Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension: Focus on Phosphodiesterase Inhibitors

Figures

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  Figure 1. Stages of pulmonary hypertension in HFpEF. A chronic increase in mean left atrial (LA) pressure causes an increase in pulmonary artery (PA) pressure (pulmonary hypertension, PH), leading to passive remodeling in pulmonary venule and capillaries and isolated postcapillary PH (Ipc-PH). In approximately 20% of patients with HFpEF, the reactive “precapillary” alterations of pulmonary vasculature occur with the development of the combined pre- and post-capillary PH (Cpc-PH). Ipc-PH is associated with a decrease in pulmonary arterial capacitance (PAC) and mild adaptive changes of the right ventricle (RV). On the other hand, Cpc-PH leads to an increase in pulmonary vascular resistance (PVR), PA-RV uncoupling, and is associated with a marked maladaptive RV remodeling with RV systolic dysfunction and dilation, tricuspid regurgitation, and increase in central venous pressure (CVP). Increased CVP results in a reduction of sodium (Na+) excretion and fluid retention, and a further increase in LA pressure. With RV dilatation and CVP increase, shifting of the interventricular septum (IVS) to the left occurs, resulting in an impaired left ventricular filling. DPG indicates diastolic pulmonary…

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  Figure 2. Cyclic nucleotide signaling in cardiomyocyte. Nitric oxide and natriuretic peptide receptor (NPR) activate soluble (sGC) and particulate guanylate cyclases (pGC), respectively, resulting in production of cyclic guanosine monophosphate (cGMP) and activation of protein kinase G (PKG). PKG phosphorylates numerous targets within myocyte. PKG-mediated phosphorylation (P) of phospholamban (PLB) activates sarcoplasmic–endoplasmic reticulum calcium ions (Ca2+)-ATPase pump (SERCA) and increases Ca2+ uptake into sarcoplasmic reticulum (SR); phosphorylation of troponin I (Tn I) reduces myofilament Ca2+ sensitivity increasing lusitropy. PKG-mediated phosphorylation of titin reduces cardiomyocyte stiffness, whereas PKG-mediated phosphorylation of L-type channels decreases Ca2+ influx, possessing a negative inotropic effect. Activation of β1-adrenergic receptors by epinephrine activates adenylate cyclase (AC), increasing the level of cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA). High PKA activity leads to a positive inotropic effect due to phosphorylation of the L-type Ca2+ channel and the ryanodine receptor (not shown), increasing the systolic Ca2+ influx. PKA…