Ranolazine for the prevention or treatment of atrial fibrillation: a systematic review.

The use of currently available antiarrhythmic drugs for atrial fibrillation is limited by their moderate efficacy and the considerable proarrhythmic risk. Ranolazine, an antianginal agent, has been reported to possess antiarrhythmic properties, resulting in a reduction of supraventricular and ventricular arrhythmias. We performed a systematic review of the clinical studies reporting the outcome of patients treated with ranolazine for the prevention or treatment of atrial fibrillation in various clinical settings. We searched PubMed and abstracts of major conferences for clinical studies using ranolazine, either alone or in combination with other antiarrhythmic agents for the prevention or treatment of atrial fibrillation. Ten relevant records were identified. These included both randomized trials and retrospective cohort studies concerning the use of ranolazine in different clinical settings; prevention of atrial fibrillation in patients with acute coronary syndrome, prevention as well as conversion of postoperative atrial fibrillation after coronary artery bypass grafting, conversion of recent-onset atrial fibrillation, sinus rhythm maintenance in drug-resistant recurrent atrial fibrillation and facilitation of electrical cardioversion in cardioversion-resistant patients. A beneficial, mostly modest effect of ranolazine was homogeneously reported in all clinical settings. There were no substantial proarrhythmic effects. No meta-analysis could be performed because for most of the clinical scenarios, there was only one study investigating the effect of ranolazine. Except for one large randomized trial, all the other studies were either relatively small randomized studies or retrospective cohort analyses, which in several cases lacked a control group. This systematic review indicates a modest beneficial effect of ranolazine administered for the prevention or treatment of atrial fibrillation across several clinical settings without substantial proarrhythmic risk.

Detection of high-burden coronary artery disease by exercise-induced changes of the E/E' ratio.

To investigate whether exercise-induced changes of the E/E' average ratio can detect high-burden coronary artery disease (CAD) in patients with chest pain and normal left ventricular (LV) systolic function. The study population consisted of 359 patients admitted for chest pain (59.8 ± 9.8 years, 75% male). Patients underwent exercise echocardiography, scintigraphy and coronary angiography. The average of the lateral and septal ratios of early diastolic transmitral velocity to early diastolic tissue velocity (E/E') at baseline and immediately after exercise was calculated. Exercise induced wall motion abnormalities were also calculated. Coronary angiography showed flow limiting CAD in 238 patients (66%). The exercise-induced changes of E/E' average ratio had a sensitivity of 87.3% and a specificity of 75.2% for detection of flow limiting CAD, whereas myocardial scintigraphy showed 79.2% sensitivity and 80.1% specificity and exercise induced wall motion abnormalities had a sensitivity of 74.3% and a specificity of 66.9%. Likelihood ratio chi square showed an incremental value of the exercise-induced changes of E/E' average ratio over regional perfusion technique (from 121.37 to 194.15, P < 0.001) and over wall motion abnormalities (from 57.03 to 146.50, P < 0.001). The exercise-induced change of the E/E' average ratio detects flow limiting CAD in patients with chest pain and normal LV systolic function showing an incremental value over regional perfusion technique and wall motion abnormalities.

Exercise-induced changes of B-type natriuretic peptide uncover the unknown coronary artery disease in patients with chest pain and normal left ventricular systolic function.

AIM: The diagnostic and prognostic utility of B-type natriuretic peptide (BNP) has been shown in patients either with heart failure or with known coronary artery disease (CAD). We aimed to investigate the utility of the exercise-induced changes of BNP in patients with chest pain, unknown CAD, and normal left ventricular systolic function. METHODS: We evaluated 100 consecutive patients (mean age 58.7 ± 9 years) (80% male) with left ventricular ejection fraction of more than 50%. Blood samples were collected and BNP was measured before exercise stress testing, at peak, and 20 min after it. All patients underwent coronary artery angiography. We used univariate and multivariate logistic regression analysis. RESULTS: An increment in BNP values of 1.3 fold (from before to peak exercise BNP values) have 11 times greater odds of having CAD [odds ratio (OR): 11.45 with 95% confidence interval (CI): 3.48­37.66, P < 0.001]. Receiver operating curve analysis revealed a sensitivity of 81.8% and a specificity of 71.8%. Multivariate analysis revealed that BNP increment from before to peak exercise remained statistically significant regardless of the presence of other risk factors for atherosclerosis (OR: 18.59 with 95% CI: 4.14­83.45, P < 0.001). Interestingly, patients showing 1.79 times increment of before to peak exercise BNP values have 19 times greater odds of having multivessel disease (OR: 19.28 with 95% CI: 4.95­75.17, P < 0.001) with a sensitivity of 81% and specificity of 81.8%. CONCLUSION: The exercise-induced changes of BNP in patients with chest pain, normal left ventricular systolic function, and unknown CAD may uncover patients with CAD and discriminate those with angiographically severe one.

