Multipoint left ventricular pacing improves response to cardiac resynchronization therapy with and without pressure-volume loop optimization: comparison of the long-term efficacy of two different programming strategies.

PURPOSE: Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing (MultiPoint™ Pacing [MPP]) improves long-term LV reverse remodeling, though questions persist about how to program LV pacing vectors and delays. We evaluated if an empirical method of programming MPP vectors and delays between pacing pulses improved CRT response similar to pressure-volume loop (PVL) optimized MPP programming. METHODS: Patients undergoing CRT implant (Quadra Assura MP™ CRT-D and Quartet™ LV lead) received MPP with programmed settings optimized either by PVL measurements at implant (PVL-OPT group) or empirically determined by maximizing the spatial separation between the two cathodes and minimal delays between the three ventricular pacing pulses (MAX-SEP group). CRT response was prospectively defined as a reduction in end-systolic volume (ESV) of ≥ 15% relative to baseline at 6 months as determined by a blinded observer. RESULTS: Patient characteristics at baseline (NYHA II-III, ejection fraction [EF] 27 ± 6%, QRS 151 ± 17 ms) were not significantly different between the PVL-OPT (n = 27) and MAX-SEP (n = 26) groups. During the follow-up period, there were no differences in the number of patients requiring reprogramming due to phrenic nerve stimulation or a high threshold for PVL-OPT vs. MAX-SEP (5/27 [19%] vs. 7/26 [27%], p = 0.53). After 6 months, ESV reduction, EF increase, and CRT response rate (RR) were similar for PVL-OPT vs. MAX-SEP (ESV - 20 ± 11 vs. - 22 ± 11%, p = 0.59; EF + 10 ± 4 vs. + 9 ± 7%, p = 0.53; RR 20/27 [74%] vs. 21/26 [81%], p = 0.74), while fewer patients in the PVL-OPT group experienced NYHA class reduction ≥ 2 (4/27 [15%] vs.15/26 [58%], p = 0.002). CONCLUSIONS: Both evaluated methods of MPP programming resulted in similar CRT outcomes. Empirical MPP programming by maximum spatial separation of LV cathodes may be an effective, simple, and non-invasive alternative to pressure-volume optimization.

Multipoint pacing improves peripheral hemodynamic response: Noninvasive assessment using radial artery tonometry.

BACKGROUND: Multipoint left ventricular (LV) pacing (MultiPoint™ Pacing [MPP], Abbott, Sylmar, CA, USA) improves the response rate to cardiac resynchronization therapy (CRT). We evaluated the feasibility of noninvasive radial artery tonometry (RAT) to characterize arterial pressure morphology changes (pre-ejection period [PEP] and ejection duration [ED]) between conventional CRT and MPP pacing interventions. METHODS: Patients with a MPP-enabled CRT device (Quadra Assura MP™, Abbott) underwent noninvasive RAT assessment (SphygmoCor CVMS, AtCor Medical Inc., Itasca, IL, USA) at 3-6 months after implantation. A pacing protocol was performed in a randomized order including one optimized conventional biventricular CRT (CONV) configuration using the distal electrode and five MPP configurations. The PEP, ED, and PEP/ED ratio were determined for each intervention from the RAT pressure waveform and electrocardiogram. RESULTS: Pressure waveforms were successfully recorded in 19 patients (89% male, QRS 147 ± 16 ms, 63% ischemic). In 17/19 (89%) patients, at least one MPP intervention resulted in improved PEP, ED, and PEP/ED compared to CONV. The MPP intervention with greatest separation of LV cathodes and minimum intra-LV delay significantly improved PEP (mean PEP -15 ± 33% vs -8 ± 32% [CONV], P = 0.04) and ED (mean ED +8 ± 8% [MPP] vs +4 ± 7% [CONV], P = 0.02), and PEP/ED (-0.07 ± 0.14 [MPP] vs -0.04 ± 0.13 [CONV], P = 0.02) compared with CONV. CONCLUSIONS: Noninvasive RAT efficiently characterizes changes in PEP and ED between CONV and MPP interventions. MPP configurations using the widest separation among LV cathodes and minimum intra-LV delay may significantly improve RAT-derived parameters as compared to conventional CRT.

Electrical Substrate Elimination in 135 Consecutive Patients With Brugada Syndrome.

