Institutionen för medicin / Department of Medicine
Abstract
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