Reverse Reaction of Nicotinamide Nucleotide Transhydrogenase Promotes ROS Production and Contributes to Right Ventricular Failure.

Right ventricular (RV) dysfunction is an important prognostic predictor and end-stage event of several clinical entities. In response to pressure overload, the RV undergoes a progressive remodeling process that is classically divided into 2 phases. In the early stage, a hypertrophic response accompanied by enhanced contractile performance occurs that preserves RV functions. However, this adaptive or compensatory hypertrophy cannot be maintained indefinitely in the face of persistent hemodynamic stress and progressively transitions to a maladaptive state, which is characterized by a self-perpetuating noxious loop of metabolic dysfunction, oxidative stress, inflammation, fibrosis, and myocyte cell death responsible for gradual decline of RV performance and potential death. Unfortunately, the molecular mechanisms and factors implicated in maladaptive RV remodeling are not well understood, and hope for effective treatment lies in researching a way to disrupt this vicious circle that nurtures the RV failure trajectory. This is all the more important because standard left heart failure therapies have failed to improve function and survival in patients with RV failure; a lack of efficiency most often attributed to the distinct embryologic, geometric, and structural properties of the 2 chambers. Basic and preclinical research on chronic RV failure relies on different animal models, including the pulmonary artery banding (PAB) model that offers the advantage of addressing direct RV treatment effects. PAB in rats and mice is thus considered a solid model, for which varying degrees of pulmonary artery constriction can be applied to induce mild to severe RV failure and for which extent and progression of RV dysfunction can be monitored by noninvasive imaging techniques.

In this issue of JACC: Basic to Translational Science, Müller et al provided a comprehensive characterization of the PAB mice model along with evidence that excessive mitochondrial reactive oxygen species (mROS) production significantly contributes to RV failure. Using C57BL/6J mice carrying a spontaneous loss-of-function mutation in the nicotinamide nucleotide transhydrogenase (Nnt) gene and their wild-type counterparts (C57BL/6N), Müller et al tested the hypothesis that genetic deficiency of Nnt confers protection against PAB-induced RV failure. NNT is a nuclear-encoded protein located in the mitochondrial inner membrane that generates nicotinamide adenine dinucleotide phosphate from nicotinamide adenine dinucleotide, thus supplying the antioxidant systems. NNT was documented to operate also in a reverse direction, compromising nicotinamide adenine dinucleotide phosphate availability and boosting mROS overload, thus making NNT a critical player in redox balance and downstream outcomes. Müller et al found that C57BL/6J mice exhibit less RV dilatation and higher values of tricuspid annular plane systolic excursion, as well as absence of signs of hepatic venous congestion when compared to C57BL/6N mice after 4 weeks of severe PAB. Although no significant change was seen with respect to the degree of cardiac hypertrophy and fibrosis, this apparent improvement in RV structure and function in PAB-operated C57BL/6J mice was accompanied by reduced tissue oxidative DNA damage and, accordingly, a diminution in the number of apoptotic cells. Moreover, treatment of PAB-subjected C57BL/6N mice with the mitochondria-targeted antioxidant MitoTEMPO (Sigma-Aldrich) ameliorated RV systolic function and cell survival, substantiating the causal role of oxidative in pressure overload-induced RV failure.

These results mirror those obtained by Nickel et al published 2015 showing that transverse aortic constriction–left ventricular (LV) pathological metabolic demand and hypertrophy switched NNT to a pro-oxidative reverse mode. Indeed, similar to results presented in this issue, the development of LV failure 6 weeks after transverse aortic constriction was found aggravated in C57BL/6N mice as illustrated by increased oxidative stress and fibrosis, impaired LV ejection fraction, and mortality; and attenuation by treatment with a mROS scavenging peptide.

Collectively, these studies are important in that they provide additional evidence underscoring oxidative stress as a shared mechanism in the development and progression of LV and RV failure. They add to recent findings showing similarly that inhibition of poly(adenosine diphosphate–ribose) polymerase-1 affords cardioprotective effects in various animal models of either left or right heart failure by interrupting a vicious circle of metabolic, oxidative DNA damage and inflammatory disturbances. Even if, to date, the therapeutic strategies aiming at preventing or reducing oxidative stress (inhibition of xanthine oxidase, administration of N-acetylcysteine, etc) have largely failed to improve prognosis of patients with heart failure, the idea of targeting it must not be discouraged. Moreover, although the RV and LV differ in many ways, these studies support the notion that new therapeutic advances in one side may be beneficial to the other side.

Another intriguing point arising from this study is the challenge of the concept that targeting RV fibrosis represents a valuable avenue to improve RV function. Indeed, Müller et al showed that NNT deficiency in C57BL/6J mice confers protection against severe PAB-induced RV dysfunction without any change in the extent of fibrosis. Similarly, they found that RV collagen accumulation was not different in patients with dilated cardiomyopathy exhibiting normal or severely impaired systolic RV function. The role of fibrosis in RV failure remains a matter of ongoing discussion. On the one hand, fibrosis is proposed to serve as part of an adaptive response to limit cardiomyocyte overstretch and preserve RV shape. On the other hand, its continued activation increases ventricular stiffness and impairs electrical impulse propagation leading to reduced RV contractility and overall performance. Although accumulation of extracellular matrix components above a certain threshold undoubtedly contributes to RV failure, qualitative changes may have a more detrimental effect than quantitative changes (most often limited to the measurement of the percentage of the tissue occupied by Masson trichrome or picrosirius red-stained collagen fibers). Indeed, changes in the relative amounts of various matrix proteins with different mechanical and functional properties likely instigate functional decline. Findings documenting increased collagen I/III ratio in rats with severe RV dysfunction assist in this way. Furthermore, differences in distribution in fibrosis within the RV should not be excluded.

Although, the findings from Müller et al advance our knowledge on the mechanisms responsible for increased ROS production on RV failure, several questions remain to be addressed. One of the objectives of the PAB, when sufficiently severe, is to reproduce the adaptive mechanisms in the short term and then the maladaptive events that naturally ensue with a progressive decline in RV function and the ultimate appearance of clinical symptoms of RV failure. The longitudinal echocardiographic and biochemical assessment of RV function in PAB-operated C57BL/6N or C57BL/6N mice revealed a significant increase in Fulton index, diastolic RV internal diameter, and expression levels of cardiac stress markers, as well as reduction of tricuspid annular plane systolic excursion at 2 weeks post severe PAB surgery when compared to their respective nonoperated mice. However, no major change was seen between weeks 2 and 4. Moreover, the higher mortality rate observed in PAB-subjected C57BL/6N mice as compared with C57BL/6J mice seems to be the consequence of the surgical procedure itself. Therefore, an echocardiographic investigation of RV function over a longer period would be instructive.

Finally, considering that chronic oxidative stress and inflammation are intimately linked to each other and with the evolution of RV failure, additional data related to the recruitment of inflammatory cells and expression and release of proinflammatory factors in both strains will yield key information.

In conclusion, the data provide new evidence that targeting oxidative stress may limit maladaptive RV remodeling. From a more general perspective, the study points out the importance of considering the genetic background for interventional studies and shades new light on previous studies using the C57BL/6J strain to study the response to RV-pressure loading.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.