QTc Interval Prolongation and Life-Threatening Arrhythmias During Hospitalization in Patients With Coronavirus Disease 2019 (COVID-19): Results From a Multicenter Prospective Registry.

BACKGROUND: Prolonged QTc intervals and life-threatening arrhythmias (LTA) are potential drug-induced complications previously reported with antimalarials, antivirals, and antibiotics. Our objective was to evaluate the prevalence and predictors of QTc interval prolongation and incidences of LTA during hospitalization for coronavirus disease 2019 (COVID-19) among patients with normal admission QTc. METHODS: We enrolled 110 consecutive patients in a multicenter international registry. A 12-lead electrocardiograph was performed at admission, after 7, and at 14 days; QTc values were analyzed. RESULTS: After 7 days, 15 (14%) patients developed a prolonged QTc (pQTc; mean QTc increase 66 ± 20 msec; +16%; P < .001); these patients were older and had higher basal heart rates, higher rates of paroxysmal atrial fibrillation, and lower platelet counts. The QTc increase was inversely proportional to the baseline QTc level and leukocyte count and directly proportional to the basal heart rate (P < .01).We conducted a multivariate stepwise analysis including age, male gender, paroxysmal atrial fibrillation, basal QTc values, basal heart rate, and dual antiviral therapy; age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.00-1.13; P < .05), basal heart rate (OR, 1.07; 95% CI, 1.02-1.13; P < .01), and dual antiviral therapy (OR, 12.46; 95% CI, 2.09-74.20; P < .1) were independent predictors of QT prolongation.The incidence rate of LTA during hospitalization was 3.6%. There was 1 patient who experienced cardiac arrest and 3 with nonsustained ventricular tachycardia. LTAs were recorded after a median of 9 days from hospitalization and were associated with 50% of the mortality rate. CONCLUSIONS: After 7 days of hospitalization, 14% of patients with COVID-19 developed pQTc; age, basal heart rate, and dual antiviral therapy were found to be independent predictors of pQTc. Life-threatening arrhythmias have an incidence rate of 3.6%, and were associated with a poor outcome.

Effect of SAcubitril/Valsartan on left vEntricular ejection fraction and on the potential indication for Implantable Cardioverter Defibrillator in primary prevention: the SAVE-ICD study.

PURPOSE: Sacubitril/valsartan has been associated with a positive reverse left ventricular remodelling in patients with heart failure with reduced ejection fraction (HFrEF). These patients may also benefit from an ICD implant. We aimed to assess EF improvement after 6 months of treatment with sacubitril/valsartan, evaluating when ICD as primary prevention was no longer indicated. METHODS: Multicentre, observational, prospective study enrolling all consecutive patients with HFrEF and EF ≤ 35% with an ICD as primary prevention and starting treatment with sacubitril/valsartan (NCT03935087). Resynchronization therapy and patients experiencing appropriate ICD therapies before sacubitril/valsartan were excluded. RESULTS: Two-hundred-and-thirty patients were enrolled (73.9% males, mean age 64.3 ± 12.1 years) After 6 months of treatment, a reduction in left ventricular end-diastolic and end-systolic volumes was noted and LVEF increased from 28.3 ± 5.6% to 32.2 ± 6.5% (p < 0.001). At 6 months, a non-ischemic aetiology of cardiomyopathy and a final dose of sacubitril/valsartan > 24/26 mg twice daily were associated with a higher probability of an absolute increase of > 5% in LVEF. A total of 5.3% of primary prevention patients still had an arrhythmic event in the first 6 months after treatment with sacubitril/valsartan started. CONCLUSIONS: Sacubitril/valsartan improves systolic function in HFrEF, mainly due to reverse left ventricular remodelling. Improvement in EF after 6 months of treatment could help prevent ICD implantation in nearly one out of four patients, with important clinical and economic implications. However, the risk of sudden cardiac death in this recovered HFrEF population has not been thoroughly studied, and the present data should be interpreted only as hypothesis-generating.

Impact of intra-aortic balloon counterpulsation on all-cause mortality among patients with Takotsubo syndrome complicated by cardiogenic shock: results from the German-Italian-Spanish (GEIST) registry.

