Does cardiac resynchronization therapy restore peripheral circulatory homeostasis?

Abstract

Aims: To evaluate whether peripheral circulatory 'remodelling' as measured by changes in vascular compliance and in markers of nitric oxide signalling contributes to patient response to cardiac resynchronization therapy (CRT).

Methods and results: Effects of CRT were evaluated in 33 patients pre-procedure and 6 months post-procedure. Peak oxygen consumption, 6 min walk distance, New York Heart Association class, and quality of life score were evaluated. Augmentation index and its interactions with nitric oxide (NO) were evaluated by applanation tonometry. Platelet NO responsiveness and content of thioredoxin-interacting protein were assessed. Plasma concentrations of N-terminal proBNP, asymmetric and symmetric dimethylarginine (SDMA), high sensitivity C-reactive protein, catecholamines, and matrix metalloproteinases-2 and -9 were assessed. Despite significant improvement in 6 min walk distance (P = 0.005), New York Heart Association class (P < 0.001), quality of life (P = 0.001), and all echocardiographic parameters post-CRT, there were no significant changes in augmentation index measurements, thioredoxin-interacting protein content, and platelet NO response. Significant falls in N-terminal proBNP (P = 0.008) and SDMA (P = 0.013; independent of renal function) occurred. Falls in SDMA predicted reduction in high-sensitivity C-reactive protein (P = 0.04) and increases in peak oxygen consumption (P = 0.04). There were no correlations between changes in echocardiographic parameters and those in vascular function.

Conclusions: These data suggest that the beneficial effects of CRT over 6 months are independent of any change in peripheral NO-related signalling. However, there is evidence that suppression of inflammation occurs, and its magnitude predicts extent of clinical improvement.

Keywords: Augmentation index (AIX); Cardiac resynchronisation therapy (CRT); Left ventricular dyssynchrony; Nitric oxide (NO) signalling; Symmetric dimethylarginine (SDMA); Thioredoxin-interacting protein (TXNIP).

Figure 1

Effects of cardiac resynchronization therapy (CRT) on clinical parameters in individual patient. (A) New York Heart Association (NYHA) functional class (n = 29: this is partially obscured graphically by identical changes in 20 patients). (B) 6 min walk distance (6MWD). (C) Peak oxygen consumption (VO₂ max). (D) Quality of life (QOL) score. All analyses were performed via paired t‐tests.

Figure 2

Effects of cardiac resynchronization therapy (CRT) on echocardiographic parameters in individual patients. (A) Left ventricular (LV) ejection fraction. (B) Left ventricular end‐systolic volume (LVESV). (C) Septal to posterior wall delay (SPWD). (D) Interventricular mechanical delay (IVMD). All analyses were performed via paired t‐test.

Figure 3

Implications of changes in plasma symmetric dimethyl arginine (SDMA) concentrations regarding renal excretion of SDMA, and variations in high‐sensitivity C‐reactive protein concentrations and peak oxygen consumption (VO₂ max) post‐cardiac resynchronization therapy (CRT). (A) Correlation between baseline estimated glomerular filtration rate (eGFR) and SDMA concentrations(r = −0.80, P < 0.001). (B) Changes in eGFR post‐CRT in individual patients (P = NS). (C) Changes in SDMA concentrations post‐CRT in individual patients (P = 0.013). (D) Changes in high‐sensitivity C‐reactive protein concentrations (P = 0.04). (E) Changes in VO₂ max values (P = 0.04).