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European Journal of Heart Failure 2004 6(2):213-218; doi:10.1016/j.ejheart.2003.10.001
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© 2003 European Society of Cardiology

Improved systolic and diastolic myocardial function with intracoronary pyruvate in patients with congestive heart failure

Hans-Peter Hermann*, Jordis Arp, Burkert Pieske, Harald Kögler, Steffen Baron, Paul M.L. Janssen and Gerd Hasenfuss

Abteilung Kardiologie und Pneumologie Georg-August-Universität Göttingen, Robert-Koch-Str. 40, Göttingen D-37075, Germany

* Corresponding author. Tel.: +49-551-392920; fax: +49-551-398918. E-mail address: phermann{at}med.uni-goettingen.de


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: Pyruvate increases myocardial performance in isolated myocardium and improves hemodynamics in patients with congestive heart failure.

Aims: To investigate the influence of pyruvate on detailed parameters of systolic and diastolic left ventricular (LV) function.

Methods and Results: In patients with heart failure due to dilated cardiomyopathy (LVEF 30±4%, n=9) pyruvate was infused intracoronarily. LV function was analysed before, during and after application of different pyruvate concentrations using a LV-micromanometer catheter. LV volumes were determined using cine ventriculography. Pyruvate increased maximum rate of LV isovolumic pressure rise (Peak +dP/dt) from 802±106 to 1125±103 mmHg/s (P<0.05). Left ventricular end-diastolic pressure declined in parallel from 17±2 to 12±2 mmHg (P<0.05) and heart rate decreased from 79±4 to 72±5 min–1 (P<0.05). Stroke volume index increased from 34±4 to 43±6 ml/m2 (P<0.05), end-diastolic LV volume remained unchanged, thus left ventricular ejection fraction increased with pyruvate from 30±4 to 39±4% (P<0.05). Maximum rate of LV isovolumic pressure decline (Peak –dP/dt) was significantly increased with pyruvate (from 794±94 to 980±108 mmHg/s; P<0.05) and mean arterial pressure increased from 80±5 to 88±4 mmHg (P<0.05). Discontinuation of pyruvate resulted in immediate reversibility of its effects.

Conclusion: Intracoronary pyruvate improves systolic and diastolic myocardial function and increases ejection fraction without increasing heart rate. Pyruvate thus exhibits the profile of a favourable inotropic agent, however, further investigation for the treatment of patients with acute heart failure is mandatory.

Key Words: Pyruvate • Inotropic agents • Heart failure • Sarcoplasmic reticulum

Received March 7, 2003; Revised June 25, 2003; Accepted October 1, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Pharmacological approaches to the treatment of acute heart failure include strategies to decrease elevated filling pressures, i.e. to unload the heart and to reduce afterload by means of arterial vasodilation. Furthermore, in the clinical setting of low output failure with hypotension, the use of positive inotropic stimulation is frequently inevitable in order to maintain adequate tissue perfusion. However, enhancement of cardiac contractility and cardiac output with positive inotropic agents such as catecholamines and phosphodiesterase-inhibitors is associated with increased oxygen- and energy consumption of the heart and may induce potentially harmful arrhythmias [1–3], long-term therapy may be associated with increased mortality [4].

It has recently been reported that the glycolytic intermediate pyruvate exerts positive inotropic effects and improves contractile function in healthy and diseased canine and swine hearts in vivo [5–8], in in vitro perfused rabbit hearts [9], in isolated rat myocytes [10] and in isolated multicellular muscle preparations from end stage failing human hearts [11]. Moreover, pyruvate was shown to potentiate β-adrenergic positive-inotropic stimulation in isolated animal [12,13] and human myocardium [14]. Thus, pyruvate alone or a combination of pyruvate and catecholamines could be of potential value in the treatment of acute heart failure. In a previous study in patients with congestive heart failure, pyruvate given into the left main coronary artery was shown to increase cardiac output while pulmonary artery pressure and heart rate decreased [15]. Because of this hemodynamic profile, pyruvate warrants further evaluation for the treatment of patients with heart failure.

