Changes in contractile protein expression are linked to ventricular stiffness in infants with pulmonary hypertension or right ventricular hypertrophy due to congenital heart disease

Abstract

BackgroundThe right ventricle (RV) is not designed to sustain high pressure leading to failure. There are no current medications to help RV contraction, so further information is required on adaption of the RV to such hypertension.MethodsThe Right Ventricle in Children (RVENCH) study assessed infants with congenital heart disease undergoing cardiac surgery with hypertensive RV. Clinical and echocardiographic data were recorded, and samples of RV were taken from matched infants, analysed for proteomics and compared between pathologies and with clinical and echocardiographic outcome data.ResultsThose with tetralogy of Fallot (TOF) were significantly more cyanosed than those with ventricular septal defect (median oxygen saturation 83% vs 98%, P=0.0038), had significantly stiffer RV (tricuspid E wave/A wave ratio 1.95 vs 0.84, P=0.009) and had most had restrictive physiology. Gene ontology in TOF, with enrichment analysis, demonstrated significant increase in proteins of contractile mechanisms and those of calmodulin, actin binding and others associated with contractility than inventricular septal defect. Structural proteins were also found to be higher in association with sarcomeric function: Z-disc, M-Band and thin-filament proteins. Remaining proteins associated with actin binding, calcium signalling and myocyte cytoskeletal development. Phosphopeptide enrichment led to higher levels of calcium signalling proteins in TOF.ConclusionThis is the first demonstration that those with an RV, which is stiff and hypertensive in TOF, have a range of altered proteins, often in calcium signalling pathways. Information about these alterations might guide treatment options both in terms of individualised therapy or inotropic support for the Right ventricle when hypertensive due to pulmoanry hypertension or congenital heart disease.

Transcriptomic Signature of Right Ventricular Failure in Experimental Pulmonary Arterial Hypertension: Deep Sequencing Demonstrates Mitochondrial, Fibrotic, Inflammatory and Angiogenic Abnormalities

“…While we have compared our data to transcript data from both mouse and human RVF, we acknowledge that this is not exhaustive and may describe specific rather than generic RV pathology and only at the transcript level. For example, comparison of our data with a recent proteomic analysis of RV from children with tetralogy of Fallot (TOF) [ 70 ] revealed only a small overlap between our data and theirs (17 proteins identified that have corresponding transcripts regulated in the rat MCT RV). While this paper also highlighted the significant enrichment of proteins involved in calcium signaling, our own functional analysis does not reveal this function as enriched.…”

Myocardial proteomic profile in pulmonary arterial hypertension

“…Although authors have demanded that these changes are related to early RV response, they are more consistent with the alterations we have observed at the end stages of the disease. Interestingly, study by Bond et al showed abnormalities in the calcium signaling pathways of the RV myocardium in children with hypertensive RV, where increased expression of myocardial contractile and extracellular proteins was accompanied by enriched calcium signaling 51 . Same increase in RV structural and contractile proteins were observed in current study however downregulation of proteins related to cardiomyocyte Ca 2+ currents were noted.…”

Role of Inflammatory Cell Subtypes in Heart Failure

“…Systolic heart failure is also known as heart failure with reduced ejection fraction (HFrEF) and occurs when a decreased force of contractility of the left ventricle reduces the pumping capacity. Diastolic dysfunction, also known as heart failure with preserved ejection fraction (HFpEF), occurs when the muscle in the left ventricle becomes stiff, due to either change in contractile proteins of cardiac myocytes or effect of fibrosis on relaxation [1–4]. Right heart failure occurs in association with lung disease leading to pulmonary hypertension and as an end stage of left ventricular failure [5].…”

“…Studies show that resident and recruited immune cells play a role in cardiac injury and are present in cardiac tissue early in disease [1–5, 9]. Initially, resident and infiltrating immune cells activate inflammatory/reparative pathways, and the relative balance between pathological inflammatory pathways and tissue reparative processes (physiological inflammation) defines the course of HF development [10].…”