Increased pulmonary vascular resistance, right ventricular dysfunction, and reversible pulmonary vasoconstriction in type 2 pulmonary hypertension: who has it and are we missing a potential therapeutic target in patients with heart failure?

Abstract

This editorial refers to ‘Pulmonary vascular response to exercise in symptomatic heart failure with reduced ejection fraction and pulmonary hypertension”†, by Verbrugge, F.H. et al., published in this issue, European Journal of Heart Failure (2015); 17: 320–328. We do not assess the performance of engines at idle so why do we design treatment strategies in patients with heart failure (HF) based on resting haemodynamics? You have to stress a system in order to assess its capabilities. Exercise intolerance is central to the diagnosis of HF and occurs in patients with systolic dysfunction, diastolic dysfunction, or both. The typical haemodynamic response to effort in patients with symptomatic heart failure is characterized by an excessive, non-linear increase in filling pressures, which occurs on early exertion and is associated with the cardinal symptoms of exercise intolerance: dyspnoea and fatigue. This abnormal response occurs both in patients with either normal or elevated pulmonary capillary wedge pressures at rest and confirms that the dyspnoea is of cardiac origin. The degree of this excessive pathological increase in filling pressures during effort determines the extent of symptoms and predicts long-term clinical outcomes. Verbrugge and colleagues deserve praise for their contribution published in this issue, which not only extends our understanding of the pathophysiology of exercise intolerance in patients with HF but also further opens the door to some intriguing potential pharmacological approaches.1 The authors report the results of an ambitious protocol designed to invasively evaluate 40 patients with chronic symptomatic HF and systolic dysfunction. All patients had high filling pressures with type 2 pulmonary hypertension (PH) and reduced cardiac index at baseline. Twenty-seven patients showed a mixed PH phenotype characterized by both elevated pulmonary vascular resistance and elevated left atrial pressure, and 13 patients demonstrated essentially post-capillary pulmonary hypertension without evidence of elevated pulmonary vascular resistance. Patients underwent invasive haemodynamic evaluation at rest and during moderate exercise with two types of pharmacological intervention following adequate decongestion. In the first session, potent nitric oxide (NO) donor support with continuous intravenous (IV) sodium nitroprusside was titrated according to a protocol targeting moderate blood pressure reduction. Patients subsequently performed the exercise protocol with afterload reduction provided by oral angiotensin-converting enzyme (ACE) inhibitor therapy and hydralazine. The results convincingly demonstrated that exercise induced pulmonary hypertension and vasoconstriction could be attenuated substantially by NO donor support in the patients with the mixed type 2 PH phenotype. Compared with oral afterload reduction treatment, NO support with IV nitroprusside therapy was associated with substantial reductions in pulmonary vascular resistance and increased right ventricular stroke work. The observation that the precapillary component of mixed PH was attenuated suggests that pulmonary vasoconstriction, as well as remodelling of the pulmonary vasculature, is operative in the early pathophysiological response to exercise. One of the key messages of this study is that exercise haemodynamics can assist us in phenotyping patients with symptomatic HF caused by systolic dysfunction and stratify them according to the degree of exercise-induced increases in pulmonary vascular resistance associated with substantial right ventricular dysfunction. It is also noteworthy that after decongestion a number of the patients responded well to oral vasodilator therapy with ACE inhibition and hydralazine alone without a subsequent exercise-induced increase in pulmonary vascular resistance. These findings clearly have potential therapeutic indications and should stimulate clinical research in patients with symptomatic HF and evidence of mixed type 2 PH. Decreased NO availability promotes endothelial dysfunction and agents that augment the NO–cyclic guanosine monophosphate axis improve endothelial function in the pulmonary vasculature. Trials designed to evaluate the efficacy of agents that enhance NO effects such as phosphodiesterase type 5 (PDE-5) inhibitors (e.g. sildenafil, vardenafil, tadalafil) and oral soluble guanylate cyclase stimulators (e.g. cinaciguat, riociguat) would be appropriate. The literature demonstrating well-tolerated, sustained, improved haemodynamic profiles in patients treated with PDE-5 inhibitors is encouraging2 and several trials assessing symptoms and submaximal functional capacity are on-going in this field.3, 4 The results of such studies may hopefully support hypotheses to be tested in larger trials powered to evaluate clinical outcomes in selected patients with type 2 PH. The authors are careful to point out the main methodological limitations of the study. This was a single-centre study with a relatively small patient population. The trial was not blinded and the titration schedules and degree of decongestion and afterload reduction with oral agents before exercise was necessarily subjective. It should be noted that the trial compared IV and oral treatment, which is far from ideal, and IV nitroprusside therapy was administered first in all patients followed by oral therapy. Although a sequential design is justified based on the pharmacokinetics of the interventions, it has a potential impact on the results. The protocol also does not permit evaluation the effects of the combination of ACE inhibitor and hydralazine vs. monotherapy with an ACE inhibitor in the patients who responded with normalization of filling pressures following decongestion and afterload reduction therapy alone. Although Verbrugge and colleagues1 studied patients with systolic dysfunction, recent work has also demonstrated evidence of excessive, rapidly increasing pulmonary vascular resistance during early exercise in patients with HF and preserved left ventricular function, and related this condition to poor long-term clinical outcomes.5 Interested readers may wish to read this important paper as well as the masterly review of the pathophysiology of exercise haemodynamics in patients with exertional dyspnoea in the same issue of the European Heart Journal.6. Excessive elevation of filling pressures during mild submaximal exercise in patients with normal resting pressures comprises a large population of patients with both systolic and diastolic dysfunction. Although these patients should be identified, the most efficacious pharmacological approach in the individual patient requires further investigation. What is the most appropriate method to non-invasively identify patients with HF and mixed type 2 pulmonary hypertension with a degree of potentially reversible, pulmonary vasoconstriction? Invasive haemodynamic evaluation, even with submaximal protocols, is not feasible in routine, clinical practice. Doppler echocardiography to assess pulmonary pressures during supine exercise requires expertise but may be appropriate in selected patients. Implantable sensors in the pulmonary artery are minimally invasive, may be an interesting option, and might provide useful information concerning exercise-induced PH thereby permitting us to tailor therapy in the individual patient. Of course, the next steps would be to understand why certain patients develop this phenotype, continue to explore the pathophysiology determining pulmonary vascular vasoconstriction, and better appreciate the mechanisms by which right ventricular dysfunction compromises functional capacity in patients with HF. The ‘take home’ message here is that although most of our patients with symptomatic HF develop excessive increases in filling pressures at the initial stages of exercise, many of these patients also exhibit a dynamic increase in pulmonary vascular resistance, which is potentially reversible with agents that improve NO bioavailability and attenuate pulmonary vasoconstriction. And just remember, regardless of gender, here the abbreviation ED refers to endothelial dysfunction. Conflict of interest: none declared.