However, there are so far no data available on the influence of pyruvate on detailed parameters of intrinsic systolic and diastolic function of the human heart in vivo. We, therefore investigated invasively left ventricular function in patients with congestive heart failure due to dilated cardiomyopathy treated with intracoronary pyruvate infusion.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patients
Nine consecutive patients with congestive heart failure NYHA class II–III were studied during routine diagnostic cardiac catheterization for evaluation of cardiomyopathy of unknown etiology. Two patients were women the median age was 61 years (range 30–69 years). All patients had a left ventricular ejection fraction below 40% and were in sinus rhythm. Patients were included if significant coronary heart disease, valvular heart disease, and a history of arterial hypertension could be excluded. Previous medication of the patients included digoxin (n=5), digitoxin (n=2), ACE-inhibitors (n=8), diuretics (n=9), spironolactone (n=5), nitrates (n=3), β-blockers (n=3), amiodarone (n=2), aspirin (n=3), heparin (n=7). All patients had given written informed consent. This patient cohort was entirely different from the patients investigated in an earlier study of our group [15].

2.2. Study protocol
The investigation conforms with the principles outlined in the Declaration of Helsinki [16], the study protocol was reviewed and approved by the Ethical Committee of the Georg-August-Universität Göttingen. Cardiac catheterization was performed from the right femoral artery in the fasting state with all medication having been withheld for at least 12 h. After exclusion of coronary artery disease or valvular heart disease, a 6 F micromanometer catheter (Micro-Tip®, model SPC-464D, Millar Instruments, Houston TX) was advanced from the left femoral artery into the left ventricular (LV) cavity. A 4 F left coronary catheter was placed into the left main coronary artery and approximately 30 min after coronary angiography an infusion of 0.9% saline into the left main coronary artery was started at 90 ml/h. After 10 min, baseline measurements of left ventricular systolic and end-diastolic pressure, the first pressure derivatives (peak positive and negative dP/dt), systolic, diastolic and mean aortic pressures were taken and a biplane left ventriculography was performed at a 40° right anterior oblique and 60° left anterior oblique projection using power infusion of 40 ml non-ionic contrast medium at 12 ml/s. Left ventricular volumes at end-diastole and end-systole were analysed using the method of Sandler and Dodge [17] and left ventricular ejection fraction was calculated. Stroke volume was obtained from consecutive LV systolic and diastolic volumes. Heart rate and rhythm were continuously monitored using standard ECG leads.

Pyruvate (300 mmol/l) was then infused into the left main coronary artery at 90 ml/h for 10 min, then at 180 ml/h for 10 min and at 360 ml/h for another 10 min. Finally, 0.9% saline was infused at 90 ml/h for a 10 min washout-phase. Assuming a coronary blood flow of 300 ml/min, the coronary arterial pyruvate concentrations were approximately 1.5, 3 and 6 mmol/l, respectively. Hemodynamic and contractile parameters were determined at baseline, 10, 20, 30 and 40 min. During infusion of the highest pyruvate concentration (timepoint 30 min), a second left ventriculography was performed under identical conditions as before pyruvate infusion.

2.3. Statistical analysis
Data are expressed as mean±one standard error of the mean. Differences between baseline and measurements taken after each intervention were compared by one way repeated measures analysis of variance followed by Student–Newman–Keuls tests. For comparison of treatment effects before and after application of pyruvate, a paired t-test was applied. A two-tailed P-value <0.05 was considered as statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
Left ventricular performance was severely impaired at baseline in patients with dilative cardiomyopathy: left ventricular ejection fraction was low (30±4%) and left ventricular end-diastolic pressure was elevated (17±2 mmHg). Intracoronary infusion of pyruvate induced a pronounced concentration-dependent increase in maximum rate of left ventricular isovolumic pressure rise (peak +dP/dt) by 40% from 802±106 to 1125±103 mmHg/s on the highest pyruvate concentration (P<0.05) (Fig. 1). The increase was already significant on the lowest tested pyruvate concentration. Left ventricular end-diastolic pressure (LVEDP) declined in parallel from 17±2 to 12±2 mmHg and heart rate decreased with pyruvate infusion from 79±4 to 72±5 min–1 (both P<0.05) (Fig. 2). Stroke volume index (SVI) increased by 27% from 34±4 to 43±6 ml/m2 (P<0.05) (Fig. 3), end-diastolic LV volume remained unchanged (Table 1), thus left ventricular ejection fraction (LVEF) markedly increased with pyruvate infusion from 30±4 to 39±4% (P<0.05) (Fig. 3).


