That is the case of adults with a sRV, such as those with congenitally corrected transposition of the great arteries or transposition of the great arteries following atrial switch repair. Those patients are steadily growing in number, and they may invariably develop some degree of sRV systolic dysfunction during follow-up, leading to a potentially tangible risk of a future epidemic of HF in a relatively young population.
Traditional HF treatment, which was proven to be highly effective in the general population, did not provide the expected positive effects in this group.3 The lack of efficacy of guideline-directed medical therapy in sRV may be partially explained with the relevant difficulties in carrying out a sufficiently powered randomised trial. However, understanding the peculiar pathophysiology of HF in this population, which accounts for an unusual fibromuscular architecture and contraction pattern, conduction system abnormalities, oxygen supply–demand mismatch, inappropriate fibrosis, stiffness of intra-atrial baffles and tricuspid valve dysplasia, may be the key for a targeted therapy.
The surprisingly excellent results of recently introduced novel pharmacological options for HF with reduced ejection fraction have recently triggered a revolution in the current treatment paradigm. However, in view of the past unsuccessful attempts in patients with a sRV, there is a certain degree of scepticism and uncertainty regarding how those new drugs should be incorporated in management of patients with CHD. Furthermore, early experience with the use of sacubitril/valsartan in small heterogenous CHD groups has failed to demonstrate any beneficial effects. In this framework, numerous questions arise: is there a role for the new drugs in the treatment of HF among patients with a sRV? Is the addition of a neprylisin inhibitor to a renin–angiotensin system blocker finally effective in sRV? Will the same revolution be applied to sRV, relieving the CHD clinician from the frustration of having no weapons in the battle for the survival of these young patients with a complex physiology?
In this scenario, Nederend and colleagues7 conducted an elegant two-centre, prospective study on the use of sacubitril/valsartan in 35 symptomatic patients with at least moderate sRV systolic dysfunction on top of their previous medical therapy. Main findings included increased exercise tolerance during the 6 min walking test, improvement of sRV function, as assessed by echocardiography in terms of fractional area change and global longitudinal strain, and reduction of N-terminal prohormone of brain natriuretic peptide values, after 6 months of treatment and up to 36 months from initiation for the 34% of patients still in the study protocol.
Those results largely overlap with those of another recently published prospective study from a single Italian centre reporting data from 50 patients with a sRV. Nederend et al described the longest experience to date with sacubitril/valsartan in sRV, highlighting the persistence of positive effects beyond the acute results. Most importantly, from both studies, sacubitril/valsartan appeared safe in patients with a sRV with no adverse events, except for the expected symptomatic hypotension in younger women and for one case of uncontrollable thirst described by Nederend and colleagues, supporting the potential role of this drug association as the new pillar for HF treatment in sRV.
It is interesting to point out that in both studies, women were more likely to tolerate lower dosage, suggesting that sex-dependent treatment responses are still to be explored in this young population.
The Italian cohort provided also the first evidence of sRV reverse remodelling, as demonstrated by tricuspid regurgitation improvement and reduced ventricular volumes assessed by three-dimensional echocardiography. However, a closer look at the key differences between baseline study populations reveals that individuals included by Nederend et al might be in a more advanced HF stage, as suggested by higher mean age and higher need of diuretics. Indeed, three patients in the Dutch cohort were excluded from analysis due to early HF events during follow-up, comprising death and ventricular assist device implant. Those differences, together with inclusion of also asymptomatic patients in the Italian cohort, seem to indicate the potential existence of an earlier window for intervention, in which reverse remodelling of the sRV may also be achievable, thanks to newer medications.
Can we finally celebrate the first success in the pharmacological treatment of CHD-related HF? There is no debate that the improvement in humoral markers or advanced echocardiographic parameters should be considered as a surrogate of harder endpoints and, thus, there is still a long way to go before claiming victory. Nevertheless, considering that in the landmark study sacubitril/valsartan was studied in a way larger population with acquired heart disease including >8400 individuals, the positive results described in two small independent CHD cohorts with homogenous physiology could be deemed an important achievement. Of course, the next steps will be the implementation of larger-scale multicentre studies, possibly with a randomised design and longer follow-up in different subsets of CHD to determine whether the beneficial effects described may translate into improved outcome.
Several questions still remain open: are we prescribing medications too late in CHD? What is the exact momentum to start a guideline-directed medical therapy? How can we prevent missing the optimal therapeutical window to obtain the best results? Should we rely mainly on sacubitril/valsartan in patients with a failing sRV? Is there a role for sodium–glucose cotransporter protein 2 inhibitors?
However, whatever the answers to those questions will be, one thing can be said with reasonable certainty: HF treatment shift has finally begun for patients with CHD.
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