Diastolic stress echocardiography detects coronary artery disease in patients with asymptomatic type II diabetes.

OBJECTIVES: Diabetes mellitus is considered as an equivalent of coronary artery disease (CAD). Aim of the study was to investigate whether in asymptomatic patients with type II diabetes, diastolic stress echocardiography may represent an alternative tool for the detection of CAD. METHODS: The study population consisted of 105 patients with diabetes mellitus (age 61+/-9 years, 26% female, duration of diabetes 37+/-14 months). We performed an exercise stress test, followed by an echo-study and a single-positron emission tomography. Coronary angiography was performed within 1 month. RESULTS: Coronary angiography revealed a coronary artery stenosis of at least 70% in 72 patients (69%, CAD group), while the remaining formed the non-CAD group. Exercise induced an increase of both E/E' lateral and septal ratios as well as their average in the CAD group and on the contrary a decrease of these ratios in the non-CAD group. Receiver operating curve analysis for discrimination between patients with and without obstructive CAD showed an optimal cut-off value of -0.0708 for the exercise-induced change of E/E' average (area under curve 0.892, P<0.001). Sensitivities of scintigraphy and of diastolic stress echocardiography for detection of CAD were 75.0 and 93.1%, respectively; specificity was 78.8% for both methods. In asymptomatic patients, sensitivities of scintigraphy and diastolic stress echocardiography were 76.9 and 92.3%; specificity of both was 80%. CONCLUSION: In patients with type II diabetes, diastolic stress echocardiography, by means of E/E' ratio exercise-induced changes, can be used for the diagnosis and severity of CAD and for the detection of occult myocardial ischemia.

Exercise-induced changes in E/E' ratio in patients with suspected coronary artery disease.

OBJECTIVES: Ischemia affects the left ventricular (LV) diastolic function earlier than the systolic function. The ratio of the early diastolic transmitral velocity to the early diastolic tissue velocity (E/E') measured by tissue Doppler echocardiography allows a reliable assessment of the diastolic function. We investigated whether exercise-induced changes in E/E' ratio may help in the detection of coronary artery disease (CAD). METHODS: The study population consisted of 114 patients undergoing coronary angiography. Patients with impaired LV ejection fraction, earlier myocardial infarction, arterial hypertension greater than stage I, or LV hypertrophy were excluded. Patients underwent a treadmill exercise test combined with an echocardiogram at baseline and within the first minute after exercise. RESULTS: Coronary angiography showed a stenosis more than 70% in 72 (63%) patients (CAD group), the remaining 42 formed the non-CAD group. The two groups did not differ regarding age, sex, LV dimensions, and function. At baseline, the E/E' lateral and septal ratios and their average did not differ between the two groups. The exercise-induced changes of the E/E' ratios were higher in the CAD group (change of E/E' average: 1.9+/-3.3 vs. -1.1+/-2.3, P<0.001). In the CAD group, 78% showed an exercise-induced increase of E/E' average compared with 24% in the non-CAD group (P<0.001). In multivariate analysis, the association between an increase of E/E' average and the presence of obstructive CAD was independent of traditional risk factors, exercise test result or exercise-induced wall motion abnormalities (odds ratio=8.1, P<0.001). CONCLUSION: Exercise-induced changes in E/E' ratio may offer significant assistance in the detection of CAD.

Effects of levosimendan versus dobutamine on inflammatory and apoptotic pathways in acutely decompensated chronic heart failure.

