Interactions between cardiac resynchronisation therapy and amelioration of peripheral vascular dysfunction: impact upon outcomes

Abstract

Cardiac resynchronisation therapy (CRT) has been well established as a treatment option for patients with chronic systolic heart failure (CHF) for over 20 years. While it is clear that benefit depends substantially on the presence of disordered intra-ventricular conduction, leading to potential for ‘resynchronisation’, it remains unclear precisely how this process induces symptomatic improvement, improved haemodynamic status and reduced mortality rates. The primary objective of this thesis was to evaluate, pathophysiologically, the factors that could impact outcomes in CRT; specifically, to see, if CRT achieves its beneficial effects via a combination of improvement in cardiac contractility as well as improvement in peripheral vascular endothelial function. The secondary objectives of the thesis were to evaluate whether the extent of improvement in functional status is associated with improvement in parameters of dyssynchrony, and whether change in electrical remodeling is related to change in dyssynchrony and which is achieved through change in neurohumoral activation and change in redox stress. We evaluated 33 consecutive patients who were scheduled for routine insertion of CRT, according to current guidelines and irrespective of ischemic or non-ischemic basis of heart failure. Peripheral vascular function was assessed with radial artery applanation tonometry that evaluated changes in augmentation indices to sublingual nitroglycerin and inhaled salbutamol for endothelium-independent and endothelium-dependent NO effects respectively. Inhibition of ADP- induced platelet aggregation was assessed, as well as changes in plasma concentrations of asymmetric dimethyl arginine (ADMA), symmetric dimethyl arginine (SDMA), and matrix metalloproteinases -2 and-9, NT-proBNP, and catecholamine metabolites. Endothelial shedding of glycocalyx layer was assessed by measurement of plasma levels of syndecan-1. Platelet content of thioredoxin interacting protein (TXNIP) was used to assess the potential for changes in redox stress. Standard echocardiographic measurements were used to evaluate changes in cardiac functions while cardiopulmonary exercise testing and 6-minute walk distance were utilised to assess functional changes. Electrical changes were measured with changes in intrinsic QRS duration, inter-ventricular conduction times using intra-cardiac electrocardiograms, and right ventricular effective refractory periods. All of these parameters were measured at baseline and at 6 months post CRT insertion. Our results showed that at baseline, there was an inverse relationship between vascular NOS function, (as assessed by fall in AIx to salbutamol) and intrinsic QRS duration, (r=-0.40, p =0.01). CRT did not result in improvement in peripheral vascular endothelial function in spite of improvement in cardiac contractility, (LVESV: 136.6 [57.5] to 98.9 [52.1] ml, p <0.001) and in most measures of functional status such as New York Heart Association (NYHA) functional class (2.7 [0.8] to 1.9 [0.7], p <0.001); 6MWD (314.5 [112.8 to 357.0 [117.0] meters, p = 0.005); and quality of life score (QOL) (40.7 [25.4] to 22.9 [22.3], p = 0.001). Apart from a significant reduction in plasma concentrations of SDMA (0.83 [0.28] to 0.74 [0.20], p =0.013), which was independent of changes in renal function, there were no other significant changes in other measures of inflammatory activation. CRT also did not affect parameters of glycocalyx shedding or redox stress although it resulted in significant reduction in plasma concentrations of NT-pro BNP (1862 [1091-3185] to 1469 [774-2841] ng/L, p = 0.008) Although there was no change in right ventricular refractoriness, there was significant improvement in inter- ventricular electrical conduction assessed by onset left ventricular pacing to the onset of right ventricular intra-cardiac electrocardiogram, (LVp-RVegm): (117 [44.5] to 97.0 [45.0] ms, p =0.019. In summary, the studies in this thesis showed that CRT exerted its salutary effects independent of changes in peripheral vascular endothelial function and without significant changes in most parameters of inflammatory activation apart from reduction in SDMA levels independent of changes in renal function. There was also improvement in measures of inter-ventricular electrical conduction following CRT.