Saverio Iacopino

Prognostic significance of endothelial dysfunction in hypertensive patients.

Background—Forearm endothelial dysfunction, characterized by an impaired vasodilating response to acetylcholine (ACh), may be associated with several cardiovascular risk factors, including essential hypertension. Although the prognostic value of coronary endothelial dysfunction has been demonstrated, that of forearm endothelial dysfunction is still unknown. Methods and Results—Endothelium-dependent and -independent vasodilation was investigated in 225 never-treated hypertensive patients (age, 35 to 54 years) by intra-arterial infusion of increasing doses of ACh and sodium nitroprusside. Patients were divided into tertiles on the basis of their increase in ACh-stimulated forearm blood flow (FBF) from basal: group 1, from 30% to 184%; group 2, from 185% to 333%; and group 3, from 339% to 760% increase from basal. During a mean follow-up of 31.5 of months (range, 4 to 84 months), there were 29 major adverse events at the cardiac (n=19), cerebrovascular (n=9), or peripheral vascular (n=1) level. Events included myocardial infarction, angina, coronary revascularization procedures, stroke, transient cerebral ischemic attack, and aortoiliac occlusive disease. Event rate per 100 patient-years was 8.17, 4.34, and 2.02 in the first, second, and third tertiles of peak percent increase in FBF during ACh infusion. The excess risk associated with an FBF increase in the first tertile was significant (relative risk, 2.084; 95% CI, 1.25 to 3.48;P =0.0049) after controlling for individual risk markers, including 24-hour ambulatory blood pressure. Conclusions—Our data suggest that forearm endothelial dysfunction is a marker of future cardiovascular events in patients with essential hypertension.

Monitoring Intrathoracic Impedance with an Implantable Defibrillator Reduces Hospitalizations in Patients with Heart Failure

Purpose: Some implantable cardioverter‐defibrillators (ICDs) are now able to monitor intrathoracic impedance. The aim of the study was to describe the use of such monitoring in clinical practice and to evaluate the clinical impact of the fluid accumulation alert feature of these ICDs.

Long-Term Complications Related to Biventricular Defibrillator Implantation Rate of Surgical Revisions and Impact on Survival: Insights From the Italian ClinicalService Database

Background— Long-term data on device-related untoward events in patients receiving defibrillators for resynchronization therapy (CRT-D) are lacking. We quantified the frequency of repeat invasive procedures and the nature of long-term complications in current clinical practice and examined possible predictors of device-related events and their association with long-term patient outcome. Methods and Results— We analyzed data from 3253 patients who underwent de novo successful implantation of CRT-D and were followed up for a median of 18 months (25th to 75th percentiles: 9 to 30) in 117 Italian centers. Device-related events were reported in 416 patients, and, specifically, surgical interventions for system revision were described in 390 patients. Four years after the implantation procedure, 50% of patients underwent surgical revision for battery depletion and 14% for unanticipated events. For comparison, at 4 years battery depletion occurred in 10% and 13% of patients who received single- and dual-chamber defibrillators at the study centers, and unanticipated events were reported as 4% and 9%, respectively. In CRT-D, infections occurred at a rate of 1.0%/y, and the risk of infections increased after device replacement procedures (hazard ratio, 2.04; 95% confidence interval, 1.01 to 4.09; P =0.045). Left ventricular lead dislodgements were reported at a rate of 2.3%/y and were predicted by longer fluoroscopy time and higher pacing threshold on implantation. Device-related events were not associated with a worse clinical outcome; indeed, the risk of death was similar in patients with and without surgical revision (hazard ratio, 0.90; 95% confidence interval, 0.56 to 1.47; P =0.682). Conclusions— In current clinical practice device-related events are more frequent in CRT-D than in single- or dual-chamber defibrillators, and are frequently managed by surgical intervention for system revision. However, a worse clinical outcome is not associated with these events. Clinical Trial Registration— URL: . Unique identifier: [NCT01007474][1]. # Clinical Perspective {#article-title-32} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01007474&atom=%2Fcirculationaha%2F123%2F22%2F2526.atomBackground— Long-term data on device-related untoward events in patients receiving defibrillators for resynchronization therapy (CRT-D) are lacking. We quantified the frequency of repeat invasive procedures and the nature of long-term complications in current clinical practice and examined possible predictors of device-related events and their association with long-term patient outcome. Methods and Results— We analyzed data from 3253 patients who underwent de novo successful implantation of CRT-D and were followed up for a median of 18 months (25th to 75th percentiles: 9 to 30) in 117 Italian centers. Device-related events were reported in 416 patients, and, specifically, surgical interventions for system revision were described in 390 patients. Four years after the implantation procedure, 50% of patients underwent surgical revision for battery depletion and 14% for unanticipated events. For comparison, at 4 years battery depletion occurred in 10% and 13% of patients who received single- and dual-chamber defibrillators at the study centers, and unanticipated events were reported as 4% and 9%, respectively. In CRT-D, infections occurred at a rate of 1.0%/y, and the risk of infections increased after device replacement procedures (hazard ratio, 2.04; 95% confidence interval, 1.01 to 4.09; P=0.045). Left ventricular lead dislodgements were reported at a rate of 2.3%/y and were predicted by longer fluoroscopy time and higher pacing threshold on implantation. Device-related events were not associated with a worse clinical outcome; indeed, the risk of death was similar in patients with and without surgical revision (hazard ratio, 0.90; 95% confidence interval, 0.56 to 1.47; P=0.682). Conclusions— In current clinical practice device-related events are more frequent in CRT-D than in single- or dual-chamber defibrillators, and are frequently managed by surgical intervention for system revision. However, a worse clinical outcome is not associated with these events. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01007474.

