lure 10 (2008) 298–307www.elsevier.com/locate/ejheart

European Journal of Heart Fai

Long-term outcome in diabetic heart failure patientstreated with cardiac resynchronization therapy

Cecilia Fantoni a,c,d, François Regoli a, Ali Ghanem a, Santi Raffa a, Catherine Klersy e,Antonio Sorgente b, Francesco Faletra b, Massimo Baravelli c,f, Luigi Inglese d,

Jorge A. Salerno-Uriarte c, Helmut U. Klein a,Tiziano Moccetti b, Angelo Auricchio a,b,⁎

a Division of Cardiology, University Hospital, Magdeburg, Germanyb Division of Cardiology, Fondazione Cardiocentro Ticino, Lugano, Switzerlandc Department of Cardiovascular Sciences, University of Insubria, Varese, Italy

d Cardiovascular Interventional Radiology Department, IRCCS Policlinico San Donato, San Donato Milanese, Italye Biometry and Clinical Epidemiology Service, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy

f Division of Cardiology, Multimedica Holdings Castellanza, Varese, Italy

Received 22 July 2007; received in revised form 20 November 2007; accepted 10 January 2008

Abstract

Background: Diabetes mellitus is an independent risk factor for increased morbidity and mortality in heart failure (HF) patients.Aims: To compare functional and structural improvement, as well as long-term outcome, between diabetic and non-diabetic HF patientstreated with cardiac resynchronization therapy (CRT).Methods: We compared response to CRT in 141 diabetic and 214 non-diabetic consecutive patients. Major events were; death from anycause, urgent heart transplantation and implantation of a left ventricular (LV) assist device. Frequencies of hospitalisation and defibrillator(CRT-D) discharges were also analyzed.Results: CRTwas able to significantly improve functional capacity, ventricular geometry and neurohumoral imbalance in both diabetic and non-diabetic patients over a median follow-up time of 34 months. Overall event-free survival was similar in diabetic and non-diabetic patients(HR 1.23, p=0.363), as was survival free from CRT-D interventions (HR 1.72; p=0.115) and hospitalisations (HR 1.12; p=0.500). Onmultivariable analysis, NYHA class IV (p=0.002), low LVejection fraction (p=0.002), absence of beta-blocker therapy (pb0.001), impairedrenal function (p=0.003), presence of an epicardial lead (p=0.025), but not diabetes (p=0.821) were associated with a poor outcome after CRT.Conclusions: Diabetic HF patients treated with CRT had a very favourable functional and survival outcome, which was comparable to non-diabetic patients.© 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Keywords: Cardiac resynchronization therapy; Diabetes mellitus; Heart failure; Outcome

⁎ Corresponding author. Division of Cardiology, Fondazione CardiocentroTicino, Via Tesserete 48, CH-6900 Lugano, Switzerland. Tel.: +41 91 80533 40; fax: +41 91 805 31 67.

E-mail address: angelo.auricchio@cardiocentro.org (A. Auricchio).

1388-9842/$ - see front matter © 2008 European Society of Cardiology. Publishdoi:10.1016/j.ejheart.2008.01.006

1. Introduction

A close relationship between heart failure (HF) anddiabetes mellitus has been largely established [1–3].Diabetes mellitus is a significant independent risk factorfor the development of HF [4,5]; moreover, once HF hasdeveloped, diabetes increases morbidity and mortality [6–8].On the other hand, HF is associated with insulin resistance

ed by Elsevier B.V. All rights reserved.

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[9] and is a risk factor for development of diabetes. Indeed,when glucose abnormalities are systematically assessed,prevalence of diabetes among HF patients is around 40% to45% [10].

Cardiac resynchronization therapy (CRT) improves func-tional capacity, reverses the maladaptive ventricular remo-delling process and reduces morbidity and mortality inselected advanced HF patients refractory to medical therapy[11–13]. Increased myocardial fibrosis [14], metabolic [15]and endothelial dysfunction [16,17], augmented oxidativestress and reduced vagal tone [18] are all diabetes-relatedcardiac and systemic abnormalities. In particular, theongoing deposition of interstitial fibrotic tissue and thechanges in myofibrillar proteins related to diabetes [14]could theoretically limit the magnitude of reverse remodel-ling and possibly reduce the survival benefit provided byCRT. Data on the efficacy of CRT in diabetic patients arelimited. Kies et al. [19] reported similar functional responseto CRT in a small population of 32 diabetic and 65 non-diabetic patients. The prospective randomised controlledCARE-HF trial [13] showed an unchanged combined risk ofdeath and hospitalisations when diabetes was analyzed [20].Notably, long-term functional changes in diabetic HFpatients treated with CRT have been investigated to alimited extent. Similarly long-term data investigating theimpact of CRT on the ventricular remodelling process,neurohumoral imbalance and morbidity, including interven-tions from implantable cardioverter-defibrillators (ICD) indiabetic patients, are entirely missing.