Aims: Takotsubo syndrome (TTS) is an acute and reversible left ventricular dysfunction and can be complicated by cardiogenic shock (CS). However, few data are available on optimal care in TTS complicated by CS. Aim of this study was to evaluate short- and long-term impact of intra-aortic balloon pumping (IABP) on mortality in this setting. Methods and results: In a multi-centre, international registry on TTS, 2248 consecutive patients were enrolled from 38 centres from Germany, Italy, and Spain. Of the 2248 patients, 212 (9.4%) experienced CS. Patients with CS had a higher prevalence of diabetes (27% vs. 19%), male sex (25% vs. 10%), and right ventricular involvement (10% vs. 5%) (P < 0.01 in all cases). Forty-three patients with CS (20% of 212) received IABP within 8 h (interquartile range 4-18) after admission. No differences in terms of age, gender, cardiovascular risk factors, and admission left ventricular ejection fraction were found among patients with and without IABP. There were no significant differences in terms of 30-day mortality (16% vs. 17%, P = 0.98), length of hospitalization (18.9 vs. 16.7 days, P = 0.51), and need of invasive ventilation (35% vs. 41%, P = 0.60) among two groups: 30-day survival was not significantly different even after propensity score adjustment (log-rank P = 0.73). At 42-month follow-up, overall mortality in patients with CS and TTS was 35%, not significantly different between patients receiving IABP and not (37% vs. 35%, P = 0.72). Conclusions: In a large multi-centre observational registry, the use of IABP was not associated with lower mortality rates at short- and long-term follow-up in patients with TTS and CS.

Prognostic role of neoplastic markers in Takotsubo syndrome.

Takotsubo syndrome (TTS) is an acute heart failure syndrome with significant rates of in and out-of-hospital mayor cardiac adverse events (MACE). To evaluate the possible role of neoplastic biomarkers [CA-15.3, CA-19.9 and Carcinoembryonic Antigen (CEA)] as prognostic marker at short- and long-term follow-up in subjects with TTS. Ninety consecutive subjects with TTS were enrolled and followed for a median of 3 years. Circulating levels of CA-15.3, CA-19.9 and CEA were evaluated at admission, after 72 h and at discharge. Incidence of MACE during hospitalization and follow-up were recorded. Forty-three (46%) patients experienced MACE during hospitalization. These patients had increased admission levels of CEA (4.3 ± 6.2 vs. 2.2 ± 1.5 ng/mL, p = 0.03). CEA levels were higher in subjects with in-hospital MACE. At long term follow-up, CEA and CA-19.9 levels were associated with increased risk of death (log rank p < 0.01, HR = 5.3, 95% CI 1.9-14.8, HR = 7.8 95% CI 2.4-25.1, respectively, p < 0.01). At multivariable analysis levels higher than median of CEA, CA-19.9 or both were independent predictors of death at long term (Log-Rank p < 0.01). Having both CEA and CA-19.9 levels above median (> 2 ng/mL, > 8 UI/mL respectively) was associated with an increased risk of mortality of 11.8 (95% CI 2.6-52.5, p = 0.001) at follow up. Increased CEA and CA-19.9 serum levels are associated with higher risk of death at long-term follow up in patients with TTS. CEA serum levels are correlated with in-hospital MACE.

Neutrophil/lymphocyte ratio predicts in-hospital complications in Takotsubo syndrome. Results from a prospective multi-center registry.

