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Cardiac resynchronization therapy (CRT) is an effective methodology indicated in selected heart failure patients. Identifying responders to the therapy is still challenging. Most studies report that at least 30% of the patients are nonresponders. Baseline characteristics of the Low-Dose Dobutamine Stress Echocardiography to Predict Cardiac Resynchronization Therapy Response (LODO-CRT) trial population are presented. The study investigates dobutamine stress echocardiography’s role in predicting CRT response. Two hundred seventy-one CRT candidates were studied. Mean age was 67±10 years, 69% were male, 96% had New York Heart Association class III disease, and 39% had heart failure of ischemic etiology. Mean QRS and left ventricular ejection fraction were 146±24 ms and 26%±6%, respectively. Seventy-seven percent of participants showed contractile reserve. Left ventricular end-diastolic volume was shown to be independently associated with contractile reserve presence. In particular, more dilated ventricles are associated with a lower chance of having contractile reserve. The LODO-CRT trial enrolled a cohort of patients fulfilling criteria for CRT. Dobutamine stress echocardiography was highly feasible and safe in this population. Contractile reserve was associated with healthier ventricles. Congest Heart Fail. 2010;16:104–110. © 2010 Wiley Periodicals, Inc.
Cardiac resynchronization therapy (CRT) is an effective therapeutic option for heart failure (HF), since it improves New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF), exercise tolerance, and quality of life and reduces hospitalizations, mortality, and costs.1–5 Currently, American College of Cardiology/American Heart Association/European Society of Cardiology guidelines rate CRT in class Ia for HF patients with NYHA functional class III or IV, QRS ≥120 ms, and LVEF ≤35%.6,7
Despite these favorable results, the identification of potential responders to the therapy is still a challenging task. Responders’ proportion appears to be strictly dependent on the definition of response. Studies report that a “clinical” response is observed in 60% to 75% of patients8,9 with current CRT indications, but according to several authors, this rate drops to 50% if objective parameters such as left ventricular (LV) reverse remodeling or oxygen consumption are used to define the response.10
The presence of LV dyssynchrony before implantation has often been associated with positive response to CRT. Over the last 10 years, many different methods have been proposed to estimate LV dyssynchrony by means of echocardiographic indexes, measured both with traditional echocardiography and with tissue Doppler imaging.11–13 Results from single-center studies have been promising, but the Predictors of Response to CRT (PROSPECT) study14 raised substantial concerns about the reproducibility of these methods and concluded that no single echocardiographic measure of dyssynchrony may be recommended to improve patient selection for CRT beyond current guidelines. Up to now, we could not rely on dyssynchrony indexes alone in selecting candidates for CRT in an attempt to increase the overall proportion of responders.
Other factors must be taken into account when selecting a patient for implantation, such as etiology15 or the extent and position of the scar.16,17 Moreover, lead placement may be a key factor in determining the response.18
In search for further factors associated with response to CRT, we hypothesized that LV contractile reserve (LVCR) presence can be of great importance to increase the chances of positive response to the therapy. Early findings claim a strong relationship between LVCR and response to CRT,19–21 bringing preliminary evidence that a necessary condition to gain improvement in LV function is the availability of a relevant amount of viable myocardial cells. In particular, from these preliminary works it seems that in advanced stages of HF, the presence of fibrotic or scar tissue may inhibit effective biventricular stimulation. LVCR presence can be easily detected in patients with HF of any etiology using dobutamine stress echocardiography (DSE), which was shown to be feasible and safe.22–25
The Low-Dose Dobutamine Stress Echocardiography to Predict Cardiac Resynchronization Therapy Response (LODO-CRT) trial is a prospective, multicenter, observational study aimed at evaluating the role of DSE in selecting suitable candidates for CRT. We hypothesize that patients showing presence of acute LVCR on DSE are more likely to positively respond to CRT at follow-up.26 In this article, the baseline clinical and echocardiographic parameters of the population enrolled in the study are presented.
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The LODO-CRT trial successfully enrolled a cohort of patients fulfilling current criteria for CRT device implantation. Patients showed major left ventricular systolic dysfunction and generally persistent symptoms of HF, despite conventional pharmacologic therapy.
