This is a transitional time in the field of pulmonary hypertension (PH), marked by succinct changes in the clinical approach to patients with this disease. Gains in defining PH pathobiology over the previous decade have led to the identification of novel pulmonary circulation-specific treatment targets, thus widening the spectrum of available pharmacotherapies that improve pulmonary vascular tone to better cardiopulmonary hemodynamics, symptom burden, and quality of life for our patients. Consequentially, in the modern era, PH is a treatable disease. In the case of phosphodiesterase type-5 (PDE5) inhibitors, for example, findings from two marquee clinical studies have demonstrated the potential utility of this drug class for the management of patients with PH due to abnormal left ventricular (LV) systolic⁽¹⁾ or diastolic⁽²⁾ function (WHO Category II PH), a subset of patients for whom co-morbid PH has been traditionally regarded as merely a poor prognostic indicator.^(3-5) Collectively, these scientific and clinical advances have contributed to an evolving paradigm shift in the field of PH, in which pulmonary vascular dysfunction is increasingly recognized as a specific entity amenable to tailored therapy administered in parallel to treatments that address underlying triggers of PH clinical expression, such as pulmonary vascular congestion or hypoxic pulmonary vasoconstriction (Figure 1).

Despite this progress, the practicing clinical cardiology community is still confronted with the challenges of assessing patient appropriateness for PH-specific treatments and timing of therapy initiation. The complexity of these issues is compounded in PH in particular, owing to two key factors. First, identifying the chief stimulus of pulmonary vascular injury (i.e., hypoxia, inflammation, thromboembolism, increased pulmonary flow, and many others) often requires a multi-disciplinary clinical evaluation individualized to each patient that may be time- and resource-intensive. Nevertheless, clinical insight into PH pathophysiology is a pivotal determinate of treatment selection. Secondly, with the exception of pulmonary arterial hypertension (PAH) (WHO Category I), which is a rare form of PH characterized by the interplay of molecular and genetic factors that promotes severe remodeling of distal pulmonary arterioles (e.g., plexogenic arteriopathy), there is currently little evidence available from sufficiently powered, prospective clinical trials to inform clinicians regarding the proper timing for initiation of PH-specific therapies.⁽⁶⁾ In the case of PDE5 inhibition in left atrial hypertension-induced PH (WHO Category II PH), which is one form of PH likely to be encountered in routine cardiology practice, this trend may change over the upcoming months following completion of the RELAX and SIDAMI (clinicaltrials.gov, NCT00763867 and NCT01046838, respectively) trials that are examining PDE5 inhibition in patients with heart failure with preserved LV function. Moreover, through clinical investigations evaluating PDE5 inhibition for other WHO Category II PH patients, including those with PH due to severe aortic stenosis (NCT01060020), it is hopeful that indications for the use of this drug class will continue to evolve in ways relevant to cardiologists on the front lines of patient care.

Here, a clinical case is used to illustrate one contemporary strategy for the implementation of PDE5 inhibition in PH.

A 64-year old man is seeking treatment recommendations for the management of long-standing dyspnea on exertion that occurs after ambulating 50 meters. He has stage II systemic hypertension (152/89 mmHg) despite maximum dose of a thiazide diuretic, angiotensin-converting enzyme inhibitor, and -adrenergic receptor antagonist. The patient also uses furosemide 40 mg daily to prevent lower extremity fluid accumulation and worsening dyspnea. Echocardiography demonstrates an LV ejection fraction of 55%, moderate concentric LV hypertrophy, Grade III diastolic dysfunction, and a mid-systolic notch on Doppler interrogation of the right ventricular (RV) outflow tract. Right heart catheterization demonstrated the following hemodynamic profile: right atrial pressure, 23 mm Hg; pulmonary artery (PA) systolic/diastolic/mean pressure, 52/29/36 mm Hg; mean pulmonary capillary wedge pressure (mPCWP), 11 mmHg; and pulmonary vascular resistance, 4.5 Wood units. The administration of a 500 cc bolus of 0.9% normal saline increased the mPCWP to 19 mm Hg.