BACKGROUND: Several hematological indices including subtypes of leukocytes populations have been associated with cardiovascular outcome. Takotsubo syndrome (TTS) is a form of acute heart failure syndrome featured by several in-hospital complications (IHCs). HYPOTHESIS: Hematological indices at admission may predict IHCs in TTS patients. METHODS: One hundred and sixty consecutive patients with TTS were enrolled in a multicenter prospective registry. Clinical data, admission hemogram, and IHCs were recorded. RESULTS: Incidence of IHCs was 37%, including pulmonary edema 9%, cardiogenic shock 9%, need of invasive ventilation 10%, death 8%, stroke 2.5%, and left ventricular thrombi 6%. Patients with IHCs were older, more frequently male, with physical stressor-induced TTS, lower left ventricular ejection fraction at admission. Neutrophil/lymphocyte ratio (NLr) (12 ± 12 vs 7 ± 8, P = .002) and white blood cells/mean platelet volume ratio (1.2 ± 0.5 vs 1.0 ± 0.5, P = .03) at admission were significantly higher in patients with IHCs. NLr values were predictor of IHCs (Odds ratios [OR] 1.07, 95% CI 1.03-1.11, P < .01). When stratified according to NLr into tertiles, the rate of IHCs was from first to third tertile was, respectively, 22%, 31%, and 58%. NLr values in the higher tertile were independent predictors of IHCs even at multivariate analysis (OR 3.7, 95% CI 1.5-9.4, P < .01). NLr values higher than 5 were able to predict IHCs with a sensitivity of 82% and specificity of 58%; negative predictive power was 84% (area under the ROC curve 0.73). CONCLUSIONS: NLr is an independent predictor of IHCs in patients admitted with TTS. Admission hemogram may represent a potential tool for prediction of IHCs in TTS.

Assessment of the German and Italian Stress Cardiomyopathy Score for Risk Stratification for In-hospital Complications in Patients With Takotsubo Syndrome.

Importance: Takotsubo syndrome (TTS) is an acute, reversible heart failure syndrome featured by significant rates of in-hospital complications. There is a lack of data for risk stratification during hospitalization. Objective: To derive a simple clinical score for risk prediction of in-hospital complications among patients with TTS. Design, Setting, and Participants: In this prognostic study, 1007 consecutive patients were enrolled in the German and Italian Stress Cardiomyopathy (GEIST) registry from July 1, 2007, through December 31, 2017, and identified as the derivation cohort; 946 patients were enrolled in the Spanish Registry for Takotsubo Cardiomyopathy (RETAKO) as the external score validation. An admission risk score was developed using a stepwise multivariable regression analysis from 2 registries. Data analysis was performed from March 1, 2018, through July 31, 2018. Main Outcomes and Measures: In-hospital complications were defined as death, pulmonary edema, need for invasive ventilation, and cardiogenic shock. Four variables were identified as independent predictors of in-hospital complications and were used for the score: male sex, history of neurologic disorder, right ventricular involvement, and left ventricular ejection fraction (LVEF). Results: Of the 1007 patients enrolled in the GEIST registry, 107 (10.6%) were male, with mean (SD) age of 69.8 (11.4) years. Overall rate of in-hospital complications was 23.3% (235 of 1007) (death, 4.0%; pulmonary edema, 5.8%; invasive ventilation, 6.4%; and cardiogenic shock, 9.1%). The GEIST prognosis score was derived by providing 20 points each for male sex and history of neurologic disorders and 30 points for right ventricular involvement and then subtracting the value in percent of LVEF (decimal values between 0.15 and 0.70). Score accuracy on area under the receiver operating characteristic curve analysis was 0.71, with a negative predictive power of 87% with scores less than 20. External validation in the RETAKO population (124 [13.1%] male; mean [SD] age, 69.5 [14.9] years) revealed an area under the curve of 0.73 (P = .46 vs GEIST derivation cohort). Stratification into 3 risk groups (<20, 20-40, and >40 points) classified 316 patients (40.9%) as having low risk; 342 (44.3%) as having intermediate risk, and 114 (14.8%) as having high risk of complications. The observed in-hospital complication rates were 12.7% for low-risk patients, 23.4% for intermediate-risk patients, and 58.8% for high-risk patients (P < .001 for trend). After 2.6 years of follow-up, patients with in-hospital complications had significantly higher rates of mortality than those without complications (40% vs 10%, P = .01). Conclusions and Relevance: The GEIST prognostic score may be useful in early risk stratification for TTS. High-risk patients with TTS may require an intensive care unit stay, and low-risk patients with TTS could be discharged within a few days. In-hospital complications in patients with TTS may be associated with increased risk of long-term mortality.

Calcium release channel RyR2 regulates insulin release and glucose homeostasis.