Figure 1
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  		Fig. 1 Influence of intracoronary pyruvate infusion on maximum rate of left ventricular isovolumic pressure rise (left panel) and maximum rate of left ventricular isovolumic pressure fall (right panel) under different pyruvate concentrations: baseline (10 min of 0.9 % saline infusion at 90 ml/h), 90, 180, 360 ml/h (10 min of 300 mmol/l pyruvate infusion at 90 ml/h, 180 ml/h and 360 ml/h, respectively), washout (10 min of 0.9 % saline infusion at 90 ml/h). +dP/dtmax=peak rate of LV isovolumic pressure rise (mmHg/s), –dP/dtmax=peak rate of LV isovolumic pressure fall (mmHg/s), *P<0.05 vs. baseline, #P<0.05 vs. washout.

 


Figure 2
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  		Fig. 2 Influence of intracoronary pyruvate infusion on left ventricular end-diastolic pressure (left panel), heart rate (right panel) and mean arterial pressure (lower panel) under different pyruvate concentrations: baseline (10 min of 0.9 % saline infusion), 90, 180, 360 ml/h (10 min of 300 mmol/l pyruvate infusion at 90 ml/h, 180 ml/h and 360 ml/h, respectively), washout (10 min of 0.9 % saline infusion). LVEDP=left ventricular end-diastolic pressure (mmHg), MAP=mean arterial pressure (mmHg), *P<0.05 vs. baseline, #P<0.05 vs. washout.

 


Figure 3
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  		Fig. 3 Influence of intracoronary pyruvate infusion on stroke volume index (left panel) and left ventricular ejection fraction (right panel) before and during pyruvate application (baseline and 360 ml/h, respectively). SVI=stroke volume index (ml/m2), LVEF=left ventricular ejection fraction (%), *P<0.05 vs. baseline.

 


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  		Table 1 Influence of intracoronary pyruvate on left ventricular volumes before and during pyruvate application. LVEDV=left ventricular end-diastolic volume (ml), LVESV=left ventricular end-systolic volume (ml)

 
The maximum rate of LV isovolumic pressure decline (peak –dP/dt) was significantly increased with pyruvate application (from 794±94 to 980±108 mmHg/s; P<0.05) (Fig. 1) reflecting improved diastolic function since left ventricular end-diastolic pressure declined in parallel. Mean arterial pressure (MAP) increased slightly by 10% (from 80±5 to 88±4 mmHg, P<0.05) (Fig. 2). All parameters returned to baseline after saline washout-infusion.

Intracoronary pyruvate infusion was well tolerated by all patients, no unwanted side effects were observed despite active inquiry. Notably, no cardiac arrhythmias were recorded during the infusion of pyruvate at any dose.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
The present study demonstrates that intracoronary pyruvate at supraphysiological concentration exhibits pronounced positive-inotropic and positive-lusitropic effects in patients with congestive heart failure due to dilated cardiomyopathy. We observed a 40% increase in peak +dP/dt as an isovolumic index of myocardial contractility. However, peak +dP/dt may also rise due to increases in preload or afterload, which was not the case in our study: Left-ventricular end-diastolic pressure reflecting preload decreased by 29% during pyruvate application and there was only a moderate 10% increase in mean arterial pressure reflecting afterload which together could not account for the observed marked increase in the maximum rate of LV isovolumic pressure rise. Besides improvements in peak +dP/dt and reduced preload, the improvement in systolic function with pyruvate infusion is underlined by pronounced increases in stroke volume index and ejection fraction by 29% and 31%, respectively. Furthermore, the decrease in LV filling pressure and the increased maximum rate of isovolumetric pressure decline reflect considerable improvements in diastolic function of the failing hearts, which may not solely be attributed to ameliorated systolic function of the myocardium.

