Renal Denervation Reduces Pulmonary Vascular Remodeling and Right Ventricular Diastolic Stiffness in Experimental Pulmonary Hypertension

Bós, Denielli da Silva Gonçalves; Happé, Chris; Schalij, Ingrid; Pijacka, Wioletta; Paton, Julian F. R.; Guignabert, Christophe; Tu, Ly; Thuillet, Raphaël; Bogaard, Harm Jan; Rossum, Albert C. van; Vonk‐Noordegraaf, Anton; Man, Frances S. de; Handoko, M. Louis

doi:10.1016/j.jacbts.2016.09.007

Cited by 34 publications

(33 citation statements)

References 43 publications

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“…While RV contractile and diastolic function have previously been characterized in SuHx rats in vivo using pressure–volume loops (Da Silva Gonçalves Bos et al. ), our study further advances the field by studying RV function independently of increases in pulmonary vascular resistance and by investigating developed RVSP, d P /d t max , and d P /d t min over a wide range of RV filling pressures (RVEDP 0–40 mmHg). Our studies also demonstrate the importance of properly normalizing the readouts obtained in this model.…”

Section: Discussionmentioning

confidence: 85%

Isolated heart model demonstrates evidence of contractile and diastolic dysfunction in right ventricles from rats with sugen/hypoxia-induced pulmonary hypertension

et al. 2017

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Although extensively used for the study of left ventricular function, limited experience exists with the isolated heart model in the evaluation of right ventricular (RV) function. In particular, no published experience exists with this tool in sugen/hypoxia‐induced pulmonary hypertension (SuHx‐PH), a frequently used model of severe and progressive PH. We sought to characterize markers of RV contractile and diastolic function in SuHx‐PH and to establish their relationship with markers of maladaptive RV remodeling. Hearts were excised from anesthetized Sprague Dawley rats with or without SuHx‐PH and perfused via the aorta using a Langendorff preparation. We explored the Frank–Starling relationship of RV function (RV developed pressure, dP/dt max, and dP/dt min; all normalized to RV mass) by increasing RV end‐diastolic pressure (RVEDP) from 0 to 40 mmHg. Functional studies were complemented by quantification of RV pro‐apoptotic signaling (bcl2/bax), procontractile signaling (apelin), and stress response signaling (p38MAPK activation). Pearson's correlation analysis was performed for functional and biochemical parameters. SuHx‐RVs exhibited severe RV dysfunction with marked hypertrophy and decreased echocardiographic cardiac output. For any given RVEDP, SuHx‐RVs demonstrated less developed pressure and lower dP/dt max, as well as less pronounced dP/dt min, suggestive of decreased contractile and diastolic function. SuHx‐RVs exhibited decreased bcl2/bax ratios, apelin expression, and p38MAPK activation. Bcl2/bax and apelin RNA abundance correlated positively with RV developed pressure and dP/dt max and negatively with dP/dt min. p38MAPK activation correlated positively with RV developed pressure. We conclude that SuHx‐RVs exhibit severe contractile and diastolic dysfunction. Increased pro‐apoptotic signaling and attenuated procontractile and stress response signaling may contribute to these functional alterations.

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Section: Discussionmentioning

confidence: 85%

Isolated heart model demonstrates evidence of contractile and diastolic dysfunction in right ventricles from rats with sugen/hypoxia-induced pulmonary hypertension

et al. 2017

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“…Beta-adrenergic blockade 109 , 110 107 , 111 3.3.2. Renin angiotensin-aldosterone system 114 3.3.3. Parasympathetic activation 115 …”

Section: Discussionmentioning

confidence: 99%

“… 104 , 112 , 113 In a recent proof-of-concept study, the effects of renal denervation were investigated in two well-established experimental models of PH. 114 Denervation delayed disease progression; pulmonary vascular remodelling and RV afterload were reduced, as was RV diastolic stiffness. It appears that renal denervation may have caused these effects by suppressing the activation of the renin–angiotensin–aldosterone system.…”

Section: Treatment Strategies Targeting the Consequences Of Rv Walmentioning

confidence: 99%

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Treatment strategies for the right heart in pulmonary hypertension

Westerhof

Saouti

Laarse

et al. 2017

Cardiovascular Research

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The function of the right ventricle (RV) determines the prognosis of patients with pulmonary hypertension. While much progress has been made in the treatment of pulmonary hypertension, therapies for the RV are less well established. In this review of treatment strategies for the RV, first we focus on ways to reduce wall stress since this is the main determinant of changes to the ventricle. Secondly, we discuss treatment strategies targeting the detrimental consequences of increased RV wall stress. To reduce wall stress, afterload reduction is the essential. Additionally, preload to the ventricle can be reduced by diuretics, by atrial septostomy, and potentially by mechanical ventricular support. Secondary to ventricular wall stress, left-to-right asynchrony, altered myocardial energy metabolism, and neurohumoral activation will occur. These may be targeted by optimising RV contraction with pacing, by iron supplement, by angiogenesis and improving mitochondrial function, and by neurohumoral modulation, respectively. We conclude that several treatment strategies for the right heart are available; however, evidence is still limited and further research is needed before clinical application can be recommended.

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“…Following this line of thought, Da Silva Gonçalves Bos et al. (6) report in this issue of JACC: Basic to Translational Science that renal artery denervation reduces pulmonary vascular remodeling and right ventricular (RV) diastolic stiffness in experimental PAH through modulation of the neurohormonal system, thus expanding the previously postulated link (5) between the renal body fluid regulating system, neurohormonal activation, and pulmonary vascular remodeling. In this elegant study, the investigators used 2 independent models of PAH and severe RVF in the rat, including the 1 induced by the combination of a vascular endothelial growth factor receptor blocker and chronic hypoxia that closely resembles PAH in humans (7) .…”

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confidence: 94%