The aim of the present study was twofold: 1) to evaluatethe functional and structural improvement and the long-termoutcome of diabetic HF patients treated with CRT; 2) tocompare these changes with those of patients without ahistory of diabetes.

2. Methods

2.1. Study design

This was an observational, retrospective, longitudinal,single-centre study, conducted in Magdeburg, Germany, overa median follow-up of 34 months (25th–75th percentiles:15–54 months).

2.2. Patients

Three-hundred and fifty-five patients with advanced HF,consecutively implanted with a CRT device at the UniversityHospital of Magdeburg (Germany) between August 1995 andMay 2005 were evaluated. All patients had been hospitalisedfor congestive HF at least once in the year preceding CRTimplantation. At the time of implantation all patients presentedwith NewYork Heart Association (NYHA) functional class IIIor IV despite stable (N3 months) optimized medical therapy,severe left ventricular systolic dysfunction of any aetiology(ejection fraction≤35%, end-diastolic diameter N55 mm) and

ventricular conduction disturbances (QRS-duration≥120ms).Mechanical asynchrony was not routinely evaluated and didnot constitute an inclusion criterion.

Diagnosis of diabetes was based on the patient's historyand medical prescription records. Aetiology was documen-ted by coronary angiography in all patients before implanta-tion. Patients were defined as having an ischemic HFaetiology if they had experienced a previous myocardialinfarction and/or had significant coronary artery disease(N50% stenosis in at least one major epicardial vessel). Renalfunction was evaluated by estimating glomerular filtrationrate from serum creatinine [21]. Renal function impairmentwas defined as a glomerular filtration rate b60 ml/min.

The present study conforms to the principles outlined inthe Declaration of Helsinki. The research protocol wasapproved by the locally appointed ethics committee and allpatients provided oral and written informed consent to deviceimplantation and agreed for data retrieval and analysis.

2.3. Cardiac resynchronization therapy

CRT was delivered using a left ventricular lead implantedeither epicardially or transvenously in the lateral, postero-lateral or antero-lateral region of the left ventricle in addition toa standard right ventricular lead and a right atrial lead. Leftventricular lead position was reviewed by two independentinvestigators (S.R., C.F.) using a previously describedanatomical scheme [22]. Indication for a CRT device withdefibrillator back-up (CRT-D) was in accordance with thecurrently available guidelines for primary and secondarypreventions of sudden cardiac death and relative trials [23–25].

In patients with sinus rhythm, CRT devices wereprogrammed to atrial-synchronous biventricular pacingwith the lower rate limit set at 40 ppm and the upper ratelimit set at 130 ppm. The atrio-ventricular delay wasoptimized by invasive monitoring of pulse pressure or leftventricular first derivate pressure as previously reported [11].In patients with permanent atrial fibrillation, the pacing ratewas set at a value which allowed at least 85% biventricularpacing, also confirmed by device counters, with rateresponse individualized from a short walk test. If rate controlwas not possible, ablation of the atrio-ventricular node wasperformed [26]. Optimization of the inter-ventricular delaywas performed only in CRT-non-responders.

2.4. Follow-up

All patients were routinely evaluated at one, three and sixmonths after CRT implantation, and every six monthsthereafter unless clinical conditions required otherwise.Recent clinical history, including NYHA functional classi-fication, and medications were recorded. Echocardiographicevaluation (Vingmed FiVe/Vivid 5, GE Vingmed UltrasoundAS, Horten, Norway) and symptom-limited cardiopulmon-ary exercise testing were performed before CRT implantationand then twice every year during follow-up. Left ventricular

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diameters were measured by the two-dimensional guided M-mode method; left ventricular ejection fraction was assessedby Simpson's equation using the apical 4-chamber and 2-chamber views.

2.5. Event classification

Information about major cardiac events (death from anycause, implantation of a left ventricular assist device or urgentheart transplantation) and causes of hospitalisations werecollected for all patients. Cause of death was classified usingall available sources of information including hospital recordsor by interviewing relatives and referring physicians. Thecauses of death were classified as HF, sudden cardiac death, orother reasons including non-cardiovascular causes [27].Classification of the cause of death was performed by twoindependent investigators (A.A., C.F.) whowere blinded to thediabetic status of the patient. Hospitalisations for any reasonwere recorded and analyzed. The number and type ofarrhythmias related to CRT-D discharges were also recorded.Arrhythmia classification was performed by two independentinvestigators (S.R., F.R.) who were blinded to the patient'shistory, diabetic status, cause of hospitalisation, or cause ofdeath. Ventricular fibrillation was defined as any ventriculararrhythmia presenting with a ventricular rate of N210 bpm.