The MOnitoring Resynchronization dEvices and CARdiac patiEnts (MORE-CARE) Randomized Controlled Trial: Phase 1 Results on Dynamics of Early Intervention With Remote Monitoring

Background Remote monitoring (RM) in patients with advanced heart failure and cardiac resynchronization therapy defibrillators (CRT-D) may reduce delays in clinical decisions by transmitting automatic alerts. However, this strategy has never been tested specifically in this patient population, with alerts for lung fluid overload, and in a European setting. Objective The main objective of Phase 1 (presented here) is to evaluate if RM strategy is able to reduce time from device-detected events to clinical decisions. Methods In this multicenter randomized controlled trial, patients with moderate to severe heart failure implanted with CRT-D devices were randomized to a Remote group (with remote follow-up and wireless automatic alerts) or to a Control group (with standard follow-up without alerts). The primary endpoint of Phase 1 was the delay between an alert event and clinical decisions related to the event in the first 154 enrolled patients followed for 1 year. Results The median delay from device-detected events to clinical decisions was considerably shorter in the Remote group compared to the Control group: 2 (25th-75th percentile, 1-4) days vs 29 (25th-75th percentile, 3-51) days respectively, P=.004. In-hospital visits were reduced in the Remote group (2.0 visits/patient/year vs 3.2 visits/patient/year in the Control group, 37.5% relative reduction, P<.001). Automatic alerts were successfully transmitted in 93% of events occurring outside the hospital in the Remote group. The annual rate of all-cause hospitalizations per patient did not differ between the two groups (P=.65). Conclusions RM in CRT-D patients with advanced heart failure allows physicians to promptly react to clinically relevant automatic alerts and significantly reduces the burden of in-hospital visits. Trial Registration Clinicaltrials.gov NCT00885677; http://clinicaltrials.gov/show/NCT00885677 (Archived by WebCite at http://www.webcitation.org/6IkcCJ7NF).

Calcium antagonist isradipine improves abnormal endothelium-dependent vasodilation in never treated hypertensive patients

