Phosphodiesterase-5 inhibitors and the heart: compound cardioprotection?

Abstract

Novel cardioprotective agents are needed in both heart failure (HF) and myocardial infarction. Increasing evidence from cellular studies and animal models indicate protective effects of phosphodiesterase-5 (PDE5) inhibitors, drugs usually reserved as treatments of erectile dysfunction and pulmonary arterial hypertension. PDE5 inhibitors have been shown to improve contractile function in systolic HF, regress left ventricular hypertrophy, reduce myocardial infarct size and suppress ischaemia-induced ventricular arrhythmias. Underpinning these actions are complex but increasingly understood cellular mechanisms involving the cyclic GMP activation of protein kinase-G in both cardiac myocytes and the vasculature. In clinical trials, PDE5 inhibitors improve symptoms and ventricular function in systolic HF, and accumulating epidemiological data indicate a reduction in cardiovascular events and mortality in PDE5 inhibitor users at high cardiovascular risk. Here, we focus on the translation of underpinning basic science to clinical studies and report that PDE5 inhibitors act through a number of cardioprotective mechanisms, including a direct myocardial action independent of the vasculature. We conclude that future clinical trials should be designed with these mechanisms in mind to identify patient subsets that derive greatest treatment benefit from these novel cardioprotective agents.

Keywords: cardiac arrhythmias and resuscitation science; cardiac risk factors and prevention; coronary artery disease; heart failure; myocardial disease basic science.

Figure 1

Cyclic nucleotide signalling in cardiac myocytes and its relation to contraction and arrhythmias. (A) Competing effects of cyclic GMP (cGMP) and cyclic AMP (cAMP) within the cardiac myocyte. Sildenafil (left side) inhibits phosphodiesterase-5 (PDE5) leading to the accumulation of cGMP within the cell. cGMP activates protein kinase-G (PKG) resulting in phosphorylation of the L-type Ca²⁺ channel and cardiac troponin I (cTnI). These effects are negatively inotropic. cAMP (right), for example, following stimulation of β₁-adrenoceptors and β₂-adrenoceptors by epinephrine, activates PKA leading to positive inotropic and proarrhythmic actions. In addition, there is also potential for crosstalk between the two axes; cGMP can inhibit phosphodiesterase-3 (PDE3) to increase cAMP. (B) Excitation–contraction coupling in the cardiac myocyte. Opening of L-type Ca channels (LTCC) during the action potential lead to influx of Ca and stimulation of Ca release from the sarcoplasmic reticulum (SR), initiating myofilament contraction. (C) Overload of the SR, as occurs in HF and under β₁-adrenergic and β₂-adrenergic stimulation, leads to spontaneous Ca waves, which activate Na⁺–Ca²⁺ exchanger (NCX) channels to cause after depolarisations and triggered arrhythmias.

Figure 2

Competing effects of the cyclic GMP–protein kinase G (PKG) and cyclic AMP–protein kinase A (PKA) axes in the heart. Left panel: sildenafil increases cGMP and activates PKG, leading to phosphorylation of (1) L-type Ca channel (LTCC) to reduce Ca influx and (2) cardiac troponin I to reduce myofilament Ca sensitivity. Both effects are negatively inotropic. Right panel: β₁-adrenergic and β₂-adrenergic stimulation increases cAMP to activate PKA, leading to phosphorylation of (1) L-type Ca channel, increasing Ca influx and (2) phospholamban (PLB) to activate sarcoplasmic-endoplasmic reticulum Ca ATPase pump (SERCA) and increase Ca uptake into the sarcoplasmic reticulum (SR). These actions lead to a greater Ca content within the SR, increased force of contraction and greater propensity to arrhythmias.

Figure 3

Effects of phosphodiestrase-5 (PDE5) inhibition in heart failure with reduced ejection fraction (HFrEF).

Figure 4

Cardioprotective effects of phosphodiesterase-5 (PDE5) inhibition in acute myocardial infarction.

Figure 5

Intracellular pathway of cardioprotection in myocardial infarction as proposed by Kukreja et al .