BACKGROUND: There is emerging evidence that localization and elimination of abnormal electric activity in the epicardial right ventricular outflow tract may be beneficial in patients with Brugada syndrome. METHODS AND RESULTS: A total of 135 symptomatic Brugada syndrome patients having implantable cardiac defibrillator were enrolled: 63 (group 1) having documented ventricular tachycardia (VT)/ventricular fibrillation (VF) and Brugada syndrome-related symptoms, and 72 (group 2) having inducible VT/VF without ECG documentation at the time of symptoms. About 27 patients of group 1 experienced multiple implantable cardiac defibrillator shocks for recurrent VT/VF episodes. Three-dimensional maps before and after ajmaline determined the arrhythmogenic electrophysiological substrate (AES) as characterized by prolonged fragmented ventricular potentials. Primary end point was identification and elimination of AES leading to ECG pattern normalization and VT/VF noninducibility. Extensive areas of AES were found in the right ventricle epicardium, which were wider in group 1 (P=0.007). AES increased after ajmaline in both groups (P<0.001) and was larger in men (P=0.008). The increase of type-1 ST-segment elevation correlated with AES expansion (r=0.682, P<0.001). Radiofrequency ablation eliminated AES leading to ECG normalization and VT/VF noninducibility in all patients. During a median follow-up of 10 months, the ECG remained normal even after ajmaline in all except 2 patients who underwent a repeated effective procedure for recurrent VF. CONCLUSIONS: In Brugada syndrome, AES is commonly located in the right ventricle epicardium and ajmaline exposes its extent and distribution, which is correlated with the degree of coved ST-elevation. AES elimination by radiofrequency ablation results in ECG normalization and VT/VF noninducibility. Substrate-based ablation is effective in potentially eliminating the arrhythmic consequences of this genetic disease. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02641431.

Atrial fibrillation detection using a novel three-vector cardiac implantable monitor: the atrial fibrillation detect study.

AIMS: Continuous rhythm monitoring is valuable for adequate atrial fibrillation (AF) management in the clinical setting. Subcutaneous leadless implantable cardiac monitors (ICMs) yield an improved AF detection, overcoming the intrinsic limitations of the currently available external recording systems, thus resulting in a more accurate patient treatment. The study purpose was to assess the detection performance of a novel three-vector ICM device equipped with a dedicated AF algorithm. METHODS AND RESULTS: Sixty-six patients (86.4% males; mean age 60.4 ± 9.4 years) at risk to present AF episodes, having undergone the novel ICM implant (BioMonitor, Biotronik SE&Co. KG, Berlin, Germany), were enrolled. External 48-h ECG Holter was performed 4 weeks after the device implantation. The automatic ICM AF classification was compared with the manual Holter arrhythmia recordings. Of the overall study population, 63/66 (95.5%) had analysable Holter data, 39/63 (62%) showed at least one true AF episode. All these patients had at least one AF episode stored in the ICM. On Holter monitoring, 24/63 (38%) patients did not show AF episodes, in 16 of them (16/24, 67%), the ICM confirmed the absence of AF. The AF detection sensitivity and positive predictive value for episodes' analysis were 95.4 and 76.3%, respectively. CONCLUSION: Continuous monitoring using this novel device, equipped with a dedicated detection algorithm, yields an accurate and reliable detection of AF episodes. The ICM is a promising tool for tailoring individual AF patient management. Further long-term prospective studies are necessary to confirm these encouraging results.

Improving cardiac resynchronization therapy response with multipoint left ventricular pacing: Twelve-month follow-up study.

BACKGROUND: Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing (MultiPoint™ Pacing [MPP], St. Jude Medical) improves acute LV function and LV reverse remodeling at 3 months. OBJECTIVE: The purpose of this study was to test the hypothesis that MPP can also improve LV function at 12 months. METHODS: Consecutive patients receiving a CRT implant (Unify Quadra MP™ or Quadra Assura MP™ CRT-D and Quartet™ LV lead, St. Jude Medical) were randomized to receive pressure-volume (PV) loop optimized biventricular pacing with either conventional cardiac resynchronization therapy (CONV) or MPP. CRT response was defined by a reduction in end-systolic volume (ESV) ≥15% relative to BASELINE as determined by a blinded observer and alive status. RESULTS: Forty-four patients (New York Heart Association class III, ejection fraction [EF] 29% ± 6%, QRS 152 ± 17 ms) were enrolled and randomized to either CONV (N = 22) or MPP (N = 22). During the observation period, 2 patients died of noncardiac causes and 2 patients were lost to follow-up. After 12 months, 12 of 21 patients (57%) in the CONV group and 16 of 21 patients (76%) in the MPP group were classified as CRT responders (P = .33). ESV reduction and EF increase relative to BASELINE were significantly greater with MPP than with CONV (ESV: median -25%, interquartile range [IQR] [-39% to -20%] vs median -18%, IQR [-25% to -2%], P = .03; EF: median +15%, IQR [8% to 20%] vs median +5%, IQR [-1% to 8%], P <.001). CONCLUSION: Sustaining the trend observed 3 months postimplant, PV loop-guided multipoint LV pacing resulted in greater LV reverse remodeling and increased LV function at 12 months compared to PV loop-guided conventional CRT.