OBJECTIVE To examine whether middle (two months) and long-term (six months) isradipine sustained-release treatment improves endothelium-dependent vasodilation in never treated hypertensive patients. METHODS The responses of the forearm vasculature to acetylcholine (7.5, 15 and 30 micrograms/min) and sodium nitroprusside (0.8, 1.6, 3.2 micrograms/min) were evaluated in 12 normotensive controls (seven men and five women, aged 25 to 49 years), and in 12 hypertensives (eight men and four women, aged 20 to 47 years) at baseline and after two and six months of isradipine sustained-release treatment. Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. RESULTS At baseline, the response to acetylcholine was significantly lower in hypertensives vs controls: at the highest dose (30 micrograms/min), forearm blood flow was 28.6 +/- 2.4 ml/100 ml of tissue per min in the controls vs 8.9 +/- 1.0 ml/100 ml of tissue per min in hypertensive (p < 0.0001). Similarly, vascular resistance was significantly (p < 0.0001) higher in hypertensives: 4.8 +/- 0.5 units (controls) vs 15.1 +/- 1.7 units (hypertensives). After isradipine treatment, the forearm blood flow in hypertensive patients changed from 8.9 +/- 1.0 ml/100 ml of tissue per min to 16.0 +/- 1.2 ml/100 ml of tissue per min (two months; p < 0.0001) and 15.2 +/- 1.4 ml/100 ml of tissue per min (six months; p < 0.0001). Isradipine treatment did not modify the vasodilating effect of sodium nitroprusside. CONCLUSIONS Our data demonstrate for the first time that the calcium antagonist isradipine improves acetylcholine-induced vasodilation in hypertensives.

Incidence and clinical relevance of uncontrolled ventricular rate during atrial fibrillation in heart failure patients treated with cardiac resynchronization therapy

Uncontrolled ventricular rate (VR) during atrial fibrillation (AF) may cause clinical deterioration in heart failure (HF) patients who need continuous biventricular pacing to achieve cardiac resynchronization therapy (CRT). We aimed at evaluating the association between AF, uncontrolled VR, and sub‐optimal CRT, defined as low biventricular pacing percentage (BIVP%).

Hypertensive left ventricular remodeling and ACE-gene polymorphism.

OBJECTIVE To evaluate the relationship between ACE-gene polymorphism and left ventricular geometry in never treated hypertensives. METHODS We enrolled 200 hypertensive outpatients that underwent clinical and ambulatory blood pressure measurements, echocardiographic evaluation and analysis for insertion (I)/deletion (D) polymorphism by PCR. Patients with normal or increased (> 125 g/m2 in males and > 110 g/m2 in females) left ventricular mass were considered to have concentric remodeling or concentric left ventricular hypertrophy if their relative wall thickness was > or = 0.45. RESULTS The left ventricular mass index values (g/m2) were 136 +/- 30 in DD genotype, 124 +/- 26 in ID genotype, and 116 +/- 20 in II genotype (DD vs. ID P < 0.005; DD vs. II P < 0.05), and were unrelated to blood pressure. Ninety-six patients presented left ventricular hypertrophy (48.0%): 51 with concentric and 45 with eccentric hypertrophy. The eccentric left ventricular hypertrophy was detected in 32 (36.8%) DD patients, in ten (10.5%) ID patients (P < 0.05), and in three (16.6%) II patients. The relative septal thickness was 0.43 +/- 0.09 in DD genotype, 0.45 +/- 0.08 in ID genotype, and 0.43 +/- 0.10 in II genotype. In DD and ID genotypes, the relative posterior wall thickness (0.37 +/- 0.07 vs. 0.41 +/- 0.07; P < 0.0001) and the end-diastolic left ventricular internal dimension (52.8 +/- 3.3 mm vs. 48.3 +/- 2.8 mm; P < 0.0001) were statistically different. CONCLUSIONS The DD genotype of the ACE-gene is associated with an increased left ventricular mass and with a significantly higher prevalence of eccentric left ventricular hypertrophy, when compared to ID genotype.

Presence of left ventricular contractile reserve predicts midterm response to cardiac resynchronization therapy—results from the LOw dose DObutamine Stress-Echo Test in Cardiac Resynchronization Therapy (LODO-CRT) Trial

BACKGROUND Cardiac resynchronization therapy (CRT) is effective in selected patients with heart failure (HF). Nevertheless, the nonresponder rate remains high. The low-dose dobutamine stress-echo (DSE) test detects the presence of left ventricular (LV) contractile reserve (LVCR) in HF patients of any etiology and may be useful in predicting response to resynchronization. OBJECTIVE The purpose of this study was to present the results of the LODO-CRT trial, which evaluated whether LVCR presence at baseline increases the chances of response to CRT. METHODS LODO-CRT is a multicenter prospective study that enrolled CRT candidates according to guidelines. LVCR presence was defined as an LV ejection fraction increase >5 units during DSE test. CRT response is assessed at 6-month follow-up as an LV end-systolic volume reduction ≥10%. RESULTS Two hundred seventy-one patients were enrolled. The DSE test was feasible without complications in 99% of patients. Nine patients died from noncardiac disease, and 31 presented inadequate data. Two hundred thirty-one patients were included in the analysis. Mean patient age was 67 ± 10 years; 95% were in New York Heart Association class III, and 42% had HF of ischemic etiology. Mean QRS and LV ejection fraction were 147 ± 25 ms and 27% ± 6%, respectively. LVCR presence was found in 185 subjects (80%). At follow-up, 170 (74%) patients responded to CRT, 145/185 in the group with LVCR (78%) and 25/46 (54%) in the group without LVCR. Difference in responder proportion to CRT was 24% (P <.001). Reported test sensitivity is 85%. CONCLUSION The DSE test in CRT candidates is safe and feasible. LVCR presence at baseline increases the chances of response to CRT.

