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of patients with HF with decreased ejection fraction also present left ventricular &#40;LV&#41; electrical dyssynchrony that results in a QRS interval greater than 120 ms&#44; most commonly with a left bundle branch block &#40;LBBB&#41; pattern&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">4</span></a> LV electrical dyssynchrony results in decreased diastolic time&#44; anomalous septal motion and increased mitral regurgitation&#44; with an overall reduction in left ventricular ejection fraction &#40;LVEF&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">1&#44;5</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Cardiac resynchronization therapy &#40;CRT&#41; has shown important clinical benefits in the treatment of HF patients with systolic dysfunction &#40;LVEF &#60;35&#37;&#41; and electrical dyssynchrony &#40;QRS &#62;120 ms&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">4&#44;6</span></a> By reducing ventricular electrical dyssynchrony&#44; CRT improves LV systolic function while reducing myocardial oxygen consumption&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">7</span></a> which results in improvement of symptoms and quality of life and in a significant reduction in mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">4&#44;8&#44;9</span></a> However&#44; up to 30&#37; of patients do not respond to CRT &#40;nonresponders&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">10&#8211;12</span></a> CRT responders undergo LV reverse remodeling&#44; which is characterized by decreases in intraventricular conduction delay and LV end-systolic volume &#40;LVESV&#41; and reduction in mitral regurgitation area&#44; with a consequent increase in LVEF&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">8&#44;12&#44;13</span></a> LV reverse remodeling is thought to be responsible for the clinical improvement in responders to CRT&#44; but the mechanisms underlying reverse remodeling are not well understood&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The autonomic nervous system &#40;ANS&#41; may play an important role in reverse remodeling&#46; The ANS has an important role in cardiovascular functional and structural regulation&#44;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">14&#44;15</span></a> but ANS function is also recognized as a prognostic marker in HF&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">16</span></a> Furthermore&#44; CRT induces a reduction in mean heart rate &#40;HR&#41; and an increase in heart rate variability &#40;HRV&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">17&#8211;19</span></a> Najem et al&#46; also showed that there was an acute increase in cardiac sympathetic activity after biventricular pacing was switched off&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">20</span></a> More recently&#44; an improvement in cardiac sympathetic activity has been demonstrated in responders to CRT&#44; assessed by <span class="elsevierStyleSup">123</span>I-MIBG scintigraphy&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">21&#44;22</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Nevertheless&#44; little is known of the impact of CRT on arterial baroreflex function&#46; The arterial baroreflex &#40;with afferents from aortic and carotid baroreceptors&#41; is crucial in the homeostatic regulation of blood pressure &#40;BP&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">23</span></a> It is also a well-established independent prognostic marker in HF&#59; there is evidence that low baroreflex sensitivity is associated with increased cardiovascular morbidity and overall mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">24</span></a> However&#44; it is not known whether baroreflex function before CRT correlates with severity of HF or with the response to cardiac resynchronization&#46; Therefore&#44; the aim of the present study was to assess baroreflex function in HF patients who were candidates for CRT&#44; and to compare it with other clinical and laboratory parameters of HF severity&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Population</span><p id="par0120" class="elsevierStylePara elsevierViewall">Patients of both sexes with class I recommendation for CRT were included&#46; We thus included patients in sinus rhythm with symptomatic HF refractory to optimal medical treatment&#44; in New York Heart Association &#40;NYHA&#41; functional class II or III or outpatients in class IV&#44; with LVEF &#60;35&#37; and QRS width &#62;120 ms&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">6</span></a> Patients in NYHA class II with wider QRS and lower LVEF &#40;QRS &#62;130 ms and LVEF &#60;30&#37;&#41; were included&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">6&#44;13</span></a> Patients with atrial fibrillation&#47;flutter&#44; second or third degree atrioventricular block or frequent supraventricular or ventricular ectopic beats&#44; and those with a pacing rhythm were excluded from this study&#44; as sinus rhythm is a prerequisite for reliable arterial baroreflex measurement&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">25</span></a> Patients were recruited at the Cardiology Department of Santa Marta Hospital&#46; All patients provided written informed consent according to the principles of the Helsinki Declaration&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Protocol</span><p id="par0125" class="elsevierStylePara elsevierViewall">This was an exploratory clinical study&#46; Before CRT implantation&#44; all patients underwent clinical assessment including NYHA functional class&#44; laboratory testing including determination of brain-type natriuretic peptide &#40;BNP&#41;&#44; a 12-lead electrocardiogram &#40;ECG&#41; &#40;Philips TRIM III&#41;&#44; transthoracic echocardiogram and