Multipoint left ventricular pacing in a single coronary sinus branch improves mid-term echocardiographic and clinical response to cardiac resynchronization therapy.

INTRODUCTION: Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing in a single coronary sinus branch improves acute LV function. We hypothesized that multipoint pacing (MPP) can improve midterm echocardiographic and clinical response compared with conventional CRT. METHODS AND RESULTS: Consecutive patients receiving a CRT implant (Unify Quadra MP™ or Quadra Assura MP™ CRT-D and Quartet™ LV lead, St. Jude Medical, Sylmar, CA, USA) were randomized to receive biventricular (BiV) pacing with either conventional LV pacing (CONV group) or MPP (MPP group). For each patient, an optimal pacing configuration for the assigned pacing mode was programmed based on intraoperative pressure-volume (PV) loop measurements. A clinical evaluation and transthoracic echocardiogram were performed before implant (BASELINE) and at 3 months postimplant and analyzed by a blinded observer. A reduction in end-systolic volume (ESV) of ≥15% relative to BASELINE was prospectively defined as response to CRT. Forty-four patients (NYHA Class III, EF 29 ± 6%, QRS duration 152 ± 17 milliseconds) were enrolled and randomized. One patient in the MPP group was lost to follow-up and excluded from further analysis. After 3 months, 11 of 22 (50%) CONV patients and 16 of 21 (76%) MPP patients were classified as responders. ESV reduction, EF increase, and NYHA class reduction relative to BASELINE were significantly greater in the MPP group than in the CONV group (ESV: -21.0 ± 13.9 vs. -12.6 ± 11.1%, P = 0.03; EF: +9.8 ± 5.1 vs. +2.0 ± 7.8 percentage points, P < 0.001; ΔNYHA: -1.05 ± 0.22 vs. -0.72 ± 0.46 functional classes, P = 0.006). CONCLUSION: PV loop optimized BiV pacing with MPP resulted in an improved rate of response to CRT.

Wolff-Parkinson-White syndrome in the era of catheter ablation: insights from a registry study of 2169 patients.

BACKGROUND: The management of Wolff-Parkinson-White is based on the distinction between asymptomatic and symptomatic presentations, but evidence is limited in the asymptomatic population. METHODS AND RESULTS: The Wolff-Parkinson-White registry was an 8-year prospective study of either symptomatic or asymptomatic Wolff-Parkinson-White patients referred to our Arrhythmology Department for evaluation or ablation. Inclusion criteria were a baseline electrophysiological testing with or without radiofrequency catheter ablation (RFA). Primary end points were the percentage of patients who experienced ventricular fibrillation (VF) or potentially malignant arrhythmias and risk factors. Among 2169 enrolled patients, 1001 (550 asymptomatic) did not undergo RFA (no-RFA group) and 1168 (206 asymptomatic) underwent ablation (RFA group). There were no differences in clinical and electrophysiological characteristics between the 2 groups except for symptoms. In the no-RFA group, VF occurred in 1.5% of patients, virtually exclusively (13 of 15) in children (median age, 11 years), and was associated with a short accessory pathway antegrade refractory period (P<0.001) and atrioventricular reentrant tachycardia initiating atrial fibrillation (P<0.001) but not symptoms. In the RFA group, ablation was successful in 98.5%, and after RFA, no patients developed malignant arrhythmias or VF over the 8-year follow-up. Untreated patients were more likely to experience malignant arrhythmias and VF (log-rank P<0.001). Time-dependent receiver-operating characteristic curves for predicting VF identified an optimal anterograde effective refractory period of the accessory pathway cutoff of 240 milliseconds. CONCLUSIONS: The prognosis of the Wolff-Parkinson-White syndrome essentially depends on intrinsic electrophysiological properties of AP rather than on symptoms. RFA performed during the same procedure after electrophysiological testing is of benefit in improving the long-term outcomes.