Low-dose dobutamine test associated with interventricular dyssynchrony: a useful tool to identify cardiac resynchronization therapy responders: data from the LOw dose DObutamine stress-echo test in Cardiac Resynchronization Therapy (LODO-CRT) phase 2 study.

BACKGROUND Cardiac resynchronization therapy (CRT) is effective in patients with heart failure, but 30% to 50% of subjects are classified as nonresponders. Identifying responders remains a challenging task. AIMS The LODO-CRT trial investigated the association between left ventricular contractile reserve (LVCR) and clinical and echocardiographic long-term CRT response. METHODS This is a multicenter, prospective, observational study. Left ventricular contractile reserve was detected using a dobutamine stress echocardiography test, defined as an ejection fraction increase of >5 points. Clinical CRT response was defined as the absence of major cardiovascular events (ie, cardiovascular death or heart failure hospitalization). Echocardiographic response was defined as a left ventricle end-systolic volume reduction of >10%. RESULTS A total of 221 CRT-indicated patients were studied (80% presented LVCR). During a mean follow-up of 15 ± 5 months, 17 patients died and 16 were hospitalized due to heart failure. The proportion of clinical responders was 155 (88%) of 177 and 33 (75%) of 44 (P = .036) in the groups with and without LVCR, respectively. Kaplan-Meier analysis showed a significant difference in cardiac survival/hospitalization between patients with and without LVCR. The proportion of echocardiographic responders was 144 (87%) of 166 and 16 (42%) of 38 in the groups with and without LVCR (P < .001), respectively; LVCR showed 90% sensitivity and 87% positive predictive value to prefigure echocardiographic CRT responders. Multivariable analysis identified LVCR and interventricular dyssynchrony as independent predictors of CRT response. The concomitant presence of both factors showed 99% specificity and 83% sensitivity in detecting responders. CONCLUSION The presence of LVCR helps in predicting a clinical and echocardiographic CRT response. Concomitant assessment of LVCR and interventricular dyssynchrony accurately stratifies responder and nonresponder patients.

Low-Dose Dobutamine Stress Echocardiography to Assess Left Ventricular Contractile Reserve for Cardiac Resynchronization Therapy: Data From the Low-Dose Dobutamine Stress Echocardiography to Predict Cardiac Resynchronization Therapy Response (LODO-CRT) Trial

Cardiac resynchronization therapy (CRT) is an effective methodology indicated in selected heart failure patients. Identifying responders to the therapy is still challenging. Most studies report that at least 30% of the patients are nonresponders. Baseline characteristics of the Low-Dose Dobutamine Stress Echocardiography to Predict Cardiac Resynchronization Therapy Response (LODO-CRT) trial population are presented. The study investigates dobutamine stress echocardiographys role in predicting CRT response. Two hundred seventy-one CRT candidates were studied. Mean age was 67+/-10 years, 69% were male, 96% had New York Heart Association class III disease, and 39% had heart failure of ischemic etiology. Mean QRS and left ventricular ejection fraction were 146+/-24 ms and 26%+/-6%, respectively. Seventy-seven percent of participants showed contractile reserve. Left ventricular end-diastolic volume was shown to be independently associated with contractile reserve presence. In particular, more dilated ventricles are associated with a lower chance of having contractile reserve. The LODO-CRT trial enrolled a cohort of patients fulfilling criteria for CRT. Dobutamine stress echocardiography was highly feasible and safe in this population. Contractile reserve was associated with healthier ventricles.