A single levosimendan administration has recently been shown to result in clinical and hemodynamic improvement in patients with decompensated heart failure (HF), but without survival benefits. In this study, the effects of levosimendan and dobutamine on plasma levels of proinflammatory and proapoptotic mediators in decompensated HF were compared and correlated with the concomitant effects on cardiac function and prognosis. Sixty-nine patients were randomized to received 24-hour intravenous infusions of levosimendan (n = 23), dobutamine (n = 23), or placebo (n = 23). Echocardiographic, hemodynamic, and biochemical assessments were performed at baseline, immediately after treatment, and 48 hours later. Patients were subsequently followed for 4 months for disease progression. End-systolic wall stress, the left ventricular ejection fraction, pulmonary capillary wedge pressure, and cardiac index were significantly improved in the levosimendan group but remained practically unaffected in the other groups. Plasma N-terminal-pro-B-type natriuretic peptide, tumor necrosis factor-alpha, and soluble Fas ligand levels were significantly decreased only in the levosimendan group (from 1,900 +/- 223 to 1,378 +/- 170 pg/ml, 13.4 +/- 1.0 to 12.3 +/- 1.2 pg/ml, and 68.2 +/- 3.7 to 59.8 +/- 3.6 pg/ml, respectively; p <0.05 for all); interleukin-6 was also borderline reduced (p = 0.051). Levosimendan-induced reduction in end-systolic wall stress was significantly correlated with respective decreases in N-terminal-pro-B-type natriuretic peptide (r = 0.671, p <0.01), tumor necrosis factor-alpha (r = 0.586, p <0.01), soluble Fas (r = 0.441, p <0.05), and soluble Fas ligand (r = 0.614, p <0.01). Event-free survival was significantly longer in the levosimendan group (p <0.05). In conclusion, the superiority of levosimendan over dobutamine in improving central hemodynamics and left ventricular performance in decompensated HF seems to be related to its anti-inflammatory and antiapoptotic effects.

Growth hormone-induced reduction of soluble apoptosis mediators is associated with reverse cardiac remodelling and improvement of exercise capacity in patients with idiopathic dilated cardiomyopathy.

OBJECTIVE: Recent experimental and clinical data indicate that abnormal inflammatory and apoptotic processes contribute to the progression of chronic heart failure (CHF). We sought to study the effects of growth hormone (GH) on circulating soluble apoptosis mediators, and to investigate whether these GH-induced anti-apoptotic effects are associated with the reduction of left ventricular (LV) volumes and attenuation of exercise intolerance in idiopathic dilated cardiomyopathy (IDC) patients. METHODS: Plasma tumour necrosis factor-alpha (TNF-alpha), its soluble receptors sTNFRI and sTNFRII, and plasma apoptosis mediators soluble Fas (sFas) and sFas Ligand (sFAsL) were measured (enzyme-linked immunosorbent assay) in 12 IDC patients (NYHA III; LVEF: 24+/-2%) before and after a 3-month subcutaneous administration of GH 4 IU every other day (randomized, crossover design). Peak oxygen uptake (VO2max), as well as LV volume indices, wall thickness, and end-systolic wall stress (ESWS) were also determined at the same period. RESULTS: Treatment with GH produced a significant reduction in plasma TNF-alpha (7.8+/-1.1 versus 5.5+/-0.9 pg/ml, P<0.02), sTNFRI (4.0+/-0.4 versus 3.3+/-0.3 ng/ml, P<0.05), sTNFRII (2.8+/-0.3 versus 2.4+/-0.2 ng/ml, P<0.05), sFas (4.7+/-0.7 versus 3.3+/-0.5 ng/ml, P<0.05) and sFasL (33.5+/-9.7 versus 20.2+/-6.2 pg/ml, P<0.01). A significant reduction in ESWS (841+/-62 versus 634+/-48 g/cm, P<0.01), LV end-systolic volume index (LVESVI, 128+/-12 versus 102+/-12 ml/m, P<0.001) and LV end-diastolic volume index (LVEDVI, 228+/-16 versus 200+/-18 ml/m, P<0.01) as well as a significant increase in VO2max (15.3+/-0.7 versus 17.1+/-0.9 ml/kg per min, P<0.01) were also observed in the patient population after GH administration. Significant correlations were found between the GH-induced decrease of sTNFRII and sFasL and respective reduction of LVESVI. CONCLUSION: Growth hormone administration reduces circulating TNF system and soluble apoptosis mediators in patients with IDC. These GH-induced anti-apoptotic effects may be associated with the improvement in exercise capacity as well as with the reverse of LV remodelling in patients with CHF and IDC.

Comparison of circulating proinflammatory cytokines and soluble apoptosis mediators in patients with chronic heart failure with versus without symptoms of depression.

This clinical study compared the expression of circulating proinflammatory (tumor necrosis factor-alpha [TNF-alpha] and interleukin-6) and anti-inflammatory (interleukin-10) cytokines and soluble apoptosis mediators (Fas/Fas ligand) between patients with stable chronic heart failure and depressive symptoms (as estimated by the Zung Self-Rating Depression Scale) (n = 15) and those without these symptoms (n = 20). Patients with depressive symptoms exhibited significantly higher levels of TNF-alpha and soluble Fas ligand, as well as significantly lower levels of interleukin-10, than patients without emotional distress. A disregulated cytokine network and activated apoptosis signaling molecules may be actively implicated in the pathophysiology of chronic emotional distress and depressive symptoms in patients with heart failure.

