Targeting the epigenome in malignant melanoma: Facts, challenges and therapeutic promises.

Malignant melanoma is the most lethal type of skin cancer with high rates of mortality. Although current treatment options provide a short-clinical benefit, acquired-drug resistance highlights the low 5-year survival rate among patients with advanced stage of the disease. In parallel, the involvement of an aberrant epigenetic landscape, (e.g., alterations in DNA methylation patterns, histone modifications marks and expression of non-coding RNAs), in addition to the genetic background, has been also associated with the onset and progression of melanoma. In this review article, we report on current therapeutic options in melanoma treatment with a focus on distinct epigenetic alterations and how their reversal, by specific drug compounds, can restore a normal phenotype. In particular, we concentrate on how single and/or combinatorial therapeutic approaches have utilized epigenetic drug compounds in being effective against malignant melanoma. Finally, the role of deregulated epigenetic mechanisms in promoting drug resistance to targeted therapies and immune checkpoint inhibitors is presented leading to the development of newly synthesized and/or improved drug compounds capable of targeting the epigenome of malignant melanoma.

The diagnostic yield of transesophageal echocardiography in patients with cryptogenic cerebral ischaemia: a meta-analysis.

BACKGROUND AND PURPOSE: The diagnostic utility of transesophageal echocardiography (TEE) in patients with cryptogenic ischaemic stroke (IS) or transient ischaemic attack (TIA) remains controversial. METHODS: A systematic review and meta-analysis was performed according to PRISMA guidelines to estimate the pooled prevalence of potential cardioembolic causes detected by TEE in prospective observational studies of cryptogenic IS/TIA. Cardiac conditions causally associated with cerebral ischaemia were considered to be intramural thrombi and intracardiac tumors according to ASCO phenotyping of IS. RESULTS: Thirty-five eligible studies, comprising 5772 patients (mean age 53.6 years, 56.9% men) were identified. The most common TEE finding was ascending aorta and/or aortic arch atheroma [51.2% (27.4%-74.5%)], followed by patent foramen ovale (PFO) [43.2% (36.3%-50.4%)]. Complex aortic plaques and large PFOs were reported in 14% (10.2%-18.9%) and 19.5% (16.6%-22.8%) of TEE evaluations. The prevalence of atrial septal aneurysm was 12.3% (7.9%-18.7%) and was significantly higher in conjunction with PFO presence (risk ratio 2.04, 95% confidence interval 1.63-2.54, P < 0.001). The prevalence of left atrial thrombus [3.0% (1.1%-8.3%)] and spontaneous echo contrast [3.8% (2.3%-6.2%)] was low. The prevalence of intracardiac tumors was extremely uncommon [0.2% (0%-0.7%)]. Significant heterogeneity was identified (I(2) > 60%) in the majority of analyses. Heterogeneity was not affected by cryptogenic stroke definition (TOAST versus alternative criteria). After dichotomizing available studies using a cut-off of 50 years, PFO was significantly (P = 0.001) more prevalent in younger than in older patients. CONCLUSION: Routine TEE in patients with cryptogenic IS/TIA commonly identifies abnormal findings. However, the prevalence of cardiac conditions considered to be causally associated with cerebral ischaemia (intracardiac thrombi and tumors) is low.

Association of soluble apoptotic markers with impaired left ventricular deformation in patients with rheumatoid arthritis. Effects of inhibition of interleukin-1 activity by anakinra.

Myocardial function is impaired in rheumatoid arthritis (RA). Inhibition of interleukin (IL)-1 activity reduces experimental myocardial infarction by limiting apoptosis. We investigated whether a) soluble apoptotic markers are related with impaired left ventricular (LV) performance and b) treatment with anakinra, an IL-1 receptor antagonist, reduces apoptotic markers leading to improved LV performance in RA. We studied 46 RA patients. In an acute, double-blind cross-over trial, 23 patients were randomised to a single injection of anakinra or placebo and after 48 hours (h) to the alternative treatment. In a chronic trial, 23 patients who received anakinra for 30 days were compared with 23 patients who received prednisolone. At baseline, 3 h and 30 days after treatment, we measured circulating IL-1ß, tumour necrosis factor (TNF)-α, Fas, Fas-ligand and caspase-9 to assess apoptosis. At baseline and 30 days after treatment, we assessed LV longitudinal strain, strain rate and E/Em ratio using 2D-speckle tracking and tissue Doppler echocardiography. At baseline, increased apoptotic markers were related with reduced LongSRS and increased E/Em (p<0.05). After 3 h and 30 days of anakinra, there was a reduction in Fas (median 481 vs. 364 vs. 301 pg/ml), Fas-ligand (median 289 vs. 221 vs. 190 pg/ml), caspase-9 (median 1.90 vs. 1.40 vs. 1.07 ng/ml), TNF-α and IL-1ß (p<0.05 for all comparisons). E/Em, LongS and LongSRS were improved after anakinra (p<0.01) and their percent changes were related with the corresponding changes of Fas and caspase-9 (p<0.05). No changes of the examined parameters were observed after prednisolone. In conclusion, inhibition of IL-1 activity by anakinra reduces apoptotic markers leading to improved LV performance in RA.

