Abstract
Objective: Although intravenous nitrates are commonly used in clinical medicine, they have been shown to increase myocardial oxygen consumption and inhibit complex IV of the electron transport chain. As such we sought to measure whether myocardial energetics were impaired during glyceryl trinitrate (GTN) infusion.Methods: 10 healthy volunteers underwent cardiac magnetic resonance imaging to assess cardiac function and 31phosphorus magnetic resonance spectroscopy to measure Phosphocreatine/ATP (PCr/ATP) ratio and creatine kinase forward rate constant (CK kf) before and during an intravenous infusion of GTN.Results: During GTN infusion, mean arterial pressure (78 ± 7 vs. 65 ± 6 mmHg, p < 0.001), left ventricular (LV) stroke work (7,708 ± 2,782 vs. 6,071 ± 2,660 ml mmHg, p < 0.001), and rate pressure product (7,214 ± 1,051 vs. 6,929 ± 976 mmHg bpm, p = 0.06) all fell. LV ejection fraction increased (61 ± 3 vs. 66 ± 4%, p < 0.001), with cardiac output remaining constant (6.2 ± 1.5 vs. 6.5 ± 1.4 l/min, p = 0.37). Myocardial PCr/ATP fell during GTN infusion (2.17 ± 0.2 vs. 1.99 ± 0.22, p = 0.03) with an increase in both CK kf (0.16 ± 0.07 vs. 0.25 ± 0.1 s−1, p = 0.006) and CK flux (1.8 ± 0.8 vs. 2.6 ± 1.1 μmol/g/s, p = 0.03).Conclusion: During GTN infusion, despite reduced LV stroke work and maintained cardiac output, there was a 44% increase in myocardial ATP delivery through CK. As PCr/ATP fell, this increase in ATP demand coincided with GTN-induced impairment of mitochondrial oxidative phosphorylation. Overall, this suggests that while GTN reduces cardiac work, it does so at the expense of increasing ATP demand beyond the capacity to increase ATP production.
Highlights
The heart has an extremely high turnover of energy, requiring around 6 kg of adenosine triphosphate (ATP) per day in order to perform contraction and relaxation
During glyceryl trinitrate (GTN) infusion, there was a reduction in the PCr/ ATP ratio
We have shown that despite its hemodynamic effect of reducing mean arterial pressure and cardiac work, ATP delivery through CK is increased; GTN simultaneously inhibits the rate of ATP production from mitochondrial oxidative phosphorylation
Summary
The heart has an extremely high turnover of energy, requiring around 6 kg of adenosine triphosphate (ATP) per day in order to perform contraction and relaxation. As ATP production is reduced in heart failure (Neubauer, 2007), many current treatments are aimed at lowering myocardial energy use by decreasing cardiac work. Nitrates predominantly dilate systemic veins, increasing the capacitance of these vessels and reducing venous return to the heart, thereby lowering ventricular filling and preload. GTN achieves this via activation of cGMP-dependent protein kinase, without donating significant amounts of the free radical nitric oxide (Kleschyov et al, 2003). At higher doses, they have effects on arterial tone, lowering systemic vascular resistance, and afterload. This is therapeutic, with the reduction in preload reducing pulmonary venous congestion and the reduction in afterload reducing cardiac work
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