In a previous study we have demonstrated that intracoronary pyruvate does not induce systemic vasodilation since pyruvate is almost completely extracted from the coronary circulation by the myocardium after intracoronary infusion, systemic pyruvate levels did not increase [15]. Furthermore, it has been previously shown, that pyruvate does not induce coronary vasodilation [18]. Thus, the observed beneficial effects on systolic and diastolic function may be mainly attributed to direct myocardial effects of pyruvate and not to altered loading conditions.

Improving hemodynamics and contractility is a predominant therapeutic goal in acute heart failure or acute decompensation of chronic heart failure with low output syndrome and organ hypoperfusion. For the restoration of adequate tissue perfusion most often positive inotropic agents including catecholamines and phosphodiesterase-inhibitors are used. This treatment is generally associated with increased heart rate and the potential of arrhythmogenesis. With pyruvate the positive inotropic effect was associated with a decrease in heart rate, and arrhythmias were not observed during acute application of pyruvate. Therefore, the mechanism of inotropic stimulation should be fundamentally different from increased cyclic AMP-dependent protein phosphorylation which is the predominant action following catecholamine application or phosphodiesterase-inhibition.

The mode of action of pyruvate has been studied in vitro in animal and human myocardium [5–14,19]. Accordingly to these studies, multiple mechanisms seem to be involved in the positive inotropic effect of pyruvate. It has been shown that pyruvate increases the intracellular calcium transient with subsequent increased activation of contractile proteins [10,11]. The increased calcium transients result mainly from energetic stimulation of the sarcoplasmic reticulum calcium pump (SERCA) due to an increase in phosphorylation potential with enhanced free energy of ATP hydrolysis [9,19]. This in turn leads to an increased calcium content of the SR and thus calcium availability for systolic release [11,20]. In addition, the increased SR calcium uptake may explain the finding of increased maximum rate of pressure decline and decreased left ventricular end-diastolic pressure and thus, improved diastolic function. Furthermore, pyruvate increases intracellular pH, which may in part result from pyruvate uptake into the mitochondria through the monocarboxylate-proton symporter [11,21]. The higher intracellular pH leads to increased calcium sensitivity of contractile proteins and hence improved systolic force [22]. These experimental and clinical data further support the evaluation and use of pyruvate for the treatment of patients with acute congestive heart failure.

Currently, the treatment of patients with pyruvate is limited by the prerequisite of intracoronary application of the agent. Because the hemodynamic effect requires pyruvate concentrations above 1 mM and pyruvate is rapidly metabolised, high doses would be necessary if pyruvate was to be given intravenously. Such high intravenous doses however, would result in sodium overload and hyperosmolarity if the sodium salt of pyruvic acid was used as it was done in the present study. However, other formulations of pyruvate such as the choline salt may be developed. Even if intracoronary application was the only route of effective administration of pyruvate, this treatment could be useful in patients with acute heart failure refractory to conventional therapy if invasive facilities are available. Pyruvate may be used in particular in addition to catecholamines or phosphodiesterase-inhibitors because it was shown that pyruvate potentiates the inotropic effect of catecholamines and therefore may reduce the corresponding doses needed for inotropic support.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Intracoronary pyruvate improves intrinsic systolic and diastolic myocardial function in patients with congestive heart failure and increases LV ejection fraction without increasing heart rate. Pyruvate thus exhibits the hemodynamic profile of a favourable inotropic agent and may be evaluated for the treatment of patients with acute heart failure either alone or in combination with catecholamines. However, further investigations are necessary to elucidate the underlying mechanisms of action and to determine a more feasible mode of application.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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