Impact of pharmacologic interventions--treating endothelial dysfunction and group 2 pulmonary hypertension

Pulmonary hypertension (PH) secondary to left heart disease (LHD) is a largely underappreciated therapeutic target. Except for a specific focus on PH consequences in patients with advanced heart failure (HF) receiving a left ventricular assist device or candidates for heart transplant, prevention and treatment of initial subclinical forms of PH are not considered a priority in the management of this chronic disease population. Nonetheless, there is recent growing evidence supporting a clinical and prognostic role of PH in the elderly populations and in HF with preserved ejection fraction (pEF). Although the prevalence of PH in these populations still remains largely unknown, there is a large potential for effective pharmacological approaches that might impact the natural history of HFpEF by targeting earlier stages. However, pharmacological studies performed to date with traditional pulmonary vasodilators (i.e. prostanoids and endothelin receptor blockers) in cohorts with HF and left-sided PH have not been positive, primarily because of concomitant systemic hypotension and hepatic toxicity. The encouraging preliminary data with more selective well-tolerated pulmonary vasodilators, such as phosphodiesterase type 5 inhibitors and guanylate cyclase stimulators/activators, however, suggest the need for new targets of pulmonary microvascular dysfunction and for treating PH-LHD at both early and later stages of the disease process.