Orta ve İleri Dereceli Kalp Yetersizliği Olgularında
Propionil L-Karnitinin Sol Ventrikül Fonksiyonları Üzerine Akut Etkisi
Faruk AYAN, Nurgül KESER, Lale KOLDAŞ, Hakan KARPUZ, Necati SIRMACI
Department of Cardiology, Cerrahpaşa Medical School, University of Istanbul, ISTANBUL
ÖZET
Karnitin serbest yağ asitlerinin oksidasyonunda major bir role sahiptir. Serbest yağ asitlerinin toksik metabolitleri olan ve patolojik durumlarda sitoplazma ve mitokondride birikerek miyokardın fonksiyonunu bozan acyl-Co A ve acetyl-Co A'ı detoksifiye etmektedir. Bu çalışma, miyokard fonksiyonu üzerine propionyl L-carnitin (PLC)’in akut etkisini konvansiyonel Doppler ekokardiografi ile değerlendirmek amacı ile düzenlenmiş ve çalışmaya NYHA III-IV kalp yetersizliği olan 16 hasta dahil edilmiştir. Bir gram PLC injeksiyonundan önce ve 20 dakika sonra pik E (cm/s), pik A (cm/s), E/A oranı, velosite-zaman integrali (EVTI, AVTI), deselerasyon velositesi/deselerasyon zamanı (dv/dt: m/s2), AFF ve EF ile, hemodinamik değişken olarak da sistolik kan basıncı (SKB: mm Hg), diastolik kan basıncı (DKB: mm Hg) ve kalp hızı (vuru/dak) incelenmiştir. E/A oranı 0.66±0.2’den 0.82±0.2'ye (p<0.05), dv/dt 2.15±0.5’den 2.3+0.4'e (p<0.05), EVTI 4.8±1.6’den 5.2±1.9'a (p<0.05), ve AFF 62.2±11.4’den 67.3±14.8'e (p<0.05) yükselirken, AVTI 7.9±2.1'den 7.3±2.2’e düşmüştür (p<0.05). EF, SKB, DKB ve kalp hızında anlamlı değişiklik kaydedilmemiştir. Kalp yetersizliği olan hastalarda PLC ile kronik tedavinin sistolik fonksiyonları iyileştirdiği bilinse de, bizim çalışmamız carnitinin pompa gücü düşük miyokardın aynı zamanda diastolik fonksiyonunun akut olarak düzeltilmesinde de etkin bir role sahip olduğunu göstermektedir. Ancak kalp yetersizliği ile sonlanan değişik tipte kalp hastalıklarında sistolik ve diastolik fonksiyonlar üzerine PLC'in uzun dönemde oluşabilecek etkilerini izlemek amacı ile geniş kapsamlı çalışmalara gerek vardır.
Anahtar Kelimeler: Karnitin, kalp yetersizliği, ekokardiografi, diastolik fonksiyon, akut etki
SUMMARY
Echocardiographic Assessment of Acute Effects of Propionyl L-Carnitine on Left Ventricular Functions in Moderate to Severe Congestive Heart Failure
Carnitine plays a major role in fatty acid oxidation and buffers the toxic metabolites of free fatty acids such as acyl-Co A and acetyl-Co A, which in pathological conditions accumulate in the cytosol or mitochondria resulting in deprivement of myocardial function. In order to investigate the short term effects of propionyl L-Carnitine (PLC) replacement, 16 patients with New York Heart Association (NYHA) class III or IV congestive heart failure underwent a conventional Doppler echo study for the evaluation of systolic and diastolic functions before and 20 minutes after PLC administration via an iv route. Following indices were measured: Peak E (cm/s), Peak A (cm/s), E/A ratio, velocity-time integrals (EVTI, AVTI), ratio of deceleration velocity to deceleration time (dv/dt: m/s2), atrial filling fraction (AFF: %) and ejection fraction (EF: %). Hemodynamic alterations were observed by systolic blood pressure (SBP: mm Hg), diastolic blood pressure (DBP: mm Hg) and heart rate (HR: bpm). After injection of 1 gr PLC (iv), E/A ratio increased from 0.66±0.2 to 0.82±0.2 (p<0.05), dv/dt from 2.15±0.5 to 2.3±0.4 (p<0.05), EVTI from 4.8±1.6 to 5.2±1.9 (p<0.05), AFF from 62.2±11.4 to 67.3±14.8 (p<0.05) and AVTI decreased from 7.9±2.1 to 7.3±2.2 (p<0.05). There was no significant change in EF, SBP, DBP and HR (p>0.05). While it has already been agreed upon the improvement of systolic function over a long period with PLC replacement therapy, our attractive preliminary results can be interpreted as evidence that PLC plays a central role in the short-term regulation of diastolic functions of the failing heart.
