ACCEL | A decade ago, the diagnosis of pulmonary arterial hypertension (PAH) heralded a uniformly poor prognosis. Progress has come in recent years via the development of carefully targeted therapies. A growing appreciation that pulmonary hypertension (PH) in left heart disease (LHD) signals poor prognosis has led to a flurry of investigational activity.

Take-aways Evidence suggests it is important to determine pulmonary hypertension (PH) burden in left heart disease (LHD). Presence of PH in LHD signals poor prognosis and influences both drug and device efficacy. Phenotyping plays an important role in determining which patients may respond to PH-directed therapies.

Heart failure (HF) is one of the most common causes of PH, which Myung H. Park, MD, and Mandeep R. Mehra, MBBS, call “the great leveler.”¹ PH is prevalent among those with reduced or preserved left ventricular ejection fraction (LVEF). While there are substantial data on the rare idiopathic PAH, only recently have we started to appreciate the predictive value of pulmonary pressures in the more common PH associated with HF.

PH AND HF

Bursi and colleagues evaluated 1,049 Olmsted County, MN, residents with HF who prospectively underwent assessment of ejection fraction (EF), diastolic function, and pulmonary artery (PA) systolic pressure by Doppler echocardiography.² There was a strong, positive, graded association between PA systolic pressure and subsequent mortality that was independent of age, sex, comorbidities, EF, and diastolic function. The investigators found that PA systolic pressure strongly predicted medium-term risk of death in patients with HF and improved prediction of death and CV death over traditional prognostic factors. Importantly, PH appeared to be not only a marker of worse HF, but also to have direct deleterious effects.

PH in HF has been postulated to result from the combination of the passive effect of elevated left ventricular end-diastolic pressure backward on the pulmonary venous circulation and an active vasoreactive process of vasoconstriction and PA remodeling. Pathology studies have shown remodeling changes in the elastic fibers of the pulmonary arterial wall, intimal fibrosis, and medial hypertrophy of pulmonary muscular arteries, with changes that are similar to or greater than those seen in idiopathic PAH.

Although PAH and PH secondary to LHD share a final common hemodynamic and prognostic outcome, translational investigations have suggested fundamental differences in the cellular basis and in outcomes related to pharmacological modulation of neurohormonal pathways in these distinct states. For example, the presence of the angiotensin-converting enzyme DD genotype is associated with adverse survival in LV failure, whereas in PAH, there are signals supporting a compensatory role in preserving right ventricular (RV) function. Similarly, beta-adrenergic neuroeffector pathways demonstrate distinct differences between right-side HF due to PAH or PH secondary to LHD.

Despite evidence for the expression of endothelin-1 excess in both PAH and LHD states, the outcome of targeting the aberration through endothelin antagonists is quite dissimilar, with a marked evidence of benefit in PAH but notable worsening in the context of LHD. Conversely, therapeutic modulation of the nitric oxide pathway with the use of phosphodiesterase-5 inhibitors may be equally beneficial between the two distinct syndromes of PAH and PH due to LHD.

PH AND CRT

In some cases, PH adversely affects the impact of cardiac resynchronization therapy (CRT), perhaps explaining in part why approximately one-third of patients fail to demonstrate clinical improvement with CRT.

Unlike previous studies looking at the relationship between PH and outcomes in CRT, Anjan K. Chatterjee, MD, recently reported using invasive hemodynamic assessment in 101 patients with systolic HF meeting standard indications for CRT. The presence of a significant pre-capillary contribution to PH (i.e., a transpulmonary gradient ≥12 mm Hg) was associated with a significantly worse clinical outcome after CRT,³ and that the presence of concomitant RV dilation in this subset conferred additional increased risk. This association between an elevated transpulmonary gradient and poor clinical outcome persisted after adjusting for clinical, echocardiographic, and hemodynamic covariates.

Interestingly, there was no significant difference in clinical outcome between patients without PH and patients with PH but a normal transpulmonary gradient.

In their paper, published in JACC Heart Failure,³ the authors wrote, “Our findings suggest a critical role of comprehensive assessment of PH subtype before CRT defibrillator device implantation. In those with high (transpulmonary gradient) PH who are candidates for CRT, assessment of PH reversibility before CRT and the efficacy of therapeutic targeting of pre-capillary PH warrants further exploration.”

In terms of other clinical advice, Gregory D. Lewis, MD, director of the Massachusetts General Hospital cardiopulmonary exercise laboratory, said that, at the present time, epoprostenol and endothelin antagonists should not be used in the treatment of PH with LV dysfunction. Phosphodiesterase-5 inhibitors appear to be promising in patients with PH-LV dysfunction but due to conflicting results of available studies, additional outcomes-based trials are necessary. On the other hand, while calcium channel blockers have a role in some patients with PH, these drugs do not have a role in patients where there is significant left ventricular systolic dysfunction due to potential deleterious effects on LV performance.

New agents include the recently approved riociguat, a novel drug that is a stimulator of soluble guanylate cyclase. It is indicated for the treatment of adults with PAH to improve exercise capacity, World Health Organization functional class, and to delay clinical worsening. It has also been shown to improve cardiac output in patients with pulmonary hypertension due to LV systolic dysfunction.⁴

Dr. Lewis added that patient selection based on careful phenotyping plays an important role in determining which patients may respond to PH-directed therapies.

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References

1. Park MH, Mehra MR. J Am Coll Cardiol. 2012;59:232-4.
2. Bursi F, McNallan SM, Redfield MM, et al. J Am Coll Cardiol. 2012;59:222-31.
3. Chatterjee NA, Upadhyay GA, Singal G, et al. JACC Heart Fail. 2014;2:230-7.
4. Bonderman D, Ghio S, Felix SB, et al. Circulation. 2013;128:502-11.

Keywords: CardioSource WorldNews Interventions, ACC Publications, Adrenergic Agents, Blood Pressure, Calcium Channel Blockers, Capillaries, Cardiac Resynchronization Therapy, Comorbidity, Cost of Illness, Cyclic Nucleotide Phosphodiesterases, Type 5, Defibrillators, Echocardiography, Echocardiography, Doppler, Elastic Tissue, Endothelin Receptor Antagonists, Endothelin-1, Epoprostenol, Genotype, Guanylate Cyclase, Heart Failure, Hypertension, Hypertension, Pulmonary, Hypertrophy, Peptidyl-Dipeptidase A, Phosphodiesterase 5 Inhibitors, Pulmonary Artery, Pulmonary Circulation, Pyrazoles, Pyrimidines, Receptors, Cytoplasmic and Nuclear, Vasoconstriction

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