Multipoint left ventricular pacing improves acute hemodynamic response assessed with pressure-volume loops in cardiac resynchronization therapy patients.

BACKGROUND: Conventional cardiac resynchronization therapy (CRT) improves acute cardiac hemodynamics. OBJECTIVE: To investigate if CRT with multipoint left ventricular (LV) pacing in a single coronary sinus branch (MultiPoint Pacing [MPP], St Jude Medical, Sylmar, CA) can offer further hemodynamic benefits to patients. METHODS: Forty-four consecutive patients (80% men, New York Heart Association III, end-systolic volume 180 ± 77 mL, ejection fraction 27% ± 6%, and QRS duration 152 ± 17 ms) receiving a CRT device implant (Unify Quadra MP or Quadra Assura MP and Quartet LV lead, St Jude Medical) underwent intraoperative assessment of LV hemodynamics by using a pressure-volume loop system (Inca, CD Leycom). A pacing protocol was performed, including 9 biventricular pacing interventions with conventional CRT (CONV) using distal and proximal LV electrodes and various MPP configurations. Each pacing intervention was performed twice in randomized order with right ventricular pacing (BASELINE) repeated after every intervention. RESULTS: Evaluable recordings were obtained in 42 patients. Relative to BASELINE, the best MPP intervention significantly increased the rate of pressure change (dP/dtmax; 15.9% ± 10.0% vs 13.5% ± 8.8%; P < .001), stroke work (27.2% ± 42.5% vs 19.4% ± 32.2%; P = .018), stroke volume (10.4% ± 22.5% vs 4.1% ± 13.1%; P = .003), and ejection fraction (10.5% ± 20.9% vs 5.3% ± 13.2%; P = .003) as compared with the best CONV intervention. Moreover, the best MPP intervention improved acute diastolic function, significantly decreasing -dP/dtmin (-13.5% ± 10.2% vs -10.6% ± 6.8%; P = .011), relaxation time constant (-7.5% ± 9.0% vs -4.8% ± 7.2%; P = .012), and end-diastolic pressure (-18.2% ± 22.4% vs -8.7% ± 21.4%; P < .001) as compared with the best CONV intervention. CONCLUSIONS: CRT with MPP can significantly improve acute LV hemodynamic parameters assessed with pressure-volume loop measurements as compared with CONV.

Improved survival in patients with chronic mild/moderate systolic heart failure followed up in a specialist clinic.

OBJECTIVE: To relate therapeutic issues, comorbidities and functional parameters to mortality/morbidity of mild/moderate heart failure patients. METHODS: From our heart failure clinic, 372 heart failure patients (269 men, aged 66 ± 11 years), with stable heart failure and ejection fraction 45% or less were recruited. Survival curves were estimated according to the Kaplan-Meier method. Associations of protective/risk factors with cardiovascular mortality/morbidity were also evaluated. RESULTS: One hundred and two patients (27%) died (aged 70 ± 10 years at diagnosis, 76 ± 10 at death) during follow-up (overall mortality at 60 months: 19.2%; mean follow-up period: 67 ± 44 months). Cardiovascular deaths were 64 (63% of total deaths, 44 men, age at diagnosis 70 ± 9). Cardiovascular mortality at 60 months was 12%; standardized mortality ratio was 5.9 for women and 6.8 for men. The remaining 38 patients (37% of total deaths, 30 men, age at diagnosis 70 ± 10) died of noncardiovascular causes. Overall, noncardiovascular mortality at 60 months was 7.2%; mean survival time from diagnosis to death was 63 ± 69 months (median 42, Q1 = 27.5, Q3 = 77.7). Average cardiovascular admission rate was 1.63 ± 1.84 admissions/patient. At multivariate analysis, only previous history of myocardial infarction [hazard ratio: 3.62 (1.70-7.73)], class of ejection fraction at diagnosis [hazard ratio: 0.36 (0.32-0.60)], acute cardiac decompensation at any time [hazard ratio: 1.55 (1.32-1.84)], implanted defibrillator [hazard ratio: 0.11 (0.01-0.83)] and use of statins [hazard ratio: 0.08 (0.007-0.42)] were independently associated with cardiovascular mortality. Factors associated to higher annual cardiovascular morbidity were age at diagnosis, chronic renal failure, diabetes, cardiac decompensation at any time, female sex and diuretic therapy. Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin-receptor-blockers reduced annual cardiovascular morbidity. CONCLUSION: Survival in mild/moderate heart failure patients has consistently improved. Further improvements are warranted in terms of morbidity reduction.