2.6. Device-based automatic monitoring

At each follow-up visit, changes in program settings,percentage of biventricular pacing and arrhythmic episodes

Table 1Clinical characteristics of the study population

All patients

Number of patients 355Male (%) 75Age (year) 63±9Body mass index (kg/m2) 26.9±4.3CAD (%) 47NYHA class III/IV 330/25Sinus rhythm (%) 79QRS-duration (ms) 163±27Renal dysfunction (%) 30Peak VO2 (ml/kg/min) 13.5±3.2LVESD (mm) 60±11LV ejection fraction (%) 21.2±6.2PAPs (mmHg) 42±16Medications

ACE-I/ARB 98Beta-blockers 89Aldost-Antag (%) 32Digitalis 61Amiodarone 20

CRT-D (%) 52Epicardial lead (%) 42

p values refer to comparison between diabetic and non-diabetic patients.ACE-I: ACE-Inhibitors; Aldost-Antag: aldosterone-antagonists; ARB: angioteresynchronization therapy device with defibrillator back-up; LVESD: left ventricuclass; PAPs: pulmonary artery systolic pressure; peak VO2: oxygen consumption

were recorded. About half of the patients received a CRTdevice (Renewal I, II and IV or Contak TR2, Guidant, St.Paul, MN, USA) capable of continuous, automatic monitor-ing of heart rate profile, heart rate variability (HRV), anddaily spontaneous physical activity. HRV was assumed bythe devices as the standard deviation of the averages ofintrinsic intervals in the 288 5-minute segments of a day(SDANN) as previously reported. Physical activity wasquantified by measurement of Activity-log Index that isdefined as the percentage of time during which theacceleration exceeds a pre-set fixed threshold at 50 mG(0.49 m/s2); this threshold corresponds to a treadmill walkspeed of about 2.0 mph, equivalent to 2.8 METS. At eachfollow-up, stored data on heart rate profile, SDANN, andphysical activity were collected and saved onto disks forfurther off-line analysis. For device-monitored parameters,the mean value of the first week after implantation wasconsidered as the baseline.

2.7. Statistical analysis

Data are described as mean and standard deviation (SD) ifcontinuous, and count and percentage if categorical. Medianfollow-up and 25th–75th percentiles were computed accord-ing to the inverse Kaplan Meier method. Baseline character-istics were compared between patients with and withoutdiabetes using the Student t test or the Fisher exact forcontinuous or categorical data, respectively. Differences inchanges over time (up to 36 months) between the two groupsof patients were assessed by testing for the interaction of

Diabetic patients Non-diabetic patients p value

141 (40%) 214 (60%)76 74 0.80364±7 62±10 0.07927.8±4.3 26.3±4.1 0.00351 44 0.233128/13 202/12 0.20873 83 0.034162±28 163±27 0.83941 23 b0.00113.2±3.1 13.7±3.2 0.25262±10 59±11 0.04721.6±6.1 21.0±6.3 0.33745±18 39±15 0.009

99 97 0.48686 91 0.17233 31 0.64367 57 0.09520 20 1.00054 50 0.51543 42 1.000

nsin-receptor blockers; CAD: coronary artery disease; CRT-D: cardiaclar end-systolic diameter; NYHA: New York Heart Association functionalat peak exercise.

Fig. 1. Functional and structural changes after CRT. Changes in leftventricular ejection fraction (a, LVEF), left ventricular end-systolic diameter(b, LVESD), and peak oxygen consumption (c, pVO2) over the follow-up indiabetic and non-diabetic patients. Bars represent standard errors.

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diabetes and time in a mixed linear model (with unstructuredcorrelation). Survival and event-free survival were describedby means of the Kaplan Meier method. The observation timestarted on implantation of the CRT device and ended at theoccurrence of the event or the last observation date forcensored patients. Rates of events per 100 persons per yearwere computed together with their 95% confidence interval(95%CI). Cox regression was used to assess the prognosticrole of diabetes, while controlling for a series of potentialconfounders. The presence of multicollinearity was assessedand excluded. The proportional hazard assumption wastested based on Schoenfeld residuals. Hazard ratios (HR) andtheir 95%CI were reported. The Harrell's c statistic and theshrinkage coefficient were computed for model validation.The number of hospitalisations and of CRT-D interventionsover the observation time was compared between groupswith the negative binomial regression. Incidence rate ratios(IRR) and 95%CI were reported.