Prognostic usefulness of echocardiographic dobutamine in younger (14 to 25 years) and older (40 to 55 years) patients with idiopathic dilated cardiomyopathy.

We studied 16 younger patients (<25 years old) and 16 older patients (>40 years old) to investigate the prognostic value of echocardiographic dobutamine-induced changes. The results of this study showed that although the percent achieved of predicted oxygen consumption was lower in the younger group, no prognostic information was given regarding the outcome of this particular group. In contrast, echocardiographic dobutamine-induced changes can distinguish high-risk younger patients.

Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Recent experimental and clinical data indicate that abnormal central and peripheral immune reactions contribute to the progression of chronic heart failure, and that immunomodulation may be an important therapeutic approach in this syndrome. Aims We sought to study the effects of growth hormone (GH) administration on circulating pro-inflammatory/anti-inflammatory cytokine balance, and to investigate whether these GH-induced immunomodulatory effects are associated with the improvement of left ventricular (LV) contractile performance in idiopathic dilated cardiomyopathy (DCM) patients. METHODS: Plasma pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF) and its soluble receptor (sGM-CSFR), chemotactic cytokine macrophage chemoattractant protein-1 (MCP-1), soluble adhesion molecules intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1), and, finally, anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor-beta2 (TGF-beta2) were measured (ELISA method) in 12 patients with DCM (NYHA class III; LV ejection fraction: 23.6+/-1.7%) before and after a 3-month subcutaneous administration of GH 4IU every other day (randomized crossover design). Peak oxygen uptake (VO2 max), LV dimensions, LV mass index, end-systolic wall stress (ESWS), mean velocity of circumferential fibre shortening (Vcfc), and contractile reserve (change of ratio Vcfc/ESWS after dobutamine administration) were also determined at the same period. RESULTS: Treatment with GH produced a significant reduction in plasma TNF-alpha (7.8+/-1.1 vs 5.5+/-0.9pg/ml, P=0.013), IL-6 (5.7+/-0.5 vs 4.7+/-0.4pg/ml, P=0.043), GM-CSF (27.3+/-1.7 vs 23.3+/-1.8pg/ml, P=0.042), sGM-CSFR (4.0+/-0.4 vs 3.2+/-0.4ng/ml, P=0.039), MCP-1 (199+/-5 vs 184+/-6pg/ml, P=0.048), sICAM-1 (324+/-34 vs 274+/-27ng/ml, P=0.008) and sVCAM-1 (1238+/-89 vs 1043+/-77ng/ml, P=0.002) in DCM patients. A significant increase in ratios IL-10/TNF-alpha (1.9+/-0.3 vs 3.5+/-0.9, P=0.049), IL-10/IL-6(2.6+/-0.6 vs 3.2+/-0.5, P=0.044) and TGF-beta2/TNF-alpha (3.1+/-0.6 vs 4.4+/-0.6, P=0.05) was alsofound with GH therapy. A significant reduction in ESWS (841+/-62 vs 634+/-48gr/cm(2), P=0.0026) and LV end-systolic volume index (LVESVI, 128+/-12 vs 102+/-12ml, P=0.035) as well as a significant increase in posterior wall thickness (PWTH, 9.2+/-0.5 vs 10.3+/-0.6mm, P=0.034), contractile reserve (0.00029+/-0.0001 vs 0.00054+/-0.0001circ*cm(2)/gr*s, P=0.00028) and VO2max (15.3+/-0.7 vs 17.1+/-0.9ml/kg/min, P=0.002) were observed after GH administration. Good correlations were found between GH-induced increase in contractile reserve and the increases in VO2max (r=0.63, P=0.028), IL-10/TNF-alpha (r=0.69, P=0.011) and TGF-beta2/TNF-alpha (r=0.58, P=0.046) ratios, as well as the reduction in plasma TNF-alpha levels (r=-0.86, P=0.0004). CONCLUSIONS: GH administration modulates beneficially circulating cytokine network and soluble adhesion molecules in patients with DCM, whilst enhancing contractile reserve and diminishing LV volumes. These GH-induced anti-inflammatory effects may be associated with the improvement in LV contractile performance and exercise capacity as well as with the reverse of LV remodelling of patients with DCM.

Growth hormone administration reduces circulating proinflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy.