cardiopulmonary exercise test &#40;CPET&#41;&#46; An orthostatic tilt test was used to study baroreflex function&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Transthoracic echocardiography</span><p id="par0130" class="elsevierStylePara elsevierViewall">Transthoracic echocardiographic images were obtained using Vivid 7 equipment &#40;General Electric-Vingmed&#44; Milwaukee&#44; WI&#41;&#46; The echocardiographic assessment was performed in M-mode&#44; biplane and Doppler modes&#46; LVEF&#44; LVESV and LV end-diastolic volume &#40;LVEDV&#41; were determined using Simpson&#39;s biplane method&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">26&#44;27</span></a> A semi-quantitative Doppler method was used to assess mitral regurgitation grade&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Cardiopulmonary exercise test</span><p id="par0135" class="elsevierStylePara elsevierViewall">Patients were instructed to avoid any intense physical activity and not to smoke or ingest any caffeine-containing drinks in the three hours preceding the exam&#46; CPET was performed on a treadmill according to the modified Bruce protocol&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">28</span></a> Patients exercised until maximal fatigue was reached&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">29</span></a> During the test an ECG and a respiratory mass spectrometer with capnography were used to continuously monitor HR&#44; ventilation&#44; oxygen consumption and carbon dioxide production&#46; Using these&#44; peak HR and peak oxygen consumption &#40;peak VO<span class="elsevierStyleInf">2</span>&#41; were determined&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Orthostatic tilt test and baroreflex function assessment</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Tilt test protocol</span><p id="par0140" class="elsevierStylePara elsevierViewall">Orthostatic tilt testing was performed in a temperature-controlled autonomic function lab&#46; Patients were instructed to avoid any kind of intense physical activity before the test and to avoid smoking or drinking any caffeine-containing drinks in the three hours preceding the exam&#46; No peripheral venous catheters were used and no drugs were administered during the entire exam&#46; All subjects underwent a 10-min basal resting period in the supine position&#44; or slightly inclined in accordance with individual sleeping habits to prevent respiratory discomfort&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">25</span></a> Subjects were tilted up to 70&#176; using a passive electronic tilt table&#46; The orthostatic period was maintained for 10 min&#44; after which subjects returned to their basal inclination for a 10-min recovery period&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">30&#44;31</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Data acquisition and analysis</span><p id="par0145" class="elsevierStylePara elsevierViewall">ECG and peripheral BP were continuously and noninvasively recorded during the tilt test &#40;Task Force Monitor&#44; CNSystems&#44; Graz&#44; Austria&#41;&#46; Hemodynamic data were then analyzed using software developed in our lab &#40;FisioSinal<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">32</span></a>&#41;&#46; This system uses an algorithm to detect systolic blood pressure &#40;SBP&#41; peaks and R-wave peaks in each QRS complex of the ECG from which the RR interval can be calculated&#46; In this way&#44; signals depicting the evolution of SBP over time &#40;systogram&#41; and RR interval &#40;tachogram&#41; were reconstructed&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">33&#44;34</span></a> The reconstructed signals were used to calculate the baroreflex effectiveness index &#40;BEI&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Baroreflex effectiveness index measurement</span><p id="par0150" class="elsevierStylePara elsevierViewall">To assess arterial baroreflex function&#44; the BEI was calculated by the sequence method&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">35&#44;36</span></a> Briefly&#44; the BEI is calculated on the basis of beat-to-beat analysis of cardiovascular signals&#46; The algorithm identifies SBP ramps of three or more consecutive beats characterized by a progressive increase &#40;up-ramp&#41; or decrease &#40;down-ramp&#41; of at least 1 mmHg&#46; Spontaneous baroreflex sequences &#40;baroreflex events&#41; were defined as SBP ramps followed by concomitant and concordant lengthening or shortening of RR intervals of at least 5 ms&#46; The RR intervals were scanned with a lag from the SBP ramp of 0&#44; 1 or 2 beats&#44; each sequence being included only once&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">36</span></a> Baroreflex events were only considered reliable when there was a strong correlation between SBP ramps and concomitant RR-interval ramps &#40;correlation coefficient &#62;0&#46;835&#41;&#46; The total number of baroreflex events per minute &#40;NBR&#41; of the analysis was calculated&#44; as well as the BEI&#44; which is defined as the ratio between baroreflex events and the total number of SBP ramps&#46; The higher the BEI&#44; the greater the effectiveness of the arterial baroreflex in hemodynamic adaptation to changes in blood pressure&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">36&#44;37</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">As assessment of baroreflex function is ideally performed under stationary conditions&#44;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">37</span></a> baroreflex analysis was divided into three periods for each patient&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#41;</span><p id="par0160" class="elsevierStylePara elsevierViewall">Basal&#58; 5 min of basal period in supine position&#59;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#41;</span><p