Stata 9.2 (StataCorp, USA) was used for computation. A 2-sided p valueb0.05 was considered statistically significant.

3. Results

Clinical and demographic characteristics of the diabeticand non-diabetic patients are presented in Table 1. Most ofthe patients were males presenting with idiopathic dilatedcardiomyopathy and sinus rhythm. The majority of patientsreceived a transvenous lead and a CRT-D device. Indicationfor a CRT-D device was a history of ventricular arrhythmias(29%) or primary prevention of sudden cardiac death (71%).About 48% (58 diabetic and 112 non-diabetic) of patientsreceived a CRT device capable of continuous, automaticmonitoring of heart rate profile, HRV and daily spontaneousphysical activity. These patients did not differ in anycharacteristics from the rest of the population. Nearly allpatients were on angiotensin-converting-enzyme inhibitorsor angiotensin-receptor blockers, and beta-blocker treatmentwith no significant differences between the two groups. Attime of implantation, 57 patients had diabetes which waswell controlled by insulin therapy; in the remaining 84 casesdiet and oral hypoglycaemic drugs were prescribed.

As shown in Table 1, diabetic patients had significantlyhigher body mass index, higher prevalence of permanentatrial fibrillation and renal dysfunction compared to non-diabetic patients. Moreover diabetic patients presented with asignificantly larger left ventricular end-systolic diameter anda higher pulmonary artery systolic pressure.

Prevalence of a defibrillator back-up, prevalence ofepicardial leads, as well as position of left ventricular leadswas not significantly different between the two groups.

3.1. Clinical and functional improvements

Functional NYHA class changed significantly after CRTimplantation; more than 85% of patients improved at least 1NYHA class after CRT. A similar proportion of diabetic and

non-diabetic patients improved their functional status, andthe change over time was not significantly different betweenthe two groups (p=0.623).

Left ventricular ejection fraction (Fig. 1) increasedsignificantly in the first 12 months after CRT in bothdiabetic (pb0.001) and non-diabetic (pb0.001) patients,while no further significant increase occurred in either groupin the following two years. LVEF scores showed greaterimprovement over time in non-diabetic patients than indiabetics (p=0.046).

Fig. 2. Device-based automatic monitoring. Changes in automatic device-based monitoring of mean heart rate (a), SDANN (b), and Activity-log Index(c) induced by CRT during follow-up in diabetic and non-diabetic patients.Bars represent standard errors.

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There was a large reduction in volume of the left ventricle atone year follow-up, which stabilized over the following twoyears (Fig. 1). Both left ventricular end-systolic and end-diastolic diameters significantly decreased in the first12 months in diabetic (pb0.001) and non-diabetic (pb0.001)patients. No significant difference was observed between thetwo groups in the change over time in left ventricular end-systolic (p=0.848) and end-diastolic diameter (p=0.417),respectively.

The magnitude of the reduction in mitral regurgitationpeaked at 6 months in both diabetic (pb0.001) and non-diabetic (pb0.001) patients, and remained unchanged overthe remaining follow-up time in both groups. No difference(p=0.422) in the change over time was observed between thetwo groups.

There was a significant increase in peak oxygenconsumption measured at cardiopulmonary testing over thefollow-up. Peak oxygen consumption improved significantlyin the first year of follow-up in both diabetic and non-diabetic patients (pb0.001 for both), remaining stable overthe following two years in both groups (Fig. 1). Over time,non-diabetic patients increased peak oxygen consumptionsignificantly more than diabetic patients (p=0.025).

3.2. Continuous device-based monitoring

Retrieval of device-based automatic measurements ofmean heart rate, HRV and Activity-log Index (a surrogate ofphysical activity) was possible in all patients.

There was a continuous reduction in mean heart rate overtime after CRT implantation. Baseline mean heart rate didnot differ between the two groups (p=0.377) and decreasedsimilarly during follow-up (Fig. 2), being significantlydifferent (pb0.001 for both groups) at three years afterCRT implantation compared to baseline. Changes over timewere not significantly different between diabetic and non-diabetic patients (p=0.834).

Baseline device-assessed SDANN was as low as 71±23 ms, with no significant difference between the two groups(p=0.655). SDANN significantly increased (pb0.001 for bothgroups) over time, peaking (104±30 ms) at one year and thenremaining stable up to three years after CRT (Fig. 2). HRV hada similar time pattern in diabetic and non-diabetic patients(p=0.298).

Device-measured level of physical activity was low in thefirst week after CRT implantation (3.9±2.3 units), and wassimilar in the two groups (p=0.931). After CRT a continuousincrease (pb0.001 for both) was observed during the first threemonths, then Activity-log Index values stabilized in a plateauphase (Fig. 2). Changes in physical activity over time were notdifferent between diabetic and non-diabetic patients (p=0.586).