Lowering interleukin-1 activity with anakinra improves myocardial deformation in rheumatoid arthritis.

OBJECTIVE: Inhibition of interleukin-1 activity improves nitro-oxidative stress, endothelial and coronary function. The authors investigated (a) the association of nitro-oxidative stress and endothelial function with myocardial deformation, (b) the effects of anakinra, an interleukin-1a receptor antagonist on myocardial deformation in patients with rheumatoid arthritis (RA). METHODS: The authors compared 46 RA patients to 23 normal controls. 23 patients received anakinra (150 mg subcutaneously once daily) and 23 patients a 5-mg increase of prednisolone dose for 30 days. At baseline and post-treatment this study assessed (a) the left ventricular (LV) longitudinal, circumferential and radial strain and strain rate, using speckle tracking echocardiography, (b) the coronary flow reserve (CFR), (c) the flow-mediated endothelial-dependent dilation of the brachial artery (FMD) and (d) nitrotyrosine (NT) and malondialdehyde blood levels. RESULTS: Patients had impaired baseline myocardial deformation indices compared to controls (p<0.05). CFR and NT levels were related to longitudinal strain, systolic and diastolic strain rate, circumferential strain and systolic strain rate (p<0.05). FMD was related to longitudinal and circumferential diastolic strain rate (p<0.01). Compared to baseline, anakinra-treated patients increased the longitudinal strain (-17.8% (3.7%) vs -22.1% (3.5%)), systolic (-1.02 (0.23) l/s vs -1.25 (0.23) l/s) and diastolic (0.96 (0.37) l/s vs 1.20 (0.39) l/s) longitudinal strain rate, circumferential strain and strain rate (p<0.05 for all comparisons). No significant changes were observed among prednisolone-treated patients CONCLUSIONS: Myocardial deformation is impaired in RA patients and is related to nitro-oxidative stress and endothelial dysfunction. Chronic inhibition of IL-1 improves LV deformation in parallel with endothelial function and nitro-oxidative stress.

Remote postconditioning is more potent than classic postconditioning in reducing the infarct size in anesthetized rabbits.

PURPOSE: Postconditioning confers protection to the heart after a potentially lethal episode of prolonged ischemia. There is evidence that it may also be protective when applied at a distal artery. In the present study, we sought to determine whether remote postconditioning within the heart (local) or outside the heart (distal) is effective in salvaging the ischemic heart in vivo and to compare its effect with that of the classic postconditioning. METHODS: Twenty seven open chest New Zealand white anesthetized male rabbits were divided into four groups and were exposed to 30 min regional myocardial ischemia (isc), after ligation of a prominent coronary artery, followed by 3 h reperfusion (rep) after releasing the snare. Control group (n = 7) was subjected to no additional interventions, postC group (n = 6) was subjected to four cycles of 1 min isc/1 min rep of the same coronary artery at the beginning of reperfusion, remote local postC group (n = 7) to four cycles of 1 min isc/1 min rep of another coronary artery 30 s before the end of index isc and remote distal postC group (n = 7) to four cycles of 1 min isc/1 min rep of another (carotid) artery again 30 s before the end of index isc. Infarct size (I) and area at risk (R) were delineated with the aid of TTC staining and green fluorescent microspheres respectively and their ratio was expressed in percent (%I/R). RESULTS: Remote local and remote distal postC reduced the % I/R ratio (17.7 +/- 1.7% and 18.4 +/- 1.6%, respectively vs 47.0 +/- 2.5% in the control group, P < 0.01). Classic PostC had an intermediate protective effect (33.1 +/- 1.7%, P < 0.05 vs all the other groups). CONCLUSION: Remote postconditioning consisted of 1 min isc/1 min rep protects the ischemic rabbit heart in vivo, independently of the site of the remote artery. This intervention seems to confer a stronger protection than the classic postconditioning.