The reported feasibility of the low-dose DSE protocol in the LODO-CRT framework was remarkably high. Dobutamine side effects were negligible in 99% of patients. The test had to be interrupted before reaching a clear indication of presence or absence of LVCR only in 3 cases in which a ventricular tachycardia was induced but eventually self-terminated. These data are in line or slightly better than those from Cigarroa and coworkers,27 who reported an overall test feasibility of 93% in 49 patients, and confirm the results from the Beta-Blocker Evaluation in Survival Trial (BEST) on safety and feasibility of the low-dose test protocol in 79 HF patients.31 However, to our knowledge this is the first large study confirming that DSE is feasible and safe in selected patients with symptomatic chronic HF.
Overall, in the LODO-CRT population, 77% of patients showed presence of LVCR. In the preliminary experience on the role of DSE in predicting response to CRT, carried out by Tuccillo and coworkers21 in 42 patients, the percentage of responders to DSE was 64%. However, the definition of response that was used was different (25% LVEF relative increase) from the one adopted in the present study.
The proportion of patients showing LVCR in the LODO-CRT trial is remarkably higher than those reported by Da Costa and coworkers19 and by Ypenburg and coworkers,20 who both identified approximately 50% of DSE responders in a population of candidates to CRT.
The main reason for this discrepancy is the different test protocol they used. In fact, in both experiences dobutamine infusion did not exceed 10 μg/kg/min, while in LODO-CRT investigators were allowed to increase the drug dosage to 20 μg/kg/min if needed. Moreover, the cutoff for positive response to the test was set at 25% LVEF relative increase and 7.5 points LVEF absolute increase, respectively, while in LODO-CRT an LVEF increase >5 absolute points was used. Furthermore, in Da Costa’s experience, a higher percentage of patients in NYHA class IV were present; this most probably influenced the average results of DSE.
In the LODO-CRT trial framework, the predefined cutoff for DSE outcome was identified according to Agricola and coworkers,23 who determined in their review on DSE that an increase in LVEF of at least 5% in absolute terms is the critical value to determine the presence of LVCR.
The evaluation of the study’s principal outcomes for specific subgroups of patients is of interest, since the characteristics of the subgroups may explain differences in outcome or baseline received therapy. Subgroup analysis of baseline characteristics identified few clinically relevant differences between patients with or without LVCR. As expected, absence of LVCR identified “sicker” patients. In particular, these patients showed more impaired ventricular function (larger volumes with worse diastolic patterns) with a higher grade of mitral regurgitation. Furthermore, in this group there were more patients showing interventricular delay. Finally, multivariable analysis showed that a more dilated left ventricle is the only parameter associated with a lower probability of LVCR presence.
To our knowledge, such a comparison is reported only by Ramahi and coworkers,32 who evaluated the association between the DSE test response and other clinical parameters in a nonischemic HF population similar to the LODO-CRT sample. In their experience, patients with low response to dobutamine presented with a greater mean NYHA functional class, larger diastolic volumes, and a higher mortality rate after 3 years from the test.
Our data confirm in an HF population of any etiology that a higher response to dobutamine identifies healthier patients, characterized by better functional capacity and smaller ventricles. These data are indeed promising, since the co-presence of factors like ischemic etiology of HF or larger ventricles has already been associated with lack of response to resynchronization.33
The resulting association between LVCR presence and other baseline conditions is not detrimental for DSE relevance. In fact, only DSE is able to detect the residual amount of viable tissue that would respond to the electrical stimulus provided by resynchronization therapy. Thus, dobutamine echocardiography provides unique information in selecting potential responders to CRT, since it takes into account the resynchronization’s own action mechanism, that is, the recruiting of a certain amount of cardiac cells, which would not actively contract if not electrically stimulated, due to the modifications induced by LV dilation.
Response to DSE seems to be independent of HF etiology. The 2 groups of ischemic and nonischemic patients did not show any significant differences in LVEF and proportion of patients with LVCR. Apparently, these data conflict with those reported in BEST in which the ischemic etiology in an unselected HF population was highly associated with absence of LVCR.31
Finally, the LODO-CRT population presented similar baseline characteristics to those of the CARE-HF and PROSPECT studies, although higher mean LVEF, shorter QRS duration, and smaller volumes in LODO-CRT may identify slightly less impaired patients. However, as the enrolled population adheres to current guidelines for CRT device implantation, the expected DSE results in terms of ability to predict the response to CRT can be compared with other predictors of response evaluated in other trials.
Study Limitations. This study presents data about the prevalence of LVCR in a population of CRT candidates and its association with other baseline clinical conditions, but it provides no information about the outcome of CRT with respect to LVCR presence. Moreover, the association between intraventricular dyssynchrony and LVCR has not been assessed yet. These two main points are now under evaluation; results will be published as soon as they become available.