id="par0165" class="elsevierStylePara elsevierViewall">Tilt&#58; 10 min at 70&#176; orthostatic position&#59;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#41;</span><p id="par0170" class="elsevierStylePara elsevierViewall">Recovery&#58; 5 min of recovery in basal supine position&#46;</p></li></ul></p></span></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Statistical analysis</span><p id="par0175" class="elsevierStylePara elsevierViewall">The statistical analysis was performed in SPSS software &#40;version 20&#44; IBM&#44; USA&#41;&#46; Categorical variables were expressed as percentages or frequencies and continuous variables as means &#177; standard deviation&#46; The Kolmogorov-Smirnov test was used to test the normal distribution of continuous variables&#46; The non-parametric Mann-Whitney test was used to compare groups&#46; Pearson&#39;s correlation coefficient was applied to test the correlation between BEI and the other continuous variables used to describe HF severity&#46; The division of patients according to HF severity was performed by k-means clustering&#46; A p value &#60;0&#46;05 was considered statistically significant&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Results</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Population</span><p id="par0180" class="elsevierStylePara elsevierViewall">In this study&#44; 25 HF patients with a mean age of 65&#177;10 years were included&#44; of whom 20&#37; were female&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the patients&#8217; demographic and clinical characteristics&#46; In approximately half of the population &#40;13 patients&#44; 52&#37;&#41; ischemic cardiomyopathy was the etiology of HF&#44; the remaining 12 &#40;48&#37;&#41; patients having HF of other causes&#46; In total&#44; 11 patients were in NYHA functional class II&#44; 13 in NYHA class III and one in class IV&#46; Mean QRS duration was 159&#177;15 ms&#46; All patients had depressed systolic function with severely dilated left cardiac chambers &#40;mean values&#58; LVEF 29&#177;5&#37;&#44; LVESV 150&#177;48 ml and LVEDV 207&#177;60 ml&#41;&#46; The population was also characterized by a significant limitation of physical activity&#44; as demonstrated by a mean peak VO<span class="elsevierStyleInf">2</span> of 18&#46;4&#177;5&#46;0 ml&#47;kg&#47;min&#46; Mean BNP was 357&#177;270 pg&#47;ml&#46; Most patients had multiple comorbidities and other cardiovascular risk factors&#44; notably hypertension &#40;88&#37;&#41;&#44; dyslipidemia &#40;80&#37;&#41;&#44; diabetes &#40;32&#37;&#41;&#44; obesity &#40;28&#37;&#41; and chronic kidney disease &#40;20&#37;&#41;&#46; All patients were under optimal medical treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Controls</span><p id="par0185" class="elsevierStylePara elsevierViewall">The group of patients were compared with a control group of 15 age-matched individuals &#40;age 58&#177;8 years&#44; p&#61;0&#46;08&#41;&#46; In the control group&#44; eight individuals &#40;53&#37;&#41; were female&#46; None had a history of cardiorespiratory disease or dysautonomia or was taking cardiovascular medication&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Baroreflex function</span><p id="par0190" class="elsevierStylePara elsevierViewall">Baroreflex function was significantly depressed in HF patients compared to controls&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> summarizes baroreflex function in HF patients in terms of NBR and BEI&#46; It shows a significant reduction of NBR in HF patients both during the basal period &#40;NBR HF&#58; 2&#46;7&#177;2&#46;3 vs&#46; NBR controls&#58; 3&#46;9&#177;1&#46;6 events&#47;min&#44; p&#61;0&#46;017&#41;&#44; and during tilt &#40;NBR HF&#58; 2&#46;7&#177;2&#46;8 vs&#46; NBR controls&#58; 5&#46;0&#177;2&#46;5 events&#47;min&#44; p&#61;0&#46;001&#41;&#46; Moreover&#44; HF patients had a lower BEI&#46; In basal supine position&#44; patients&#8217; BEI &#40;34&#177;14&#37;&#41; was significantly lower &#40;p&#61;0&#46;001&#41; than controls&#8217; &#40;51&#177;15&#37;&#41;&#46; Similar results were found for the orthostatic tilt period &#40;BEI HF&#58; 31&#177;12&#37; vs&#46; BEI controls&#58; 49&#177;18&#37;&#44; p&#61;0&#46;001&#41;&#46; Interestingly&#44; no differences in baroreflex function were found during recovery&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Association between baroreflex function and other clinical parameters of heart failure severity</span><p id="par0195" class="elsevierStylePara elsevierViewall">Of all the parameters assessed&#44; the following were selected to better characterize HF severity&#58; NYHA functional class&#44; QRS duration&#44; BNP&#44; peak VO<span class="elsevierStyleInf">2</span>&#44; LVEF&#44; LVESV&#44; LVEDV and mitral regurgitation grade&#46; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the calculated correlation coefficients between the above variables and NBR or BEI&#46; During tilt&#44; a lower BEI was associated with higher BNP values &#40;r&#61;-0&#46;435&#44; p&#61;0&#46;038&#41;&#44; higher LVESV &#40;r&#61;-0&#46;541&#44; p&#61;0&#46;031&#41; and lower peak VO<span class="elsevierStyleInf">2</span> &#40;r&#61;0&#46;472&#44; p&#61;0&#46;048&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#46; Furthermore&#44; there was a significant negative correlation between basal BEI and BNP &#40;r&#61;-0&#46;505&#44; p&#61;0&#46;033&#41;&#44; as well as between NBR during tilt and BNP &#40;r&#61;-0&#46;517&#44; p&#61;0&#46;018&#41;&#44; demonstrating that depressed baroreflex function is associated with increased BNP values&#46; During tilt&#44; the associations between BEI and LVEDV &#40;r&#61;-0&#46;486&#44; p&#61;0&#46;056&#41; and between NBR and peak VO<span class="elsevierStyleInf">2</span> were non-significant &#40;r&#61;0&#46;428&#44; p&#61;0&#46;077&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0200" class="elsevierStylePara elsevierViewall">In view of the above results&#44; BEI during tilt was used to stratify patients&#44; as it was the baroreflex function measurement that correlated with most HF severity variables &#40;LVESV&#44; BNP and peak VO<span class="elsevierStyleInf">2</span>&#41;&#46; Applying k-means clustering&#44; a cut-off value of 25&#37; for BEI during tilt was found to stratify patients into two clusters of different HF severity &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>&#41;&#58; a low-risk cluster &#40;BEI &#62;25&#37;&#41; with QRS duration of 153 ms&#44; LVESV 129 ml&#44; BNP 146 pg&#47;ml&#44; and peak VO<span class="elsevierStyleInf">2</span> 19&#46;0 ml&#47;kg&#47;min&#59; and a high-risk cluster &#40;BEI &#8804;25&#37;&#41; with QRS duration 167 ms&#44; LVESV 189 ml&#44; BNP 590 pg&#47;ml&#44; and peak VO<span class="elsevierStyleInf">2</span> 16&#46;2 ml&#47;kg&#47;min&#46; These clusters demonstrate that baroreflex function can be used to better stratify HF patients who are candidates for CRT&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Discussion</span><p id="par0205" class="elsevierStylePara elsevierViewall">Our results show that HF patients who are candidates for CRT have depressed baroreflex function&#46; This is in agreement with the literature&#44; since this population consisted of selected HF patients and HF is a syndrome classically characterized by compensatory chronic neurohormonal hyperstimulation&#44; with hypersympathetic activation and attenuation of the arterial baroreflex&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">38&#44;39</span></a> The extent of the reduction in baroreflex function has important prognostic value in HF&#44; lower values of baroreflex sensitivity being associated with increases in overall mortality&#44; cardiovascular morbidity and mortality and HF hospital admissions&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">24</span></a> Moreover&#44; BEI correlated well with other variables of HF severity&#46; Patients with lower BEI were those with increased cardiac volumes &#40;LVESV and LVEDV&#41;&#44; increased BNP and lower functional capacity &#40;peak VO<span class="elsevierStyleInf">2</span>&#41;&#46; BNP and peak VO<span class="elsevierStyleInf">2</span> are two independent prognostic markers in HF&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">28&#44;40</span></a> They are widely used in risk stratification of HF patients&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">40</span></a> with important implications for HF clinical management and treatment&#44; including the utility of peak VO<span class="elsevierStyleInf">2</span> in stratifying patients for cardiac transplantation&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">41</span></a> Besides the importance of baroreflex function as a prognostic marker in HF&#44;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">24</span></a> our results show that it correlates well with other risk stratification variables including BNP and peak VO<span class="elsevierStyleInf">2</span>&#44; supporting the idea that baroreflex function itself may be used in HF risk stratification&#46; We found that BEI during tilt could be used to divide patients into low-risk and high-risk HF groups &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>&#41;&#46; In our study&#44; patients with BEI lower than 25&#37; had more severe HF&#46; We suggest further studies to use this cut-off value for BEI in order to identify patients selected for CRT that have more significant HF risk&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">The importance of the baroreflex in CRT is still not clear as there are few studies on this subject in the literature&#46; However&#44; Braga et al&#46; reported one patient who fully recovered baroreflex function to normal values three months after CRT&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">39</span></a> Moreover&#44; Gademan et al&#46; demonstrated that there was an acute increase in baroreflex sensitivity and HRV after the implantation of a biventricular pacemaker<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">25</span></a> and that this increase was predictive of the response to CRT&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">42</span></a> However&#44; in these studies baroreflex function was assessed only after the implantation of a CRT device&#44;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">25&#44;42</span></a> with biventricular pacing switched on and off&#46; It would be valuable to assess baroreflex function before and after CRT device implantation to better understand the autonomic impact of CRT on cardiovascular function&#46; Moreover&#44; the importance of a predictive index is greater when assessed before implantation&#46; Likewise&#44; there are no studies demonstrating that the increase in baroreflex function is sustained chronically&#44; nor if this increase correlates with cardiac reverse remodeling&#46; Further follow-up studies are necessary to better answer all these questions&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Our methodological approach is based on the sequence method&#44;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">35</span></a> which measures baroreflex function through a non-invasive beat-to-beat measurement of HR and SBP&#46; Although the studies that established the prognostic value of the baroreflex used the classic method for measurement of baroreflex sensitivity &#40;the phenylephrine technique&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">24</span></a> there is significant evidence that non-invasive methods give similar results to those obtained through the phenylephrine technique and obviate the use of vasoactive drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">43&#44;44</span></a> The sequence method is used to calculate BEI&#44; a new baroreflex function index that measures the effectiveness with which the HR responds to SBP variations&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">36&#44;37&#44;45</span></a> BEI is less liable to be influenced by ectopic beats&#44; which were quite frequent in our patients&#44; than baroreflex sensitivity&#46; Recently&#44; the assessment of baroreflex function through non-invasive methods by the use of provocative maneuvers has been extended to different clinical entities including reflex syncope&#44;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">30&#44;37</span></a> atrial fibrillation&#44;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">31</span></a> and HF&#44;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">25</span></a> in which it appears to improve specificity&#46; Our work is the first to use a tilt test in HF patients and the results during the orthostatic period provided more consistent data than during the supine basal period&#44; as BEI during tilt correlated with more HF severity variables&#46; Our approach is innovative in the use of tilt testing in patients with HF and our results show that it is a reproducible&#44; consistent and well-tolerated test&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">The size of our study group &#40;n&#61;25&#41; is the main limitation of this work&#46; Moreover&#44; the control group also presents some limitations&#44; as it was age-matched but not gender-matched&#46; Furthermore&#44; the fact that all patients were under optimal medical treatment may also be considered a limitation to a work that aims to assess basal baroreflex function&#44; as 96&#37; of patients were taking a beta-blocking agent&#46; Nevertheless&#44; La Rovere et al&#46; have recently shown in a prospective study that there are no significant differences in baroreflex sensitivity between HF patients treated with beta-blockers and those that are not&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">46</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Our work shows the importance of baroreflex assessment in risk stratification of HF patients who are candidates for CRT&#46; In the future&#44; prospective studies with at least a six-month post-CRT follow-up are needed in order to demonstrate the existence of autonomic remodeling associated with CRT and to assess whether baroreflex measurements have predictive value concerning response to CRT&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Ethical disclosures</span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Protection of human and animal subjects</span><p id="par0230" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association &#40;Declaration of Helsinki&#41;&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Confidentiality of data</span><p id="par0235" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Right to privacy and informed consent</span><p id="par0240" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article&#46; The corresponding author is in possession of this document&#46;</p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Conflicts of interest</span><p id="par0245" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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                  "titulo" => "Transthoracic echocardiography"
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                  "titulo" => "Orthostatic tilt test and baroreflex function assessment"
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              "titulo" => "Controls"
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              "titulo" => "Baroreflex function"
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              "titulo" => "Association between baroreflex function and other clinical parameters of heart failure severity"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2015-09-01"
    "fechaAceptado" => "2015-11-22"
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          "clase" => "keyword"
          "titulo" => "Keywords"
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          "palabras" => array:3 [
            0 => "Heart failure"
            1 => "Cardiac resynchronization therapy"
            2 => "Arterial baroreflex"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palavras-chave"
          "identificador" => "xpalclavsec679387"
          "palabras" => array:3 [
            0 => "Insufici&#234;ncia card&#237;aca"
            1 => "Ressincroniza&#231;&#227;o card&#237;aca"
            2 => "Reflexo barorrecetor arterial"
          ]
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    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Baroreflex function is an independent marker of prognosis in heart failure &#40;HF&#41;&#46; However&#44; little is known about its relation to response to cardiac resynchronization therapy &#40;CRT&#41;&#46; The aim of this study is to assess arterial baroreflex function in HF patients who are candidates for CRT&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The study population consisted of 25 patients with indication for CRT&#44; aged 65&#177;10 years&#44; NYHA functional class &#8805;III in 52&#37;&#44; QRS width 159&#177;15 ms&#44; left ventricular ejection fraction &#40;LVEF&#41; 29&#177;5&#37;&#44; left ventricular end-systolic volume &#40;LVESV&#41; 150&#177;48 ml&#44; B-type natriuretic peptide &#40;BNP&#41; 357&#177;270 pg&#47;ml&#44; and peak oxygen consumption &#40;peak VO<span class="elsevierStyleInf">2</span>&#41; 18&#46;4&#177;5&#46;0 ml&#47;kg&#47;min&#46; An orthostatic tilt test was performed to assess the baroreflex effectiveness index &#40;BEI&#41; by the sequence method&#46; This group was compared with 15 age-matched