Evaluation of left atrial longitudinal function in patients with hypertrophic cardiomyopathy: a tissue Doppler imaging and two-dimensional strain study.

OBJECTIVE: We sought to quantify left atrial longitudinal function by tissue Doppler (TDI) and two-dimensional (2D) strain in patients with hypertrophic cardiomyopathy (HCM). DESIGN: Case-control study. SETTING: Tertiary university hospital. PATIENTS: 43 consecutive patients with familial HCM, aged 49 (SD 18) years, along with 21 patients with non-HCM left ventricular hypertrophy (LVH, aged 52 (12) years) and 27 healthy volunteers (aged 42 (13) years). INTERVENTIONS: Subjects were studied by both TDI and 2D left atrial strain during all three atrial phases (reservoir, conduit, contractile), as well as by left ventricular systolic strain; total atrial deformation (TAD) was defined as the sum of maximum positive and maximum negative strain during a cardiac cycle. MAIN OUTCOME MEASURES: Left atrial longitudinal function. RESULTS: Both TDI and 2D atrial strain and TAD were significantly reduced in HCM, compared to the other two groups in all atrial phases (p<0.001 in most cases); left ventricular systolic strain was also significantly reduced in HCM (p<0.001). Adding 2D contractile atrial strain to a model of conventional echo measurements (including left atrial diameter and volume index, interventricular septal thickness and E/A ratio and E/e' ratios) increased its prognostic value in differentiating HCM from non-HCM LVH (p value of the change <0.001), while addition of TDI atrial strain or left ventricular strain did not. A cut-off for 2D contractile strain of -10.82% discriminated HCM from non-HCM LVH with a sensitivity of 82% and a specificity of 81%. Intra-observer and inter-observer variabilities for atrial strain in HCM were 16% and 17.5% for TDI and 8% and 9.5% for 2D, respectively. Processing time per case in HCM was 12.5 (2.6) minutes for TDI versus 3.8 (1.2) minutes for 2D strain (p<0.001). CONCLUSION: Left atrial longitudinal function is reduced in HCM compared to non-HCM LVH and healthy controls. In addition, 2D atrial strain has an additive value in differentiating HCM from non-HCM LVH and it is more reproducible and less time consuming than TDI strain.

Clinical and prognostic implications of self-rating depression scales and plasma B-type natriuretic peptide in hospitalised patients with chronic heart failure.

BACKGROUND: Depression is common among patients with chronic heart failure (CHF) and has been independently associated with a poorer prognosis. PURPOSE: This study evaluated the clinical and prognostic value of depression scales (Beck Depression Inventory (BDI), Zung Self-rating Depression Scale (Zung SDS)) along with plasma B-type natriuretic peptide (BNP) in CHF. METHODS: 155 hospitalised CHF patients (ejection fraction 26.9% (SD 6.4%)) were studied by depression (BDI, Zung SDS) and functional questionnaires (Kansas City Cardiomyopathy Questionnaire (KCCQ), Duke Activity Status Index (DASI)), BNP and 6-minute walk test (6MWT). Patients were followed for 6 months for cardiovascular events, including death from any cause or rehospitalisation for CHF decompensation. RESULTS: Seventy-six (49%) patients with depressive symptoms, as estimated by both scales, had significantly lower DASI and KCCQ scores (13.2 (SD 9.9) vs 23.6 (SD 13.0) and 26.6 (SD 15.0) vs 45.0 (SD 17.0), respectively; p<0.001), higher BNP (921 (SD 889) vs 439 (SD 267) pg/ml, p = 0.001) and reduced 6MWT (270 (SD 130) vs 337 (SD 133); p<0.001). According to logistic regression analysis, Zung SDS and BNP were independently associated with adverse clinical outcomes; values of Zung SDS >or=40 and of BNP >or=290 pg/ml predicted future events with a sensitivity of 82% and 94% and a specificity of 45% and 46%, respectively. The combination of Zung SDS plus BNP had an additive prognostic value, predicting events with a sensitivity of 77% and a specificity of 70% (event-free survival: Zung <40 and BNP <290 pg/ml; 170 (SD 9) days; Zung >or=40 and BNP <290 pg/ml, 159 (SD 14) days; Zung <40 and BNP >or=290 pg/ml, 118 (SD 15) days; Zung >or=40 and BNP >or=290 pg/ml, 73 (SD 8) days, p<0.001). CONCLUSIONS: CHF patients with depressive symptoms have impaired physical activity, associated with excessive neurohormonal activation. Among the studied scales, Zung SDS seemed to independently predict clinical outcome, especially in patients with increased plasma BNP concentration. Hence, the combination of those two modalities provides a practical means for risk stratification in CHF.