3.3. Mortality

Median follow-up time was 35 months (25th–75thpercentiles: 14–58months) in diabetic patients and 34months

(25th–75th percentiles: 16–50 months) in non-diabetic ones.A total of 79 (22%) patients died with a similar proportion indiabetic (37 patients, 26%) and non-diabetic patients (42patients, 20%; p=0.153). The most common cause of deathwas worsening HF (39 patients), followed by sudden cardiacdeath (19 patients) and other reasons (17 patients); in fourcases, it was not possible to classify the cause of death. Modeof death was equally distributed between diabetic and non-diabetic patients.

The 2- and 5-year survival rates were 87% (95%CI: 81–92%) and 63% (95%CI: 51–73%) for non-diabetic patients,

Fig. 3. Long-term outcome after CRT. Kaplan Meier curves representing theevent-free survival (a), survival free from appropriate interventions from ICDdevices (b) and survival free fromhospitalisation (c) in diabetic (dotted line) andnon-diabetic patients (continuous lines). LVAD: left ventricular assist device;HTX: heart transplantation. Subjects at risk at selected times are reported.

Table 2Multivariable analysis for the combined end-point death, urgent hearttransplantation and implantation of a left ventricular assist device after CRT

Hazard ratio 95% Confidence interval p value

Diabetes 0.95 0.59–1.52 0.821Gender 1.38 0.71–2.68 0.338Age 0.98 0.95–1.01 0.200Aetiology 1.51 0.87–2.63 0.143NYHA IV 3.22 1.56–6.65 0.002LV ejection fraction 0.93 0.89–0.97 0.002Rhythm 1.62 0.96–2.75 0.070QRS-duration 1.00 0.99–1.01 0.517Renal dysfunction 2.08 1.29–3.35 0.003Beta-blockers 0.29 0.16–0.52 b0.001Epicardial lead 1.74 1.07–2.84 0.025CRT-D 0.77 0.46–1.32 0.346

CRT-D: cardiac resynchronization therapy device with defibrillator back-up;LV: left ventricular; NYHA: New York Heart Association functional class.Model validation: Harrell's C=0.75; shrinkage coefficient=0.79.

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respectively. These survival rates were comparable to thoseobserved in diabetic patients: 85% (95%CI: 77–91%) at2 years, and 54% (95%CI: 40–66%) at 5 years (Fig. 3).

Overall event-free survival was similar in diabetic and non-diabetic patients (HR 1.23, 95%CI: 0.79–1.92; p=0.363).There was no difference in survival after CRT between thetwo groups when considering ischaemic (HR 1.22, 95%CI:0.65–2.29; p=0.536) and non-ischaemic (HR 1.19, 95%CI:0.63–2.25; p=0.587) patients separately. Finally, event-freesurvival after CRT was not different between insulin- andnon-insulin-dependent diabetic patients (HR 0.63, 95%CI:0.32-1.26; p=0.273). Multivariable analysis showed thatNYHA functional class IV (p=0.002), a lower leftventricular ejection fraction (p=0.002), absence of beta-blocker therapy (pb0.001), impaired renal function(p=0.003), implantation of an epicardial lead (p=0.025),but not diabetes (p=0.821) were all associated with a pooroutcome after CRT (Table 2).

The mean number of appropriate ICD interventions perpatient per year was slightly, but not significantly, differentin diabetic (0.12, 95%CI: 0.09–0.17) versus non-diabetic(0.06, 95%CI: 0.04–0.09) patients (IRR 2.23, 95%CI: 0.89–5.61; p=0.087). The ICD intervention-free survival (Fig. 3)was not significantly different between the two groups (HR1.72, 95%CI: 0.88–3.38; p=0.115).

On multivariable analysis (Table 3), diabetes mellitus wasassociated with neither an increased risk of HF death (HR0.89, 95%CI: 0.33–2.34; p=0.806) nor sudden death (HR1.03, 95%CI: 0.19–5.51; p=0.972), nor an increasedincidence of appropriate ICD interventions (HR 1.45, 95%CI: 0.58–3.63; p=0.423), even when adjusting for con-founding variables (Table 3).