Key Words: Carnitine, heart failure, echocardiography, diastolic function, acute effect
INTRODUCTION
Carnitine, a water soluble, naturally occurring aminoacide synthesized in liver, brain and renal paranchyme, plays a major role in fatty acid oxidation and is the major energy providing pathway of the myocardium (1). With normal oxygen bioavailability, the most utilized energetic substrate employed by myocardial cells is represented by long chain fatty acids (2). However their oxidation only takes place in the presence of carnitine at the mitochondrial level. The accumulation of fatty acids is highly toxic for the cardiac cell. In fact, free fatty acids (FFA) organized in lysophosphatides, damage ventricular membranes, are arrhythmogenic, block certain enzymatic functions and eventually alter myocardial contractility. It was thought that exogenous PLC could be used to develop a cardioprotective effect, facilitate fatty acid metabolism and increase the intramitochondrial availability of ATP (3).
The aim of this study was to assess the short term effects of PLC on left ventricular systolic and diastolic functions by echocardiography in patients with NYHA class III-IV heart failure.
PATIENTS and METHODS
Sixteen patients (10 males, 6 females, mean age, 55+12 years) with congestive heart failure in NYHA class III-IV and in chronic treatment with digitalis and diuretics for at least 3 months who still displayed symptoms were enrolled in the study. The etiology of heart failure was dilated cardiomyopathy (DCMP) in 6 patients, ischemic heart disease in 5, hypertension in 3 and valvular heart disease in 2 patients.
Complete 2-D and spectral Doppler echocardiographic studies including color-flow imaging were obtained mainly with a phased array system (Vingmed CFM 750 or Hewlett-Packard Sonos 1500) with a 3 mHz transducer. A comprehensive 2-D echocardiographic examination (4) and a complete pulsed and continuous wave Doppler examination was performed as described (5).
EF was calculated by the method of Simpson's as the directions of American Society of Echocardiography from apical 4-chamber view (6).
To record left ventricular (LV) inflow velocities, the apical 4-chamber view was used and the pulsed wave-Doppler sample volume was placed at the level of the leaflet tips at the mitral valve. The E/A ratio was calculated as the ratio of the peak velocity at the early phase of left ventricular filling (E) to that during active atrial contraction (A). The deceleration time (dt:s) was measured as the time from peak E velocity to the baseline value. Deceleration rate (dv/dt: m/s2), velocity-time integrals (EVTI, AVTI) and atrial filling fraction (the velocity integral A/time velocity integral of flow during total diastole: %) were calculated as described (7,8).
SBP (mm Hg)/DBP (mm Hg) and HR (bpm) were also obtained before and after treatment with the patient lying in the supine position.
Statistical significance of the differences was tested by student t-test. p<0.05 was considered to represent significance.
RESULTS
Although short term carnitine therapy had no effect on SBP, DBP, HR and EF, a significant acute effect on LV early and late diastolic filling was observed as can be noticed from the parameters listed in the Table 1.
DISCUSSION
Although the heart is able to synthesize structural lipids for incorporation into the membranes, the most likely fate of a fatty acid molecule taken up by the heart is oxidation. The overall steps of FFA oxidation can be summarized as follows:
Extramitochondrial formation of acyl-Co A, transfer of the acyl group to carnitine by the outer transferase, delivery of the carnitine ester to the inner transferase, transfer of the acyl group to the matrix Co A, beta-oxidation and finally transfer of intramitochondrial carnitine outside the mitochondria by a carnitine-Acyl carnitine translocase system (9).