Effects of serial levosimendan infusions on left ventricular performance and plasma biomarkers of myocardial injury and neurohormonal and immune activation in patients with advanced heart failure.

BACKGROUND: Levosimendan is a novel inodilator that improves central haemodynamics and symptoms of patients with decompensated chronic heart failure. The role, however, of repeated levosimendan infusions in the management of these patients has not yet been properly assessed. PURPOSE: This randomised placebo-controlled trial investigated the effects of serial levosimendan infusions on cardiac geometry and function, and on biomarkers of myocardial injury and neurohormonal and immune activation (troponin T, N-terminal B-type natriuretic pro-peptide (NT-proBNP), C reactive protein (CRP) and interleukin (IL) 6) in patients with advanced heart failure. METHODS: 25 patients with decompensated chronic heart failure were randomised (2:1) to receive five serial 24-h infusions (every 3 weeks) of either levosimendan (n = 17) or placebo (n = 8), and were evaluated echocardiographically and biochemically before and after each drug infusion and 30 days after the final infusion. RESULTS: Following treatment, cardiac end-systolic and end-diastolic dimension and volume indices were significantly reduced only in the levosimendan-treated patients (p<0.01). A significant decrease in NT-proBNP (p<0.01), high-sensitivity CRP (p<0.01) and plasma IL6 (p = 0.05) was also observed in the levosimendan group, whereas these markers remained unchanged in the placebo group; similar changes were observed after each drug infusion. Although the number of patients with a positive troponin T (>or=0.01 ng/ml) was not different between the two groups at baseline, it was significantly higher in the placebo-treated group during the final evaluation (p<0.05). CONCLUSION: Serial levosimendan treatments improved left ventricular performance and modulated neurohormonal and immune activation beneficially in patients with advanced heart failure, without increasing myocardial injury.

Increased C reactive protein and cardiac enzyme levels after coronary stent implantation. Is there protection by remote ischaemic preconditioning?

AIM: To investigate whether remote ischaemic preconditioning (RIPC) can attenuate the inflammatory response and enzyme leakage that can occur after uncomplicated routine percutaneous coronary intervention (PCI). METHODS: 41 consecutive normotensive patients with stable angina and single-vessel disease were assigned to be exposed to RIPC (n = 20) or not (control group; n = 21) before elective PCI with stent implantation. RIPC was induced by three cycles of 5-min ischaemia-reperfusion of both upper limbs (inflation/deflation of blood pressure cuff). C reactive protein (CRP), creatine phosphokinase (CK), CK cardiac isoenzyme (CK-MB) and troponin I (TNI) were serially measured for 48 h. RESULTS: No difference in baseline values was observed between the groups. The CRP rose significantly (p<0.001) and at 48 h was similarly increased (>fourfold) in both groups (15.7 (2.6) v 14.0 (3.3) mg/l, RIPC v control; p = NS). However, sub-group analysis on the basis of statin use showed that the highest rise was in the group of patients with RIPC not taking statins and was significantly greater than in patients with RIPC taking statins (23.8 (3.71) v 11.4 (3.0) mg/l, respectively, p<0.01). Both CK-MB and TNI leakage were raised (slightly but significantly) after PCI in controls at 24 h compared with baseline values. However, this small rise was significantly worse after RIPC (CK-MB, 1.33 (0.27) v 3.57 (0.97) ng/ml, p<0.01; TNI, 0.255 (0.059) v 0.804 (0.232) ng/ml, p<0.05, respectively at 24 h). The increase was more marked in the RIPC subgroup not taking statins. CONCLUSIONS: RIPC does not reduce, but exacerbates, the enzyme and TNI release from the heart after single-vessel angioplasty with stent. Furthermore, the increased circulating CRP remains raised. It seems that there is an enhanced inflammatory response after RIPC in the absence of statin treatment.