healthy individuals&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">HF patients showed a significantly depressed BEI during tilt &#40;31&#177;12&#37; vs&#46; 49&#177;18&#37;&#44; p&#61;0&#46;001&#41;&#46; A lower BEI was associated with higher BNP &#40;p&#61;0&#46;038&#41;&#44; lower peak VO<span class="elsevierStyleInf">2</span> &#40;p&#61;0&#46;048&#41;&#44; and higher LVESV &#40;p&#61;0&#46;031&#41;&#46; By applying a cut-off value of 25&#37; for BEI&#44; two clusters of patients were identified&#58; lower risk cluster &#40;BEI &#62;25&#37;&#41; QRS 153 ms&#44; LVESV 129 ml&#44; BNP 146 pg&#47;ml&#44; peak VO<span class="elsevierStyleInf">2</span> 19&#46;0 ml&#47;kg&#47;min&#59; and higher risk cluster &#40;IEB &#8804;25&#37;&#41; QRS 167 ms&#44; LVESV 189 ml&#44; BNP 590 pg&#47;ml&#44; peak VO<span class="elsevierStyleInf">2</span> 16&#46;2 ml&#47;kg&#47;min&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Candidates for CRT show depressed arterial baroreflex function&#46; Lower BEI was observed in high-risk HF patients&#46; Baroreflex function correlated closely with other clinical HF parameters&#46; Therefore&#44; BEI may improve risk stratification in HF patients undergoing CRT&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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            "titulo" => "Conclusions"
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      "pt" => array:3 [
        "titulo" => "Resumo"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introdu&#231;&#227;o</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">O barorreflexo arterial &#233; comprovadamente um marcador independente de progn&#243;stico na IC&#46; Contudo&#44; pouco se sabe sobre a rela&#231;&#227;o entre a fun&#231;&#227;o do barorreflexo e a resposta &#224; TRC&#46; Assim&#44; o objetivo deste estudo &#233; avaliar a fun&#231;&#227;o barorreflexa em doentes com IC candidatos a TRC&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A popula&#231;&#227;o deste estudo prospetivo consistiu em 25 doentes com 65&#177;10 anos&#44; classe NYHA &#8805;III em 52&#37;&#44; QRS 159&#177;15 ms&#44; fra&#231;&#227;o de eje&#231;&#227;o do ventr&#237;culo esquerdo &#40;FEVE&#41; 29&#177;5&#37;&#44; volume telessist&#243;lico do ventr&#237;culo esquerdo &#40;VTSVE&#41; 150&#177;48 mL&#44; p&#233;ptido natriur&#233;tico tipo-B &#40;BNP&#41; 357&#177;270 pg&#47;ml&#44; consumo m&#225;ximo de oxig&#233;nio &#40;VO2 max&#41; 18&#44;4&#177;5&#44;0 ml&#47;kg&#47;min&#46; Foi implementado um teste de ortostatismo passivo para avaliar o &#237;ndice de efic&#225;cia do barorreflexo &#40;IEB&#41;&#44; atrav&#233;s do m&#233;todo sequencial&#46; O grupo controlo foi constitu&#237;do por 15 indiv&#237;duos saud&#225;veis emparelhados para a idade&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Os doentes com IC apresentaram um IEB significativamente reduzido durante o tilt &#40;31&#177;12&#37; <span class="elsevierStyleItalic">versus</span> 49&#177;18&#37;&#44; p&#61;0&#44;001&#41;&#46; Um IEB diminu&#237;do associou-se a um BNP elevado &#40;p&#61;0&#44;038&#41;&#44; a um VO2 diminu&#237;do &#40;p&#61;0&#44;048&#41; e a um VTSVE aumentado &#40;p&#61;0&#44;031&#41;&#46; Aplicando um <span class="elsevierStyleItalic">cut-off</span> 25&#37; para o IEB&#44; foram identificados dois clusters de doentes&#58; cluster de risco menor risco &#40;IEB&#62;25&#37;&#41; QRS 153 ms&#44; VTSVE 129 mL&#44; BNP 146 pg&#47;mL&#44; VO2 max 19&#44;0 mL&#47;kg&#47;min&#59; cluster de maior risco &#40;IEB&#8804;25&#37;&#41; QRS 167 ms&#44; VTSVE 189 mL&#44; BNP 590 pg&#47;mL&#44; VO2 max 16&#44;2 mL&#47;kg&#47;min&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#245;es</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Doentes candidatos a TRC apresentam barorreflexo deprimido&#46; O BEI diminu&#237;do foi observado nos doentes de maior risco&#46; O barorreflexo correlacionou-se bem com outros par&#226;metros de gravidade de IC&#46; Desta forma&#44; o BEI pode contribuir para a estratifica&#231;&#227;o de risco dos doentes com IC submetidos a TRC&#46;</p></span>"
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      0 => array:3 [
        "identificador" => "nom0005"
        "titulo" => "<span class="elsevierStyleSectionTitle" id="sect0065">List of abbreviations</span>"
        "listaDefinicion" => array:1 [
          0 => array:1 [
            "definicion" => array:19 [
              0 => array:2 [
                "termino" => "ACE"
                "descripcion" => "<p id="par0005" class="elsevierStylePara elsevierViewall">angiotensin-converting enzyme</p>"
              ]
              1 => array:2 [
                "termino" => "ANS"
                "descripcion" => "<p id="par0010" class="elsevierStylePara elsevierViewall">autonomic nervous system</p>"
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              2 => array:2 [
                "termino" => "BEI"
                "descripcion" => "<p id="par0015" class="elsevierStylePara elsevierViewall">baroreflex effectiveness index</p>"
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              3 => array:2 [
                "termino" => "BNP"
                "descripcion" => "<p id="par0020" class="elsevierStylePara elsevierViewall">brain-type natriuretic peptide</p>"
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                "termino" => "BP"
                "descripcion" => "<p id="par0025" class="elsevierStylePara elsevierViewall">blood pressure</p>"
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                "termino" => "CRT"
                "descripcion" => "<p id="par0030" class="elsevierStylePara elsevierViewall">cardiac resynchronization therapy</p>"
              ]
              6 => array:2 [
                "termino" => "HF"
                "descripcion" => "<p id="par0035" class="elsevierStylePara elsevierViewall">heart failure</p>"