BACKGROUND: Recent studies have shown that an abnormal proinflammatory cytokine expression and apoptotic process contribute to adverse left ventricular remodeling and progress of chronic heart failure. This study investigates the effects of growth hormone (GH) administration on serum levels of representative proinflammatory cytokines and soluble apoptosis mediators in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy (IDC). METHODS: Serum levels of tumor necrosis factor-alpha (TNF-alpha), its soluble receptors (sTNF-RI, sTNF-RII), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), soluble Fas (sFas) and soluble Fas Ligand (sFasL) were determined (enzyme-linked immunosorbent assay method) in 10 patients with IDC (New York Heart Association class III, ejection fraction 24% +/- 2%) before and after a 3-month subcutaneous administration of 4 IU GH every other day (randomized crossover design). Peak oxygen consumption (Vo(2)max) was also used to evaluate the functional status of patients with IDC. RESULTS: Treatment with GH produced a significant reduction in serum levels of TNF-alpha (8.2 +/- 1.2 vs 5.7 +/- 1.1 pg/mL, P <.05), sTNF-RI (3.9 +/- 0.4 vs 3.2 +/- 0.3 ng/mL, P <.05), sTNF-RII (2.6 +/- 0.3 vs 2.2 +/- 0.2 ng/mL, P <.05), IL-6 (5.5 +/- 0.6 vs 4.4 +/- 0.4 pg/mL, P =.05), sIL-6R (32.7 +/- 3.0 vs 28.2 +/- 3.0 ng/mL, P <.05), sFas (4.4 +/- 0.8 vs 3.1 +/- 0.6 ng/mL, P <.05), and sFasL (34.2 +/- 11.7 vs 18.8 +/- 7.3 pg/mL, P <.01). A significant improvement was also observed in VO2max after the completion of 3 months' treatment with GH (15.0 +/- 0.8 vs 17.2 +/- 1.0 mL/kg/min, P <.05). Good correlations were found between GH-induced reduction in TNF-alpha levels and increase in VO2max (r = -0.64, P <.05) as well as between GH-induced reduction in sFasL and increase in VO2max (r = -0.56, P =.08). CONCLUSIONS: GH administration reduces serum levels of proinflammatory cytokines and soluble Fas/FasL system in patients with IDC. These immunomodulatory effects may be associated with improvement in clinical performance and exercise capacity of patients with IDC.

Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fas ligand system in patients with chronic heart failure.

OBJECTIVES: We sought to investigate the effects of physical training on circulating proinflammatory cytokines and the soluble apoptosis mediators Fas (sFas) and Fas ligand (sFasL) in patients with chronic heart failure (CHF). BACKGROUND: Recent investigations have shown an overexpression of circulating proinflammatory cytokines and soluble apoptosis mediators in patients with CHF, which may be related to their exercise intolerance and clinical deterioration. METHODS: Plasma levels of tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors I and II (sTNF-RI and sTNF-RII, respectively), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), sFas and sFasL were measured in 24 patients with stable CHF (New York Heart Association functional class II/III; left ventricular ejection fraction 23.2 +/- 1.3%) and in 20 normal control subjects before and after a 12-week program of physical training in a randomized, crossover design. Functional status of patients with CHF was evaluated by using a cardiorespiratory exercise test to measure peak oxygen consumption (VO2max). RESULTS: Physical training produced a significant reduction in plasma levels of TNF-alpha (7.5 +/- 1.0 pg/ml vs. 4.6 +/- 0.7 pg/ml, p < 0.001), sTNF-RI (3.3 +/- 0.2 ng/ml vs. 2.7 +/- 0.2 ng/ml, p < 0.005), sTNF-RII (2.6 +/- 0.2 ng/ml vs. 2.3 +/- 0.2 ng/ml, p = 0.06), IL-6 (8.3 +/- 1.2 pg/ml vs. 5.9 +/- 0.8 pg/ml, p < 0.005), sIL-6R (34.0 +/- 3.0 ng/ml vs. 29.2 +/- 3.0 ng/ml, p < 0.01), sFas (5.5 +/- 0.7 ng/ml vs. 4.5 +/- 0.8 ng/ml, p = 0.05) and sFasL (34.9 +/- 5.0 pg/ml vs. 25.2 +/- 4.0 pg/ml, p < 0.05), as well as a significant increase in VO2max (16.3 +/- 0.7 ml/kg per min vs. 18.7 +/- 0.8 ml/kg per min, p < 0.001). Good correlations were found between a training-induced increase in VO2max and a training-induced reduction in levels of the proinflammatory cytokine TNF-alpha (r = -0.54, p < 0.01) and the apoptosis inducer sFasL (r = -0.57, p < 0.005) in patients with CHF. In contrast, no significant difference in circulating cytokines and apoptotic markers was found with physical training in normal subjects. CONCLUSIONS: Physical training reduces plasma levels of proinflammatory cytokines and the sFas/sFasL system in patients with CHF. These immunomodulatory effects may be related to the training-induced improvement in functional status of patients with CHF.