Electromechanical effects and optimization modalities of cardiac resynchronization therapy

Background and aims: Heart failure is a major health care problem, with high morbidity and mortality rates. In recent years, cardiac resynchronization therapy (CRT) has become an established additive treatment for patients with advanced heart failure, left ventricular (LV) dysfunction, and wide QRS complex. CRT is a stimulation technique based on right ventricular (RV) and LV pacing, usually in synchrony, delivered by a pacemaker or a cardioverter-defibrillator. Significant improvements in heart failure symptoms, hospitalization rates and mortality have been documented after initiation of CRT treatment. However, to date, 20% to 30% of patients do not respond to CRT (non responders), and improved management strategies are important. This thesis explores the acute and long-term electromechanical effects of CRT at rest and during stress, and investigates novel methods for CRT optimization.

Study I: Twenty-one heart failure patients, responders to CRT, were assessed by low-dose dobutamine stress echocardiography, clinical evaluation and analysis of brain natriuretic peptide at two times: during active CRT (on) and after withholding of CRT for two weeks (off). Clinical, neurohormonal and echocardiographic results were compared between on and off conditions. This short-term cessation of CRT was associated with a deterioration of LV performance and a slight clinical impairment. Conclusion: The beneficial effects of CRT on LV systolic and diastolic function, observed at rest, were sustained during dobutamine stress, and this was mainly owing to maintained improvement in inter- and intraventricular synchrony.

Study II: Twenty-two heart failure patients with idiopathic dilated cardiomyopathy (without any evidence of significant coronary artery disease at previous angiography), who had successfully responded to CRT, underwent echocardiographic assessment of left anterior descending coronary artery (LAD) flow and intraventricular dyssynchrony during different pacing modes. Changes in LAD flow variables were correlated with simultaneous variations in intraventricular dyssynchrony. The mean coronary flow velocity increased by comparison with intrinsic conduction during simultaneous biventricular pacing (p = 0.0063) and biventricular pacing with LV preactivation (p < 0.0001), and was higher in the latter programming mode (p = 0.027). Conclusion: In patients with idiopathic dilated cardiomyopathy, simultaneous biventricular pacing and biventricular pacing with LV preactivation increase LAD flow, and this is associated with a reduction in intraventricular dyssynchrony.

Study III Long-term variations in atrioventricular (AV) and interventricular (VV) delays were prospectively investigated in 37 heart failure patients subjected to echo-guided CRT optimization. All patients underwent CRT optimization within 48 hours of implantation and again after 6 months. Additionally, optimization at 12 months was performed in the first 14 patients enrolled. Conclusion: Echocardiographic optimization of AV and VV delays is associated with broad intraindividual variability. A new assessment of optimized VV delays during long-term follow-up reveals nonconcordance with previous values and provides a further increase in forward stroke volume.

Study IV Twenty-four CRT patients were assessed both by echocardiography and by an automated intracardiac electrogram (IEGM) method with regard to optimal AV and VV delays. In addition, the acute impact of exercise CRT optimization on hemodynamic variables was investigated. Significant rest-to-exercise changes in optimal VV delay, but not in AV delay, were observed. Reassessment of optimal device programming during ongoing exercise resulted in an improvement in LV dyssynchrony and hemodynamic parameters, giving an additional benefit to that provided by optimization performed at rest. Conclusion: The IEGM method seems to be a promising alternative to the standard echocardiographic approach, both at rest and during exercise.

Study V Twelve heart failure patients were evaluated for acute changes in multiple vector intracardiac impedance (ICZ) signals during implantation of a CRT device operating in different pacing modes. Bipolar (Z1) and quadripolar (Z2) impedance signals, recorded in the RV and between the LV and RV, respectively, were analyzed with respect to amplitude and systolic slope, and correlated with noninvasive hemodynamic and echocardiographic variables. The Z1 and Z2 variables correlated positively with all noninvasive hemodynamic variables and LV and RV ejection fractions, and inversely with LV and RV volumes. The Z2 systolic slope correlated with the interventricular conduction delay (r = 0.33, p < 0.05). Conclusion: Multiple vector ICZ measurement may be a feasible tool for hemodynamic assessment in patients treated with biventricular pacing.

Summary: In heart failure patients, CRT has been shown to improve symptoms, exercise capacity and survival. Our findings suggest that in long-term responders, the benefits of CRT on LV synchrony and function that are observed at rest are sustained during pharmacological stress, thereby providing a link between pathophysiological mechanisms and clinical evidence of improved exercise capacity. The finding of increased LAD flow during biventricular pacing highlights a possible additional mechanism responsible for the beneficial effects of CRT. CRT optimization has been shown to provide acute hemodynamic benefits. The dynamic changes in optimal AV and VV delays during long-term follow-up and from rest to exercise suggest that reevaluations of CRT programming may be useful. Novel automated device-based algorithms seem to be a feasible alternative to echocardiography for CRT optimization. Furthermore, multiple vector ICZ measurement may be a promising tool for hemodynamic assessment and optimization in CRT patients.

List of scientific papers

I. Valzania C, Gadler F, Eriksson MJ, Olsson A, Boriani G, Braunschweig F (2007). "Electromechanical effects of cardiac resynchronization therapy during rest and stress in patients with heart failure." Eur J Heart Fail (6-7): 644-50. Epub 2007 Mar 7
https://pubmed.ncbi.nlm.nih.gov/17347041

II. Valzania C, Gadler F, Winter R, Braunschweig F, Brodin LA, Gudmundsson P, Boriani G, Eriksson MJ (2008). "Effects of cardiac resynchronization therapy on coronary blood flow: evaluation by transthoracic Doppler echocardiography." Eur J Heart Fail 10(5): 514-20. Epub 2008 Apr 24
https://pubmed.ncbi.nlm.nih.gov/18436475

III. Valzania C, Biffi M, Martignani C, Diemberger I, Bertini M, Ziacchi M, Bacchi L, Rocchi G, Rapezzi C, Branzi A, Boriani G (2007). "Cardiac resynchronization therapy: variations in echo-guided optimized atrioventricular and interventricular delays during follow-up." Echocardiography 24(9): 933-9
https://pubmed.ncbi.nlm.nih.gov/17894571

IV. Valzania C, Eriksson MJ, Boriani G, Gadler F (2008). "Cardiac resynchronization therapy during rest and exercise: comparison of two optimization methods." Europace 10(10): 1161-9. Epub 2008 Aug 27
https://pubmed.ncbi.nlm.nih.gov/18753213

V. Valzania C, Eriksson MJ, Holmström N, Järverud K, Gadler F (2009). "Feasibility of multiple vector impedance measurements during biventricular pacing." (Submitted)