3.4. Morbidity

Mean number of all-cause hospitalisations per patient peryear was similar in diabetic (0.42, 95%CI: 0.36–0.50) andnon-diabetic patients (0.30, 95%CI: 0.25–0.35) with an IRRof 1.46 (95%CI: 0.99–2.15; p=0.053). The hospitalisation-free survival (Fig. 3) did not differ between the two groups(HR 1.12, 95%CI: 0.80–1.57; p=0.500). On multivariable

Table 3Multivariable analysis: impact of diabetes on different end-points

Rate 100 persons/year in diabetic (95%CI) Rate 100 persons/year in non-diabetic (95%CI) HRa (95%CI) p value

Death from any cause 10.3 (7.5–14.2) 8.1 (6.0–11.0) 0.88 (0.46–1.69) 0.710Cardiovascular death 7.8 (5.4–11.3) 5.8 (4.1–8.3) 0.85 (0.38–1.87) 0.679Heart failure death 5.0 (3.2–8.0) 4.1 (2.6–6.2) 0.89 (0.33–2.34) 0.806Sudden death 2.8 (1.5–5.2) 1.7 (0.9–3.3) 1.03 (0.19–5.51) 0.972Time to first CRT-D intervention 5.9 (3.7–9.2) 3.3 (2.0–5.4) 1.45 (0.58–3.63) 0.423Time to first hospitalisation 25.3 (19.6–32.6) 22.6 (18.2–28.1) 0.97 (0.63–1.50) 0.897

CI: Confidence interval; CRT-D: cardiac resynchronization therapy device with defibrillator back-up; HR: hazard ratio compares diabetic and non-diabeticpatients.a Hazard Ratio and 95% Confidence Interval adjusted for confounding variables (see Table 2).

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analysis after adjusting for other known risk factors(Table 3), diabetes mellitus was not associated with anincreased risk of hospitalisations (HR 0.97, 95%CI: 0.63–1.50; p=0.897).

4. Discussion

The impact of diabetes in advanced HF patients treatedwith CRT was first addressed in a small study by Kies et al.[19] and more recently in the randomised controlled CARE-HF [20] trial, which showed a similar incidence of thecombined end-point of death and unplanned hospitalisationsfor cardiac reasons between diabetic and non-diabeticpatients treated with CRT. Our study, although observational,retrospective and smaller than CARE-HF, adds some newdata about the efficacy of CRT in patients with advanced HFand diabetes mellitus. In particular, functional capacity,reverse remodelling, neurohumoral modulation and ICD-discharges after CRT have been analysed. All of the positiveeffects induced by CRT in diabetic as well as in non-diabeticpatients were sustained over a long period of time.Furthermore, morbidity and survival were as low amongdiabetics as in the non-diabetic population.

4.1. Heart failure and diabetes

Diabetes mellitus is a well known independent risk factorfor development of HF [4,5]. On the other hand, HF isstrongly associated with insulin resistance [9] and representsa risk factor for development of diabetes. It has beendemonstrated that prevalence and severity of insulinresistance are directly related to HF severity [10,28]. Thus,prevalence of diabetes in NYHA functional class IV was36% in the Beta-Blocker Evaluation of Survival Trial(BEST) [29], and 44% in the Acute Decompensated HeartFailure National Registry (ADHERE) [30]. Consistent withthese data, about 40% of our advanced HF patients referredfor and treated with CRT had diabetes mellitus. In goodagreement with previous reports [31,32], our diabeticpatients were sicker than non-diabetic ones and presentedwith a significantly higher prevalence of permanent atrialfibrillation and renal function impairment, larger leftventricles, as well as higher pulmonary artery systolic

pressure. These pathophysiological findings may be relatedto interstitial fibrotic tissue and alterations in myofibrillarproteins, which are frequently observed in diabetic patients.These cardiac abnormalities together with other majorsystemic changes induced by diabetes mellitus maytheoretically impact on the efficacy of CRT.

4.2. Functional and structural improvement after CRT

Diabetes-induced myocardial, neural and systemic struc-tural changes are considered to be responsible for the lowerfunctional capacity of diabetic patients even with optimizedHF therapy [10]. Encouraging physical activity in diabeticpatients is particularly desirable [33] as it reduces insulinresistance [34], favours glucose uptake and utilization bymuscles [35], modulates hormonal and neurohumoralactivity and eventually increases functional capacity.Because CRT improves functional capacity and quality-of-life in HF patients by a variety of mechanisms, includingimproved haemodynamic status, reduced sympathetic driveand neurohumoral hyperactivation; CRT prescribed todiabetic patients may help to counteract the sedentarylifestyle of such patients, and by doing so may interruptthe vicious cycle of “reduced functional capacity – notfeeling well.”