              ]
              7 => array:2 [
                "termino" => "HR"
                "descripcion" => "<p id="par0040" class="elsevierStylePara elsevierViewall">heart rate</p>"
              ]
              8 => array:2 [
                "termino" => "HRV"
                "descripcion" => "<p id="par0045" class="elsevierStylePara elsevierViewall">heart rate variability</p>"
              ]
              9 => array:2 [
                "termino" => "LBBB"
                "descripcion" => "<p id="par0050" class="elsevierStylePara elsevierViewall">left bundle branch block</p>"
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                "termino" => "LV"
                "descripcion" => "<p id="par0055" class="elsevierStylePara elsevierViewall">left ventricular</p>"
              ]
              11 => array:2 [
                "termino" => "LVEDV"
                "descripcion" => "<p id="par0060" class="elsevierStylePara elsevierViewall">left ventricular end-diastolic volume</p>"
              ]
              12 => array:2 [
                "termino" => "LVEF"
                "descripcion" => "<p id="par0065" class="elsevierStylePara elsevierViewall">left ventricular ejection fraction</p>"
              ]
              13 => array:2 [
                "termino" => "LVESV"
                "descripcion" => "<p id="par0070" class="elsevierStylePara elsevierViewall">left ventricular end-systolic volume</p>"
              ]
              14 => array:2 [
                "termino" => "NBR"
                "descripcion" => "<p id="par0075" class="elsevierStylePara elsevierViewall">number of baroreflex events per minute</p>"
              ]
              15 => array:2 [
                "termino" => "NYHA"
                "descripcion" => "<p id="par0080" class="elsevierStylePara elsevierViewall">New York Heart Association</p>"
              ]
              16 => array:2 [
                "termino" => "RR"
                "descripcion" => "<p id="par0085" class="elsevierStylePara elsevierViewall">R-R interval on electrocardiogram</p>"
              ]
              17 => array:2 [
                "termino" => "SBP"
                "descripcion" => "<p id="par0090" class="elsevierStylePara elsevierViewall">systolic blood pressure</p>"
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              18 => array:2 [
                "termino" => "VO<span class="elsevierStyleInf">2</span>"
                "descripcion" => "<p id="par0095" class="elsevierStylePara elsevierViewall">oxygen consumption</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Baroreflex function in candidates for cardiac resynchronization therapy &#40;green&#41; compared to healthy controls &#40;blue&#41;&#44; measured by BEI and NBR&#46; Heart failure patients have significant decreased baroreflex function&#46; Statistical significance p&#60;0&#46;05 &#40;Mann-Whitney test&#41;&#46; BEI&#58; baroreflex effectiveness index&#59; NBR&#58; number of baroreflex events per minute&#59; NS&#58; non-significant&#46;</p>"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">A lower BEI was associated with higher BNP values&#44; lower peak oxygen consumption and increased cardiac volumes&#46; Statistical significance p&#60;0&#46;05 &#40;Pearson&#39;s r linear correlation coefficient&#41;&#46; BEI&#58; baroreflex effectiveness index&#59; BNP&#58; brain-type natriuretic peptide&#59; LVESV&#58; left ventricular end-systolic volume&#59; VO<span class="elsevierStyleInf">2</span>&#58; oxygen consumption&#46;</p>"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Applying a cut-off value of 25&#37; for BEI&#44; two HF risk clusters were obtained&#46; In cluster 2 HF patients who present low baroreflex function have wider QRS complexes&#44; higher LVESV and BNP values and reduced functional status as shown by peak VO<span class="elsevierStyleInf">2</span>&#46; This is therefore the patient group with higher HF clinical risk &#40;K-means clustering&#44; variables expressed as means&#41;&#46; BEI&#58; baroreflex effectiveness index&#59; BNP&#58; brain-type natriuretic peptide&#59; HF&#58; heart failure&#59; LVESV&#58; left ventricular end-systolic volume&#59; VO<span class="elsevierStyleInf">2</span>&#58; oxygen consumption&#46;</p>"
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">BNP&#58; brain-type natriuretic peptide&#59; HF&#58; heart failure&#59; LVEDV&#58; left ventricular end-diastolic volume&#59; LVEF&#58; left ventricular ejection fraction&#59; LVESV&#58; left ventricular end-systolic volume&#59; NYHA&#58; New York Heart Association&#59; VO<span class="elsevierStyleInf">2</span>&#58; oxygen consumption&#46;</p>"
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Female</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;20&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Age &#40;years&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">65&#177;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">HF etiology</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ischemic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 &#40;52&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Non-ischemic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 &#40;48&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">NYHA class II&#47;III&#47;IV</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&#47;13&#47;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">QRS duration &#40;ms&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">159&#177;15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">LVEF &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29&#177;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">LVESV &#40;ml&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">150&#177;48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">LVEDV &#40;ml&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">207&#177;60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Peak VO</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">&#40;ml&#47;kg&#47;min&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&#46;4&#177;5&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">BNP &#40;pg&#47;ml&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">357&#177;250&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">ACE&#58; angiotensin-converting enzyme&#59; ARBs&#58; angiotensin receptor blockers&#46;</p>"