Dobutamine echocardiographic study in patients with nonischemic dilated cardiomyopathy and prognostically borderline values of peak exercise oxygen consumption: 18-month follow-up study.

OBJECTIVES: We sought to study the prognostic value of dobutamine echocardiography in patients with nonischemic dilated cardiomyopathy (DCM) and prognostically borderline values of peak oxygen consumption (VO2max) during exercise. BACKGROUND: Changes in echocardiographic variables assessed by dobutamine echocardiography can be used to evaluate the functional status of patients with chronic heart failure (CHF) and DCM. METHODS: In 27 consecutive patients (mean age 55 +/- 15 years) with VO2max values between 10 and 14 ml/kg body weight per min, a low infusion rate (10 microg/kg per min) dobutamine echocardiographic test was performed. The induced changes in echocardiographic variables were measured, and an 18-month follow-up study was done. RESULTS: At the end of the protocol, 9 patients (group I) had died from cardiac reasons, whereas the remaining 18 patients (group II) survived. After dobutamine infusion, the left ventricular end-systolic diameter (LVESD) was smaller in group II (6.22 +/- 0.94 cm) than in group I (6.99 +/- 0.76 cm; p < 0.05), whereas end-systolic wall stress (ESWS) was higher in group I (1030.66 +/- 193.98 g/cm2) than in group II (691.57 +/- 297.06 g/cm2; p < 0.05). The changes in LVESD and ESWS were greater in group I (0.75 +/- 0.36 cm and 463.11 +/- 159.87 g/cm2, respectively) than in group II (-0.04 +/- 0.36 cm and 83.16 +/- 291.74 g/cm2, respectively; p < 0.01 for both). CONCLUSIONS: In the "gray" zone of VO2max, dobutamine echocardiography seems to be a valuable prognostic indicator in patients with CHF and DCM.

Serial evaluation of coronary flow reserve by transesophageal doppler echocardiography after angioplasty of proximal left anterior descending coronary artery: a 6-month follow-up study.

BACKGROUND: Coronary flow reserve can be estimated by transesophageal Doppler echocardiography (TDE). OBJECTIVE: To evaluate the coronary flow reserve by TDE, serially over 6 months' follow-up, after successful percutaneous transluminal coronary angioplasty (PTCA) of proximal left anterior descending coronary artery (LADA). METHODS AND RESULTS: We performed TDE examination of 30 patients (mean age 55 +/- 9 years) 72 h, 3 months, and 6 months after PTCA of LADA. Selective angiography of LADA was repeated 72 h and 6 months after PTCA of LADA. Velocity of flow in LADA was measured before and 2 min after cessation of intravenous infusion of dipyridamole (0.56 mg/kg in 4 min). The dipyridamole: rest mean diastolic velocity ratio was considered as an index of coronary flow reserve (CFR). For 20 of 21 patients with CFR > 2 there was no restenosis, whereas coronary angiography revealed restenosis in eight of nine patients with CFR < 2. The sensitivity was 88.9% and the specificity was 95.2%. For the 21 patients without restenosis mean CFR was 2.1 +/- 0.1 72 h after PTCA, had increased to 3.1 +/- 0.3 (P < 0.0001) 3 months after PTCA, and remained stable thereafter (3.0 +/- 0.9). CONCLUSION: CFR after PTCA of proximal LADA can be evaluated serially by transesophageal Doppler echocardiography. CFR of LADA in patients without restenosis is increased 3 months after PTCA and remains stable thereafter.

Assessment of the functional status of heart failure in non ischemic dilated cardiomyopathy: an echo-dobutamine study.