In our non-diabetic population, CRT significantlyimproved functional class and peak oxygen consumptionand also promoted ventricular reverse remodelling as havebeen reported in large clinical controlled trials [12,13].Similar significant changes were observed in our diabeticpatients, confirming that cardiac and systemic improvementselicited by CRT also occur in patients with more severeabnormalities. Indeed CRT-induced improvements ofNYHA functional class, daily spontaneous physical activity(evaluated by automatic monitoring of Activity-log Indexfrom last-generation devices), left ventricular end-systo/diastolic diameters of diabetic patients were comparable tonon-diabetic patients. The trend towards lower baseline peakoxygen consumption and larger ventricular dimensions indiabetic versus non-diabetic patients indirectly confirms thegreater severity of illness in the diabetic group. Consistentwith these data, overall changes over time of left ventricularejection fraction and of oxygen consumption at peak were

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significantly greater in non-diabetic compared to diabeticpatients, suggesting a probable better improvement offunctional capacity after CRT in the non-diabetic population.

Our findings confirm and expand on the data by Kies et al.[19] with less diabetic HF patients, and from the CARE-HFstudy [20] collected over a comparable period of time. Puttingthese results into the context of other therapies, it is of interestto note that treatment with carvedilol in a population ofdiabetic HF patients similar to ours improved functionalcapacity and induced ventricular structural changes of similarmagnitude to those observed in our diabetic HF patients overa comparable follow-up time [31,32]. This further suggeststhat CRT may help restore responsiveness to pharmacologi-cal therapy, underscoring the potential value of a synergisticdevice-plus-drugs approach.

4.3. CRT-induced autonomic changes

Automatic device-based evaluation of heart rate and HRVis feasible and reliable [22,36]. Mean heart rate values closeto the upper range of normal and HRV below 100 ms arecharacteristics of the sympathetic/parasympathetic derange-ments in HF patients, and have been well documented inpatients undergoing CRT [22,36]. HF patients treated withCRT typically have a continuous reduction in mean andminimum heart rate, which is associated with an increase inHRV [22]. Diabetes mellitus is known to be associated early-on with reduced vagal tone and altered sympathetic/parasympathetic balance, as documented by reduced HRV[37]. Although in our study diabetic patients had a morecompromised functional status and a greater degree ofcardiac dilatation than non-diabetic patients, both showedsimilar baseline reductions in HRV.

It has been reported that angiotensin-converting enzymeinhibitors [38] and beta-blocking agents [31] may increaseHRVand reduce heart rate, even in diabetic patients. Similarly,our diabetic HF patients treated with CRTshowed a significantreduction in mean heart rate and an increase in HRV, both anexpression of reduced sympathetic drive to the heart. Themean increase in HRV at six months was comparable to thatobserved by Adamson et al. [36], suggesting the possibility ofa significantly improved prognosis for diabetic patients. Theincrease in HRV and the reduction in mean heart rate indiabetic patients, which occurred to a similar extent as in non-diabetic patients, were surprising, because diabetic patientshave a more diseased autonomic tone, therefore a lesspronounced response to CRT would be expected. We haverecently suggested [22] that CRT may improve the autonomicimbalance that characterizes HF by modulating sensory inputsfrom cardiac receptors to the central nervous system by avariety of mechanisms, including improved coordination ofseptal and lateral wall contraction, reduction of mitralregurgitation, improved filling mechanics and prolongedfilling time, and reduced myocardial oxygen demand. There-fore, a possible explanation for the increase of HRV in diabeticpatients may be the fact that the sensory inputs from cardiac

receptors to the central nervous system are less compromisedthan expected.

All together, this evidence seems to show that diabeticpatients, despite their more compromised status and theadditional burden conferred by diabetic cardiomyopathy, stillretain a functional reserve which remains responsive to bothpharmacological and non-pharmacological interventions.For these reasons, diabetic patients probably deserve greaterconsideration in CRT evaluation and screening.

4.4. Long-term outcome after CRT

Diabetes mellitus is a well known independent risk factorfor increased morbidity and mortality in HF patients,especially in those patients with ischaemic cardiomyopathy[6–8]. Drugs targeting neurohumoral activation, such asangiotensin-converting enzyme inhibitors, angiotensin-receptor blockers and beta-blockers, have significantlyimproved the prognosis of HF patients [29,39,40], beingsimilarly effective in both diabetic and non-diabetic patients[31,32,41,42].

