7:185-192. 17. Maron BJ, Spirito P, Green KJ, et al. Noninvasive assessment of left ventricular diastolic function by pulsed Doppler echocardiography in patients with hypertrophic cardiomyopathy. J A m Coll Cardiol 1987; 10:733-742. 18. Spirito P, Maron BJ. Noninvasive assessment of left ventricular diastolic function: Comparative analysis of Doppler echocardiographic and radionuclide angiographic techniques. J A m Coll Cardiol 1986; 7:518-526. 19. Douglas PS, Berko B, Lesh M, Reichek N. Alterations in diastolic function in response to progressive left ventricular hypertrophy. J A m Coll Cardiol 1989; 13:461-467. 20. Lorell BH, Grossman W. Cardiac hypertrophy: The consequences for diastole. J A m Coll Cardiol 1987; 9:1189-1193. 21. Phillips RA, Coplan N, Krakoff LR, et al. Doppler echocardiography and analysis of left ventricular filling in treated hypertensive patients. J A m Coll Cardiol 1987; 9:317-322. 22. Scognamiglio R, Fasoli G, Visentin L, Dalla Volta S. Effects of unloading and positive inotropic interventions of left ventricular function in asymptomatic patients with chronic severe aortic insufficiency. Clin Cardiol 1987; 10:804-810. 23. Ruda M Ya, Samarenko MB, Afonskaya NI, Saks VA. Reduction of ventricular arrhythmias by phosphocreatine (Neoton) in patients with acute myocardial infarction. A m Heart J 1988; 116:393-397. 24. Camilova UK, Katsenovich RA, Kostco SZ. Combined use of phosphocreatine and nifedipine for treatment of patients with acute myocardial infarction. Curr Ther Res 1991; 50:591-598. 25. Cini R, Stazi GC, Giacopino F, et al. Creatinfosfato nella fase acuta dell'IMA. Risultati preliminari di uno studio clinico. Il Cuore 1987; IV, Gennaio/Marzo:91-102. 26. Ferraro S, Maddalena G, Fazio S, et al. Acute and short-term efficacy of high doses of creatine phosphate in the treatment of cardiac failure. Curr Ther Res 1990; 47:917-923. 27. Grazioli I, Melzi G, Strumia E. Multicenter controlled study of creatine phosphate in the treatment of heart failure. Curr Ther Res 1992; 52:271-280. 28. Andreev NA, Andreeva TN, Bichkov IV. Effect of phosphocreatine in congestive heart failure. C u r t Ther Res 1992; 51:649-660. 29. Semenovsky ML, Shumakov VI, Sharov VG, et al. Protection of ischemic myocardium by exogenous phosphocreatine. Clinical, ultrastructural and biochemical evaluation. J Thorac Cardiovasc Surg 1987; 94:762-769. 30. D'Alessandro LC, Cini R, Pucci A, et al. Protezione miocardica: Uso del creatin fosfato

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