So in the myocardium, L-carnitine scavenges the toxic metabolites of FFA such as acyl-Co A and acetyl-Co A, which in pathological conditions accumulate in the cytosol and/or in the mitochondria. These compounds are not able to cross heart membranes. L-carnitine reacts with acyl and acetyl-Co A to form acyl and acetyl carnitines able to diffuse through the heart membranes and by this way they can be eliminated in the urine (9,10).
Since in the aerobic heart, the oxidation of FFA accounts for %70 of the utilized substrates, primary or secondary carnitine deficiencies (as in the case of ischaemia or anoxia) lead to a substantial reduction in energy production. It was demonstrated that ischaemia induces a loss of free carnitine from myocardium which determines a secondary carnitine deficiency (11-13).
The hypothesis that myocardial carnitine deficiency may cause malfunction of the heart has been confirmed in several animal models and in humans (13,14) and systemic carnitine deficiency has also been shown to lead to dilated or hypertrophic cardiomyopathy (15).
In our study, 6 patients had heart failure resulting from DCMP and 5 were found to have heart failure resulting from ischaemia. The reason for including 3 patients with hypertension and 2 patients with valvular heart disease is because of the results of the DHZB (Deutsches Herzzentrum Berlin) studies (16-19) which were done to assess whether myocardial carnitine deficiency was specific for DCMP or if it also occurred in heart failure of different origin. They found that carnitine levels in hearts from patients with DCMP and coronary heart disease were not different from each other. Patients with DCMP and heart failure due to coronary or valvular heart disease do show a comparable loss of myocardial carnitine in several other studies (20,21). So, myocardial carnitine loss in heart failure is not a primary, disease-specific finding. It probably represents a secondary phenomenon following pressure or volume load, or a response to increased wall stress or filling pressures or a compensatory metabolic mechanism.
In our study, patients with NYHA III-IV class with an average EF of 34±7% were included again because of the results of DHZB study (22) where the decrease in myocardial carnitine was found to be more pronounced in patients with more severe heart failure than in patients with less severe reduction of EF.
As for evaluating the therapeutic results of L-carnitine replacement, several studies have been undertaken. Thomsen et al. (23) and Kamikawa et al. (24) and Cherchi et al. (3) had found that administration of carnitine to patients with ischaemic heart disease and angina was associated with increased exercise tolerance and reduced ST depression. Chiariello et al. (25) has stated that administration of carnitine might limit infarct size and protect against arrhythmia. Ghidini et al. (26) reports that in elderly patients with congestive heart failure secondary to ischaemic or hypertensive heart disease, treatment with L-carnitine resulted in reduced heart rate, edema and dyspnea, increased diuresis and reduced digitalis consumption compared with the group not treated with carnitine. Objective improvements in exercise tolerance or EF were not documented in this study. However, it has already been agreed upon the improvement of systolic function over a long period with L-carnitine replacement therapy (27).
The most recent study showing the acute and chronic effects of propionyl L-carnitine on the hemodynamics, exercise capacity and hormones in patients with congestive heart failure was done by Anand et al. (28). They found that acute administration of PLC caused a significant reduction in pulmonary artery and pulmonary wedge pressure which may partially be responsible for the improvement of diastolic functions, as have been demonstrated by us.
The CEDIM study was the largest trial demonstrating the effects of PLC therapy on left ventricular functions using echocardiography where only the patients surviving from acute anterior myocardial infarction were enrolled (29).
As a result of our study which appears to be the first one including patients with various forms of heart disease resulting in heart failure, we propose that PLC when applied via an iv route produces no hemodynamic deterioration as recorded from blood pressure and heart rate and improvement in diastolic function acutely seems to result from solutary effects on LV relaxation, atrioventricular compliance and late diastolic filling. This may be due to the activation of neurohumoral mechanisms leading to a decrease in LV end-diastolic pressure, suggesting a prior and early effect on diastolic and a late effect on LV systolic function.
REFERENCES
ADDRESS FOR CORRESPONDENCE:
Dr. Nurgül KESER
Erdoğdu sok. Manolya apt. 5/7
Feneryolu, İSTANBUL