In this patient, echocardiography was performed to investigate an etiology for exertional dyspnea, which revealed preserved LV systolic function and a diastology pattern indicative of impaired LV relaxation. Interestingly, the flow profile assessed from the RV outflow tract by pulsed wave Doppler interrogation revealed a mid-systolic notch, which suggests abnormal pulmonary vascular compliance and correlates with the presence of RV dysfunction.⁽⁸⁾ Right heart catheterization established the diagnosis of PH owing to the presence of a mean PA pressure >25 mmHg and a pulmonary vascular resistance >3.0 Wood units in the setting of a normal mPCWP.⁽⁷⁾ Confrontational fluid challenge is an effective diagnostic maneuver to assess for impaired diastolic function in patients with exertional symptoms despite normal LV end-diastolic filling pressure. In this patient, an increase in the mPCWP to ≥15 mm Hg following fluid administration is suggestive of abnormal LV compliance and corroborates echocardiographic data demonstrating abnormal LV lusitropy.⁽⁹⁾

In the absence of comorbid conditions associated with pulmonary vascular injury (e.g., hypoxic lung disease), this patient’s clinical profile is most consistent with PH due to impaired LV relaxation occurring as a consequence of systemic hypertension-induced LV remodeling. In the appropriate clinical setting, however, cardiac MRI may be useful to assess for alternate causes of ventricular dysfunction, including restrictive myocardial disease, which requires disease-specific treatment.⁽¹⁰⁾ The primary therapeutic objective in this case is aggressive control of systemic hypertension, since this is an independent predictor of adverse changes to RV geometry and function,⁽¹¹⁾ and is a key contributor to the development of PH in patients with abnormal LV compliance.⁽¹²⁾ Guazzi and colleagues⁽²⁾ recently reported on the effects of sildenafil therapy in a patients with a clinical profile akin to the case patient. In this study, 44 patients with heart failure, LV EF ≥50%, and PA systolic pressure >40 mmHg were randomized to receive placebo or sildenafil 50 mg three times daily. Following 6 months of therapy, PDE5 inhibition decreased mPAP and right atrial pressure by 42% and 52%, respectively, which was associated with normalization of PVR from 3.4 to 1.2 Wood units. An important further observation in this study linked improvements to pulmonary hemodynamics with an increase in RV systolic ejection time and tricuspid annular plane systolic exertion (TAPSE) detected echocardiographically, indicating that the attendant effect of pulmonary vascular dysfunction on RV performance may be reversible in this form of PH. Similar findings have also been reported in patients with PH due to decreased LV systolic function, where sildenafil (25-75 mg three times daily) administered to patients with severe heart failure (mean LV and RV EF 20% and 33%, respectively) for 12 weeks improved significantly key cardiopulmonary hemodynamic indices and increased exercise tolerance assessed by the 6 minute walk test.⁽¹⁾

Impaired RV performance has long been appreciated as a predictor of increased morbidity and mortality in patients with a wide range of cardiovascular diseases, even in the absence of PH or when present in advance of frank RV heart failure.^(13-15) Thus, the observation that PDE5 inhibition may abrogate RV-pulmonary vascular uncoupling to potentially delay (or prevent) cor pulmonale supports further investigation into the application of therapeutic strategies that target pulmonary vascular dysfunction in this patient population. In patients with left atrial hypertension, PDE5 inhibition is believed to modulate beneficial effects on the pulmonary circulation and RV performance via restoring nitric oxide-dependent signaling to attenuate flow-mediated remodeling of pulmonary arterioles and improve RV contractility (Figure 2).^(16,17)

Universally accepted clinical guidelines outlining indications for the initiation of PDE5 inhibitors in WHO Category II patients is lacking. Moreover, the long-term effects of PDE5 inhibition on maintaining improvements to cardiopulmonary hemodynamics or other important measures of treatment efficacy, including functional capacity and survival, have not been studied adequately. At present, PDE5 inhibitors are FDA-approved for use in PAH (WHO Category I) and not other forms of PH, including due to LV dysfunction or hypoxic lung disease. Key side effects of PDE5 inhibition include systemic hypotension, visual disturbances, dyspepsia, and, less commonly, priaprasm.⁽¹⁶⁾

It is important to note that despite the presence of PH-induced RV dysfunction and impaired functional capacity in the case patient, the efficacy of alternative pulmonary circulation-specific pharmacotherapies, including endothelin receptor antagonists, prostacyclin analogues, dihydropyridine calcium channel antagonists, or nitric oxide replacement therapies is unknown and may not be safe; thus, the use of these agents is not currently recommended in patients with WHO Category II PH outside the care of specialized PH referral centers.⁽⁷⁾

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References

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Keywords: Hypertension, Pulmonary, Phosphodiesterase 5 Inhibitors, Phosphoric Diester Hydrolases, Pulmonary Circulation, Systole, Vasoconstriction

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