BACKGROUND: The functional status of heart failure (HF) is conventionally evaluated by peak exercise oxygen consumption (VO2 max). Dobutamine echocardiography can be used to evaluate myocardial reserve. The aim of this study was to estimate the functional status of chronic HF in patients with dilated cardiomyopathy, by investigating the changes in echo-variables, as assessed by echo-dobutamine, in relation with VO2 max. METHODS AND RESULTS: A low infusion rate echo-dobutamine test (10 micrograms/kg/min) was performed in 30 patients with dilated cardiomyopathy and 1 h later VO2 max was measured. VO2 max (ranging from 7.6 to 23 ml/kg/min, mean 14.06 +/- 0.64 ml/kg/min) was correlated with the changes (values obtained after inotropic stimulation minus those obtained at baseline) in left ventricular end-systolic diameter (r:0.80, p:0.001), in left ventricular end-systolic posterior wall thickness (r:0.73, p:0.001) and in left ventricular heart-rate corrected mean velocity of circumferential fiber shortening (Vcfc)/end-systolic meridional wall stress ratio (r:0.64, p:0.0001). A negative correlation was found between VO2 max and the changes in end-systolic meridional wall stress (r: -0.76, p:0.001). After dobutamine infusion Vcfc/systolic meridional wall stress ratio increased in patients with VO2 max > 14 ml/kg/min but decreased in patients with VO2 max < 14 ml/kg/min (0.0001 +/- 0.0001 vs -0.0002 +/- 0.0003 circ x cm2/g x s, p:0.0001). End-systolic meridional wall stress was decreased in patients with VO2 max > 14 ml/kg/min but increased in patients with VO2 max < 14 ml/kg/min (-126.97 +/- 34.24 vs 205.77 +/- 56.71 g/cm2, p:0.0001). CONCLUSION: The changes in echo-variables assessed by echo-dobutamine are well correlated with VO2 max and seem to be accurate for evaluating the functional status of chronic HF in patients with dilated cardiomyopathy.

Pulmonary vein flow analysis by transoesophageal echocardiogr phy in patients with chronic atrial fibrillation; 1 year follow-up after cardioversion.

AIMS: Left and right upper pulmonary vein flow can be adequately recorded by transoesophageal Doppler echocardiography. The aim of this study was to investigate whether analysis of the pulmonary venous flow velocity pattern can predict the long-term maintenance of sinus rhythm after successful cardioversion of chronic atrial fibrillation. METHODS AND RESULTS: Thirty-six consecutive patients, aged 53+/-9 years, with chronic atrial fibrillation of 5.33+/-2 months duration, were subjected to transoesophageal Doppler echocardiography to record left and right upper pulmonary venous flow, 24 h and 3 months following successful cardioversion. One year following cardioversion, 12 patients (33.3%) were in sinus rhythm (sinus rhythm group) while the remaining 24 patients were in atrial fibrillation (atrial fibrillation group). At 24 h following cardioversion, biphasic systolic forward flow in the left and/or right upper pulmonary venous flow velocity was detected in 10 patients of the sinus rhythm group and in four patients of the atrial fibrillation group (P<0001). The systolic fraction was significantly higher in the sinus rhythm group, 0.48+/-0.04 and 0.39+/-0.06, P<0.001 for the left upper pulmonary venous flow, and 0.52+/-0.05 and 0.41+/-0.04, P<0.001 for the right upper pulmonary venous flow, respectively. In patients who displayed a biphasic systolic forward flow and in whom the right upper pulmonary venous flow systolic fraction was higher than 0.50 at 24 h post-cardioversion, the probability of maintenance of sinus rhythm at 1 year exceeded 95%. CONCLUSION: The detection of a biphasic systolic forward flow in the pulmonary venous flow velocity, and of a right upper pulmonary vein systolic fraction higher than 0.50 as early as 24 h following cardioversion of chronic atrial fibrillation, identifies patients who will remain in sinus rhythm 1 year after cardioversion.

Prospective randomized trial of external versus internal transcatheter cardioversion in patients with chronic atrial fibrillation.

To evaluate the safety and long-term efficacy of internal transcatheter cardioversion, forty patients with chronic, lone atrial fibrillation were studied. The patients were randomised to internal transcatheter cardioversion or to conventional external cardioversion. In cases where the procedure was unsuccessful, cross-over to the alternate method was performed. Oral anticoagulation therapy was started three weeks prior to the procedure and was maintained for another three weeks following successful cardioversion. Sinus rhythm was restored in 16/18 patients (88%) in the internal cardioversion group, versus 9/22 patients (40%) in the external cardioversion group (p < 0.01). In addition, 8/13 (61%) patients who were crossed-over to internal cardioversion were successfully cardioverted to sinus rhythm. In contrast, both patients who were crossed-over to external cardioversion remained in atrial fibrillation. During a mean follow-up period of 23 months, 13 (39.3%) patients maintained sinus rhythm. Using the intention to treat principle, the recurrence rate was not statistically different between the two methods. It is concluded that internal cardioversion is more effective in acutely restoring sinus rhythm compared to external cardioversion. However, both methods have similar long-term recurrence rates.