Effect of partial inhibition of fatty acid oxidation by trimetazidine on whole body energy metabolism in patients with chronic heart failure.

OBJECTIVE: Trimetazidine may have beneficial effects on left ventricular (LV) function in patients with systolic heart failure. The authors assessed whether long-term addition of trimetazidine to conventional treatment could improve, along with LV function, resting whole body energy metabolism in patients with chronic systolic heart failure. DESIGN: Single blind randomised study. SETTING: University Hospital. PATIENTS: 44 patients with systolic heart failure receiving full medical treatment. INTERVENTIONS: Indirect calorimetry and two-dimensional echocardiography at baseline and after 3 months. MAIN OUTCOME MEASURES: Whole body resting energy expenditure (REE), percentage of predicted REE, LV ejection fraction (EF), NYHA class, quality of life. RESULTS: Trimetazidine increased EF compared with conventional therapy alone (from 35±8% to 42±11% vs from 35±7% to 36±6%; p=0.02, analysis of variance for repeated measures). NYHA class and quality of life also improved compared with conventional therapy (p<0.0001). REE (from 1677±264 to 1580±263 kcal/day) and percentage of predicted REE (based on the Harris-Benedict equation: from 114±10% to 108±9%) decreased in the trimetazidine group, but not in the control group (REE from 1679±304 to 1690±337 kcal/day and percentage of predicted REE from 113±12% to 115±14%). The variation was different between groups (p=0.03 and 0.023, respectively). CONCLUSIONS: In patients with systolic heart failure, improvement in functional class and LV function induced by middle-term trimetazidine therapy is paralleled by a reduction in whole body REE. The beneficial cardiac effects of trimetazidine may be also mediated by a peripheral metabolic effect.

Safety and efficacy of doxazosin as an "add-on" antihypertensive therapy in mild to moderate heart failure patients.

OBJECTIVE: Doxazosin treatment has been discouraged in hypertensive patients in order to prevent heart failure (HF) development. However, this drug is still prescribed as an "add-on" medication to achieve a better blood pressure (BP) control. The aim of this study was to evaluate the safety and efficacy of doxazosin as an "add-on" medication in HF patients with uncontrolled hypertension. METHODS AND RESULTS: We reviewed our HF clinic files to collect patient variables recorded at baseline and during follow-up visits in patients receiving, or not, doxazosin. We compared HF-related hospitalization rates and all-cause and cardiovascular mortality rates between patients on doxazosin and those not on doxazosin. We constructed cumulative risk curves for time to first event (HF-related hospitalization and/or death) for both groups of patients. Fifty-two HF patients had been prescribed doxazosin. At baseline, several relevant variables were unevenly distributed between patients receiving doxazosin and those not receiving doxazosin (N=122), such as left ventricular ejection fraction (LVEF) and NYHA class. HF-related hospitalization and death rates were similar between patients on doxazosin and those not on doxazosin at the end of the follow-up. Even after adjustment for all potentially confounding variables, doxazosin was not associated with HF-related hospitalization and/or death. Doxazosin significantly reduced BP, but did not affect NYHA class. CONCLUSIONS: Doxazosin, "on top" of other antihypertensive treatments was safe and effective, and did not appear to be associated with HF-related hospitalization and mortality rates in our patients with mild/moderate HF.

Differential long-term effects of carvedilol on proinflammatory and antiinflammatory cytokines, asymmetric dimethylarginine, and left ventricular function in patients with heart failure.

