Diastolic dysfunction in pulmonary artery hypertension: Creatine kinase and the potential therapeutic benefit of beta‐blockers

Abstract

SummaryPassive properties of the myocardium influence diastolic filling and cardiac output. In heart failure, changes in contributors to the passive properties of the ventricle, such as titin and collagen, and loss of the metabolic enzyme creatine kinase, increase resistance to filling resulting in diastolic dysfunction. Pulmonary artery hypertension (PAH) arises from interactions between the pulmonary vasculature and the right ventricle (RV) which ultimately leads to RV failure. Beta1‐adrenergic receptor blockers (BB) act on the myocardium and are beneficial in left heart failure but are not used in PAH. We investigated whether BB improved survival and RV function in a rat model of PAH. Rats were injected with monocrotaline (60 mg/kg) to induce PAH and RV failure, or saline as controls (CON). When PAH was established, rats were treated with metoprolol (10 mg/kg per day) (MCT+BB) or vehicle (sucrose) (MCT); CON were treated with vehicle. In vivo measurement of RV compliance using pressure–volume catheter, indicated diastolic dysfunction in the RV of MCT rats was improved with BB treatment. Expression of creatine kinase protein and mRNA was lower in MCT rats compared to CON, with a trend for reversion by BB treatment. Isolated CON RV myocytes had a positive contraction response to faster pacing, whereas it was negative in MCT. MCT+BB cells had an intermediate response, indicating improved ability to respond to increased demand. BB improved diastolic function, partially restored metabolic enzymes and augmented contractility in PAH. These data support the hypothesis that BB may be beneficial in PAH by supporting RV function.

Beta1-adrenoceptor antagonist, metoprolol attenuates cardiac myocyte Ca2+ handling dysfunction in rats with pulmonary artery hypertension

“…The downregulation of SERCA in MCT is likely to limit the ability to cycle Ca 2+ normally and this too was improved by BB. In addition we have previously shown that the contraction-frequency relationship in MCT myocytes is influenced by BB via expression of creatine kinase [ 15 , 16 ]. Repolarization profile can modulate Ca 2+ handling [ 5 ] and we have shown that in MCT myocytes the stimulation frequency dependent fall in contraction is, at least in part, caused by the stimulation frequency dependent fall in action potential duration (APD) [ 3 , 22 ].…”

Dynamic Action Potential Restitution Contributes to Mechanical Restitution in Right Ventricular Myocytes From Pulmonary Hypertensive Rats

“…It is a characteristic of the MCT model that in FAIL myocytes contraction shows negative restitution whilst CON myocytes show a biphasic response (Benoist et al, 2012 ; Fowler et al, 2015 , 2018 ; Natali et al, 2015 ). These contractile responses are linked to changes in the amplitude of the [Ca 2+ ]i transient (Benoist et al, 2012 ).…”

“…Similar electrical remodeling, including steeper APD restitution, is seen in the MCT rat model of PAH and RV failure (Piao et al, 2010 ; Benoist et al, 2011 , 2012 ). This model is also characterized by a steep negative contraction-frequency relationship (Benoist et al, 2012 ; Fowler et al, 2015 , 2018 ; Natali et al, 2015 ). This mechanical response is linked to a more steeply decreasing [Ca 2+ ]i transient amplitude (Benoist et al, 2012 ).…”

The Role of G Protein-Coupled Receptors in the Right Ventricle in Pulmonary Hypertension

“…The beneficial effect of carvedilol is mediated through the modulation of TGFβ1-CTGF signaling (149) as well as signaling pathways involved in cardiac hypertrophy, protein ubiquitination and mitochondrial function (111). Similarly, another beta-blocker, metoprolol improves the remodeling and function of the pressure overloaded RV in MCT rats (110, 151), mainly by improving RV metabolism (110) and calcium handling (151). In contrast, bisoprolol does not exert beneficial effects on the RV in PAB-operated rats (90).…”