In our cohort of advanced HF patients treated with CRTplus state-of-the-art medical therapy, the long-term event-free(death from any cause, implantation of a left ventricular assistdevice and urgent heart transplantation) survival rate wasquite favourable and comparable to that observed in largerandomised controlled trials [13] and in an observationallarge registry [43]. Notably, diabetes mellitus was notassociated with an increased risk of total death, HF andsudden death, nor was it associated with an increasedincidence of CRT-D interventions and hospitalisations.These surprising results are probably related to the similarmagnitude of reverse remodelling and neurohumoral mod-ulation induced by CRT in both groups of patients. Moreover,these data confirm previous reports about the prognosticimprovement induced by drugs targeting neurohumoralhyperactivation in diabetic HF patients [31,32,41,42], andwith data from the CARE-HF [20] study reporting a similarreduction of the combined end-point mortality and hospita-lisations in diabetic and non-diabetic patients treated withCRT. In particular, our univariable estimate of the HR forevent-free survival (HR 1.23, 95%CI: 0.79–1.92; p=0.363)is similar with a slightly larger 95% CI to that reported byHoppe et al. [20] in CARE-HF (HR 1.30, 95%CI: 0.99–1.70;p=0.06), indicating a small but non significant increase inrisk in diabetic patients.

It may be speculated that HF is the strongest outcomedeterminant in diabetic CRT candidates and that improvinghaemodynamic status and heart geometry, through bothpharmacological and non-pharmacological interventions, isthe key to improving the prognosis of these patients. Indeed,multivariable analysis shows that markers for advanced HF,such as NYHA functional class IV, low LVEF, presence ofrenal function impairment, and absence of beta-blockertherapy, were associated with a poorer outcome after CRT,but diabetes was not. It has to be pointed out that there was a

306 C. Fantoni et al. / European Journal of Heart Failure 10 (2008) 298–307

smaller increase in LVEF and peak oxygen consumptionover time following CRT implantation, in diabetic comparedto non-diabetic patients. These findings are not contra-dictory, since patients who are evaluated for their functionare survivors, and as such are probably in better clinicalcondition. Nevertheless, it is possible that over a longerfollow-up a somewhat different outcome between the twogroups could be appreciated.

The presence of an epicardial lead was also associatedwith a poor outcome after CRT. Most of our epicardial leadswere implanted in the early years of our CRT programme(1995–1998) when the importance of LV lead position hadnot been ascertained. Most of the leads were placed in anantero-lateral position compared to the most commonpostero-lateral position of the transvenous leads. In ouropinion, this difference is able to explain the results of ourmultivariable analysis.

Moreover, despite evidence that diabetes mellitus is astronger negative prognostic factor in ischaemic patientscompared to the non-ischaemic ones [8,31,44], the outcome inour diabetic patients treated with CRT was not related toaetiology. Mortality in diabetic patients with ischaemiccardiomyopathy is almost entirely due to HF deaths [31,44].This observation fits well with recent data from a registry study[43], which showed that HF was the predominant mode ofdeath inCRTpatients. However, in terms of absolutemortality,death from HF was lower than reported in other pharmaco-logical trials which included similar groups of patients[39,42].

Finally, in our population the outcome after CRT was notrelated to insulin therapy, a well known negative prognosticparameter in diabetic patients [7]. Lower power and smallersample size may explain some differences in outcomebetween insulin- and non-insulin-dependent CRT patientsnoted in our study compared to the most recent CARE-HFresults [20]. Alternatively, our findings could be explainedby the fact that in such advanced HF patients, metabolicstatus and severity of diabetic disease have less importantprognostic power compared to the clinical and haemody-namic status related to HF.

5. Limitations

This study has several limitations. Retrospective analysisand the lack of a control group of HF patients not treated withCRT may be considered significant limitations. This is,however, mitigated by the fact that the outcome in non-diabetic patients was comparable to that reported in largecontrolled randomised trials and in an observational registry.Moreover, due to the limited number of events, our studymay not have enough power to prove similarity of responseto CRT between diabetic and non-diabetic patients.

Few patients (less than 15%) experienced a modificationin beta-blocker therapy after CRT implantation that couldhave represented a confounding effect. Diagnosis of diabeteswas only made on the basis of patient's history and therapy.

Mean duration of diabetes was not available and there was noattempt to evaluate glucose tolerance, insulin resistance orglycosylated haemoglobin levels. Together these deficien-cies could have limited the accuracy of our analysis.Furthermore, no direct tests to assess neurohumoral functionand diabetic autonomic neuropathy were performed. Finally,one might speculate from our study that the systemic andhaemodynamic improvements in diabetic CRT patientsmight permit better diabetic control, and could possiblyreduce systemic insulin requirements for maintainingadequate glucose levels; however, this could not beaddressed in our study and remains to be determined.

6. Conclusions

In our group of advanced HF patients, CRT significantlyimproved functional capacity, promoted reversal of themaladaptive remodelling process, and reduced the sympatheticdrive to the heart in both diabetic and non-diabetic patients,over a long period of time. Consistently, morbidity andmortality were comparable between diabetic and non-diabeticCRTpatients. Further evidence to support or refute the negativeprognostic role of diabetes in CRT patients is now required.

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