Neuroendocrine/inflammatory and endothelial functions have been indicated as crucial for heart failure (HF) patients. We evaluated relation in HF patients among cytokines and asymmetric dimethylarginine (ADMA) and left ventricular ejection fraction (LVEF) at baseline and after long-term administration of carvedilol. Interleukin 10 (IL-10), interleukin 18 (IL-18), and ADMA were measured in 22 NYHA class II to IV HF patients at baseline and after 40 +/- 14 months of carvedilol treatment. Patients were divided into 2 groups according to whether, after treatment with carvedilol, LVEF had increased at least 5% (responders) or less than 5% (non-responders). In responders (11 of 22 patients), LVEF increased from 38 +/- 6% to 50 +/- 7%, (P < 0.001); in non-responders, it decreased from 36 +/- 9% to 31 +/- 6%, (P = 0.02); NYHA class significantly decreased in both groups. IL-18 decreased in responders (from 586.4 +/- 128 to 183.13 +/- 64.4 pg/mL; P < 0.001) and in non-responders (from 529.3 +/- 116.25 to 142.4 +/- 58.9 pg/mL; P < 0.001). IL-10 increased in responders (from 0.49 +/- 0.25 to 2.01 +/- 1.01 pg/mL; P < 0.001) and in non-responders (from 0.64 +/- 0.31 to 1.33 +/- 0.59 pg/mL; P < 0.001). Conversely, ADMA levels decreased only in responders (from 0.67 +/- 0.16 to 0.44 +/- 0.15 micromol/L; P < 0.001), and an inverse correlation was observed between basal ADMA levels and changes in LVEF after treatment. In HF patients, carvedilol appears to reduce symptoms and the expression of inflammation, regardless of the LV functional response. In those patients showing improvement of LVEF, the reduction of inflammation is paralleled by a reduction of ADMA. We surmise that carvedilol could be effective at various independent levels as a result of possible pleiotropic effects of this agent.

Validation of remote cardiopulmonary examination in patients with heart failure with a videophone-based system.

BACKGROUND: The aim of this study was to evaluate feasibility and accuracy of a videophone-based system for remote cardiopulmonary examination of patients with heart failure. METHODS AND RESULTS: Fifty patients were examined by 2 cardiologists, 1 with a conventional stethoscope and 1 remotely with a videophone-based method, employing an electronic stethoscope and transmitting through an integrated services digital network line. During both sessions, the cardiologists filled out a 27-item questionnaire, which was then compared; concordance between standard and remote examination was evaluated. In 92% of patients, electronic and acoustic auscultation concurred. Only in 3 patients (4%) did teleauscultation not permit a correct interpretation of lung examination. In one patient, bilateral fine crepitant rales were not detected during teleauscultation. Conversely, in the second, patient bilateral fine crepitant rales were recognized during teleauscultation, which were not confirmed during real-life auscultation. In the third nonconcordant patient, moderate-degree wheezing was not detected during teleauscultation. Fine crepitant rales were present at the lungs lower fields in 12 and wheezing in 3 additional patients, and were always correctly identified during teleauscultation. Overall, sensitivity, specificity, positive, and negative predictive value of remote lung auscultation were 88%, 97%, 94%, and 94%, respectively. CONCLUSIONS: Remote cardiopulmonary examination appears as a feasible method for assessing patients with heart failure. Telestethoscopy can therefore be reliably used in the context of comprehensive telecare programs.

New directions in the treatment of heart failure: targeting free fatty acid oxidation.

The possibility of modifying cardiac metabolism by switching the fuel used by the myocardium could become increasingly important. Inhibitors of free fatty acid (FFA) oxidation could have an important role in therapeutic strategy for patients with heart failure, and shifting the energy substrate preference away from FFA metabolism and toward glucose metabolism may be an effective adjunctive treatment. Additionally, abnormalities of glucose homeostasis in patients with heart failure contribute to the progression of the primary disease. If not adequately treated, these abnormalities can contribute to the occurrence of complications, including severe left ventricular dysfunction. Apart from meticulous metabolic control of frank diabetes, special attention should be paid to insulin resistance, a distinct clinical entity. The observed combined beneficial effects of FFA inhibitors on left ventricular function and glucose metabolism represent an additional advantage of these drugs, especially when abnormalities of myocardial and glucose metabolism coexist.

Modulation of fatty acids oxidation in heart failure by selective pharmacological inhibition of 3-ketoacyl coenzyme-A thiolase.

A direct approach to manipulate cardiac energy metabolism consists in modifying substrate utilization by the heart. Pharmacological agents that directly inhibit fatty acid oxidation include inhibitors of 3-ketoacyl coenzyme A thiolase (3-KAT), the last enzyme involved in ss-oxidation. The most extensively investigated agents of this group of drugs are trimetazidine and ranolazine. Clinical studies have shown that these agents can substantially increase the ischemic threshold in patients with effort angina. However, the results of current research is also supporting the concept that shifting the energy substrate preference away from fatty acid metabolism and toward glucose metabolism by 3-KAT inhibitors could be an effective adjunctive treatment in patients with heart failure, in terms of left ventricular function and glucose metabolism improvement. In fact, these agents have also been shown to improve overall glucose metabolism in diabetic patients with left ventricular dysfunction. In this paper, the recent literature on the beneficial effects of this new class of drugs on left ventricular dysfunction and glucose metabolism is reviewed and discussed.