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Comorbidities</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">88&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dyslipidemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">80&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Diabetes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">32&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Obesity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Chronic kidney disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Medication</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>ACE inhibitors&#47;ARBs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">96&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Beta-blockers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">96&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Diuretics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">80&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Spironolactone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">52&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Digoxin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Comorbidities and pharmacologic treatment&#46;</p>"
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          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">BEI&#58; baroreflex effectiveness index&#59; BNP&#58; brain-type natriuretic peptide&#59; LVEDV&#58; left ventricular end-diastolic volume&#59; LVEF&#58; left ventricular ejection fraction&#59; LVESV&#58; left ventricular end-systolic volume&#59; MR&#58; mitral regurgitation&#59; NBR&#58; number of baroreflex events per minute&#59; NYHA&#58; New York Heart Association&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Baroreflex function</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">NYHA class&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">QRS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">BNP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Peak VO<span class="elsevierStyleInf">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LVEF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LVESV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">LVEDV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">MR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Basal BEI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pearson&#39;s r&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;177&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;505&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;206&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;022&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;221&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;129&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;111&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;431&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;398&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;033&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;428&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;926&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;428&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;646&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tilt BEI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pearson&#39;s r&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;251&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;287&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;435&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;472&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;195&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;541&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;486&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;248&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;184&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;038&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;048&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;385&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;031&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;056&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;931&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Basal NBR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pearson&#39;s r&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;059&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;071&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;314&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;256&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;193&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;314&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;243&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">-0&#46;162&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;779&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;736&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;191&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;304&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;366&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Correlation between baroreflex function and parameters of heart failure severity&#46;</p>"
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