Hypertension Induces Pro-arrhythmic Cardiac Connexome Disorders: Protective Effects of Treatment

Abstract

Prolonged population aging and unhealthy lifestyles contribute to the progressive prevalence of arterial hypertension. This is accompanied by low-grade inflammation and over time results in heart dysfunction and failure. Hypertension-induced myocardial structural and ion channel remodeling facilitates the development of both atrial and ventricular fibrillation, and these increase the risk of stroke and sudden death. Herein, we elucidate hypertension-induced impairment of “connexome” cardiomyocyte junctions. This complex ensures cell-to-cell adhesion and coupling for electrical and molecular signal propagation. Connexome dysfunction can be a key factor in promoting the occurrence of both cardiac arrhythmias and heart failure. However, the available literature indicates that arterial hypertension treatment can hamper myocardial structural remodeling, hypertrophy and/or fibrosis, and preserve connexome function. This suggests the pleiotropic effects of antihypertensive agents, including anti-inflammatory. Therefore, further research is required to identify specific molecular targets and pathways that will protect connexomes, and it is also necessary to develop new approaches to maintain heart function in patients suffering from primary or pulmonary arterial hypertension.

Connexin43, A Promising Target to Reduce Cardiac Arrhythmia Burden in Pulmonary Arterial Hypertension

“…Structural remodeling is always linked with electrical remodeling, mostly due to Cx43 disorders and defective electrical signal propagation among the cardiomyocytes that increase arrhythmogenesis [ 19 , 59 , 60 ]. Indeed, the heterogeneous expression of Cx43 in the myocardium of the right ventricular outflow tract may promote its dysfunction and serve as substrate for idiopathic ventricular arrhythmia [ 61 ].…”

“…Indeed, the heterogeneous expression of Cx43 in the myocardium of the right ventricular outflow tract may promote its dysfunction and serve as substrate for idiopathic ventricular arrhythmia [ 61 ]. Available data suggest that the impairment of intercellular electrical coupling and signaling via Cx43 channels may be involved in both the pathomechanisms underlying PAH [ 28 , 62 , 63 ] and the occurrence of cardiac arrhythmias in PAH, as in primary HTN [ 19 , 26 , 64 , 65 , 66 ].…”

“…Comprehensive research indicates that Cx43 may be implicated in all proarrhythmic processes in hypertension affected heart as it is illustrated in Figure 2 and Figure 6 . Reduced Cx43 expression and its abnormal topology on the lateral sides of hypertrophied cardiac myocytes, as well as their disordered distribution in the fibrotic ventricles of rodents with HTN [ 19 , 26 , 80 , 81 ] or with PAH [ 28 , 62 , 72 , 82 , 83 , 84 ], may underly arrhythmogenic setting [ 27 ], which promotes non-uniform anisotropy, conduction defects and re-entry [ 85 , 86 , 87 , 88 ], as well as ventricular mechanical dysfunction [ 89 , 90 ]. Abnormal Ca2+handling and Ca2+ overload [ 56 , 57 , 58 , 91 ], as well as acidosis (due to ischemia or insufficient perfusion [ 75 ]), may induce alterations in the phosphorylation and dephosphorylation of GJCx43 channels with reduced permeability and even electrical uncoupling [ 29 , 92 , 93 , 94 ], thereby promoting the triggered ectopic excitation and conduction slowing [ 95 ].…”

“…Early diagnosis is also crucial in the context of the prevention of chronic supraventricular tachyarrhythmias, such as atrial fibrillation (AF) and life-threatening ventricular fibrillation (VF). These arrhythmias develop in the conditions of systemic inflammation and oxidative stress, associated with hypertension [ 5 , 13 , 19 , 20 , 21 ], that induce cardiomyocyte and extracellular matrix (ECM) remodeling, which are the dominant cardiac pathological characteristics in PAH.…”

“…Myocardial structural remodeling (i.e., hypertrophy and fibrosis) is considered a crucial factor in the occurrence of cardiac arrhythmias as well as mechanical dysfunction in PAH [ 12 , 22 , 23 ] and in essential hypertension (HTN) [ 19 ]. As shown in Figure 1 , the response of LV to HTN demonstrates the heterogeneity of the subcellular alterations of the cardiomyocytes and their junctions that underlie disorders in electrical and mechanical coupling.…”