Transesophageal Doppler evaluation of left anterior descending coronary artery angioplasty.

Transesophageal Doppler echocardiography can noninvasively evaluate the functional results of left anterior descending coronary artery angioplasty. Coronary flow reserve assessed by this technique is significantly increased only in those patients with less severe residual stenosis as detected by intravascular ultrasound, thus allowing a noninvasive assessment of the results of left anterior coronary artery angioplasty.

Coronary collateral blood-flow velocity improves with repeated coronary occlusions during angioplasty in patients with coronary artery disease and systemic hypertension.

BACKGROUND: Cardiac hypertrophy is associated with numerous alterations in the coronary circulation. OBJECTIVE: To test the hypothesis that, during angioplasty, the coronary collateral blood flow during repetitive coronary occlusions increases more in hypertensives than it does in normotensives. METHODS: We studied 34 patients (22 normotensives and 12 hypertensives) with stable angina and single-vessel disease undergoing coronary angioplasty during two similar balloon inflations. Each balloon inflation was maintained for 120 s. The coronary blood flow velocity was estimated using the Doppler-flow guide wire, which was positioned distally to the lesion. Flow velocities were recorded before balloon deflation. RESULTS: The average peak velocity increased by 29.0 +/- 14.7 mm/s in the hypertensives and decreased by 9.4 +/- 4.9 mm/s in the normotensives (P < 0.01) during the second balloon inflation, whereas the velocity-time integral increased by 33.1 +/- 19.2 mm and decreased by 14.3 +/- 11.3 mm (P < 0.05), respectively. The ST-segment elevation decreased by 1.13 +/- 1.27 and by 0.17 +/- 0.16 mV, respectively (P = 0.01). The increase in the average peak velocity which occurred during the second balloon inflation was related to the left ventricular mass (r = 0.47, P = 0.004). CONCLUSION: These results indicate that the coronary collateral blood flow velocity improves with repetitive coronary occlusions during angioplasty in patients with systemic hypertension and that this increase is correlated to the left ventricular mass.

Coronary flow reserve assessed by transesophageal echocardiography identifies early restenosis of the left anterior descending coronary artery angioplasty.

Although an increase in diastolic coronary flow velocity can be detected by transesophageal echocardiography 72 hours after both successful and unsuccessful left anterior coronary artery angioplasty, a significant improvement in coronary flow reserve is observed only in patients with a successful procedure. Transesophageal echocardiography-derived coronary flow reserve can identify early restenosis and thus serve as an index of the outcome of the procedure.

Protection from preconditioning can be reinstated at various reperfusion intervals.

The aim of this study was to evaluate the way in which short-term protection declines and is eventually lost in preconditioning and to determine the efficacy of a second preconditioning at various reperfusion intervals. Male rabbits were divided into six groups. Forty-five minutes (sustained) ischemia followed by 120 minutes reperfusion was applied 60, 65, 70, 75, and 80 minutes after a 5 minute preconditioning (groups A, B, C, D, and E) and in a control group (F) after no preconditioning. The infarct to risk ratio (I/R) was 38.3 +/- 3.5% in group A, 46.0 +/- 7.8% in B, 61.6 +/- 9.7% in C, 68.1 +/- 4.2% in D, 64.5 +/- 7.8% in E, and 61.0 +/- 7.7% in F. Group A had a smaller I/R compared with groups C, D, E, and F (p < 0.05). In another series, groups G, H, and I were exposed to two 5-minute preconditioning stimuli, separated, respectively, by 45, 60, and 75 minutes of reperfusion; 10 minutes after the last preconditioning, the animals were exposed to 45-minutes ischemia and 120 minutes reperfusion. Groups A and D (with the smaller and higher I/R ratio) were also incorporated into this protocol in order to compare the effect of the additional preconditioning with the single one. The I/R ratio was 25.4 +/- 8.5% in group G, 22.8 +/- 7.0% in group H, and 14.7 +/- 4.0% in group I (p = NS). Group D showed a higher I/R compared with groups G, A, and H (p < 0.01), and group I had a smaller I/R compared with groups A (p < 0.01) and D (p < 0.001). Cardioprotection after a first preconditioning declines gradually and is eventually lost. An additional preconditioning is always effective, and the longer the interval from the first preconditioning, the more potent is the effect.