The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic ß cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in ß cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a "leaky" RyR2 channel, we exploited them to assess RyR2 channel function in ß cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and ß cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.

[Safe dose rTPA for massive pulmonary embolism associated with high bleeding risk: a case report and review of the literature]. / Utilizzo di safe dose di rTPA nel trattamento dell'embolia polmonare massiva associata ad elevato rischio emorragico: caso clinico e revisione della letteratura.

Systemic thrombolysis is a well known treatment for massive pulmonary embolism (PE) but it remains often underutilized in clinical practice because of the risk of major bleeding, especially intracranial hemorrhage. Recently, the use of safe-dose recombinant tissue-type plasminogen activator (rTPA) has been proposed for the treatment of moderate PE demonstrating to be safe and more effective than standard anticoagulation. We report the case of an 83-year-old male patient affected by massive PE associated with high bleeding risk, and treated with half-dose of rTPA that resulted in rapid clinical improvement. This clinical experience led us to focus on the role of reduced doses of rTPA to decrease bleeding risk in patients with PE. We conclude that the new concept of "safe-dose thrombolysis" with rTPA may be considered a reasonable and interesting option in high-bleeding risk patients with massive PE.

[The effectiveness of the elastic bandage in reducing residual limb volume in patients with lower limb amputation: literature review]. / L'efficacia del bendaggio elastico nel ridurre il volume del moncone nei pazienti con amputazione degli arti inferiori: revisione della letteratura.

UNLABELLED: The effectiveness of the elastic bandage in reducing residual limb volume in patients with lower limb amputation: literature review. INTRODUCTION: Several banding techniques are available to contain and reduce the edema of the stump after an amputation of a limb, but there is also uncertainty on the most effective way to treat this problem. AIMS: The aim of this review is to compare the effectiveness of the elastic bandage, with other types of bandage, in reducing the stump's volume in patients with lower limb amputation. MATERIALS AND METHODS: A literature review up to april 2011 was performed on Medline, Trip Database, Ovid, CINAHL and Pedro. The outcome measure was the reduction of edema and volume of the stump expressed as circumference and number of days elapsed between the operation and the prosthesis. RESULTS: Ten articles were retrieved: five randomized controlled trials, a comparative study, a multicentre retrospective study, a retrospective audit, a case control study and a systematic review of the literature. The volume reduction of the stump of patients treated with the elastic bandage require longer compared to a stump treated with removable or semi-rigid bandage even though the gain was significant only in the first two weeks. DISCUSSION: The semi rigid and semi-rigid removable dressing are more effective in the reduction of the edema of the stump compared to the elastic bandage, but only in the short to medium term. There are, however, conflicting results on their effectiveness in the long term period (>3 weeks).

Randomised trial comparing biweekly oxaliplatin plus oral capecitabine versus oxaliplatin plus i.v. bolus fluorouracil/leucovorin in metastatic colorectal cancer patients: results of the Southern Italy Cooperative Oncology study 0401.

PURPOSE: Oxaliplatin combined with either fluorouracil/leucovorin (OXAFAFU) or capecitabine (OXXEL) has a demonstrated activity in metastatic colorectal cancer patients. We aimed at comparing these two regimens in terms of response rate (RR), safety, progression-free survival (PFS), and quality of life (QoL) of patients. METHODS: A total of 322 patients with metastatic colorectal cancer were randomized to receive biweekly: oxaliplatin 100 mg/m(2) i.v. on day 1, capecitabine 1,000 mg/m(2) orally twice daily from day 1 to day 11 (OXXEL); or oxaliplatin 85 mg/m(2) i.v. on day 1; 6S-leucovorin 250 mg/m(2) i.v. and fluorouracil 850 mg/m(2) i.v. on day 2 (OXAFAFU). RESULTS: Eleven complete and 42 partial responses were registered with OXXEL (RR = 34%); six complete and 48 partial responses were obtained with OXAFAFU (RR = 33%) (P = 0.999). Severe adverse events were less frequent (32 vs. 43%) with OXXEL, which also reduced the occurrence of severe neutropenia (10 vs. 27%) and febrile neutropenia (6 vs. 13%), but produced more gastric side effects (8 vs. 3%) and diarrhea (13 vs. 8%). QoL did not differ across the two arms. Median PFS was 6.6 months in the OXXEL, and 6.5 months in the OXAFAFU arm (HR = 1.12, P = 0.354). Median overall survival was 16.0 and 17.1 months (HR = 1.01, P = 0.883). CONCLUSIONS: OXXEL and OXAFAFU regimens were equally active in metastatic colorectal cancer. The choice should be based on patient preference and on pharmacoeconomic evaluations.

Oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer: a multicenter phase II trial of the Southern Italy Cooperative Oncology Group.

PURPOSE: This phase II trial assessed the tolerability and efficacy of a triplet of oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer. METHODS: Patients with unresectable or metastatic gastric cancer, unexposed to palliative chemotherapy, received oxaliplatin 85 mg/m(2) iv and irinotecan 150 mg/m(2) iv on day 1, 6S-folinic acid 250 mg/m(2) iv and fluorouracil 750 mg/m(2) iv on day 2, every 2 weeks. Response rate (RR) was assessed after a minimum of four cycles, and treatment continued up to 12 cycles. RESULTS: Sixty-three patients were treated, with a median of eight (range 1-12) cycles/patient. Two complete and 19 partial responses were registered (RR 33% [95% CI, 22-46%]). Median progression-free survival was 7.5 (95% CI, 5.6-9.4) months, and median overall survival was 12.1 (95% CI, 10.8-13.4) months. Most common grade > or =3 toxicities were neutropenia (59%), febrile neutropenia (7%), vomiting (20%), and diarrhoea (10%). All-grade neurotoxicity affected 33% of patients. CONCLUSIONS: Oxaliplatin, irinotecan, and fluorouracil/folinic acid administered every 2 weeks are safe and active in advanced gastric cancer.

Capecitabine plus oxaliplatin for the first-line treatment of elderly patients with metastatic colorectal carcinoma: final results of the Southern Italy Cooperative Oncology Group Trial 0108.

BACKGROUND: In patients with metastatic colorectal carcinoma (MCC), capecitabine has demonstrated a superior response rate (RR), equivalent disease progression-free (PFS) and overall survival (OS), and an improved overall tolerability profile compared with bolus 5-fluorouracil/leucovorin (5-FU/LV). The FOLFOX4 regimen, combining oxaliplatin with LV and bolus plus infusional 5-FU (LV5FU2), has been shown to improve RR and PFS versus LV5FU2, and it was more effective and less toxic than irinotecan plus bolus 5-FU/LV. Capecitabine (an oral fluoropyrimidine) may be an effective, well tolerated, and more convenient alternative to 5-FU/LV in combination with oxaliplatin, especially in older patients. METHODS: Elderly (> or = 70 years) patients with MCC were treated with a 3-weekly regimen of oxaliplatin at an initial dose of 85 mg/m(2) intravenously on Day 1 plus capecitabine 1000 mg/m(2) orally twice daily from Days 2 to 15 (XELOX regimen). In the absence of Grade > or = 2 hematologic toxicity, oxaliplatin was increased to 100 mg/m(2) in the second cycle, and in the absence of Grade > or = 2 nonhematologic adverse events during Cycle 2, capecitabine was increased to 1250 mg/m(2) twice daily in the third and subsequent cycles. After the first 35 patients (first series), the treatment protocol was amended so that only an oxaliplatin increase to 110 mg/m(2) and 130 mg/m(2) during Cycles 2 and 3, respectively, was planned in the remaining 41 patients (second series). RESULTS: Seventy-six patients with a median age of 75 years (range, 70-82 years) entered the current study. In the first series, the oxaliplatin dose was increased in 18 (51%) patients, and the capecitabine dose was increased in 4 (11%) patients. In the second series, the oxaliplatin dose was increased to 110 mg/m(2) in 26 (63%) patients, and to 130 mg/m(2) in 19 (46%) patients. In all, 2 complete and 29 partial responses were observed, for an overall RR of 41% (95% confidence interval [CI], 30-53%). The median PFS was 8.5 months (95% CI, 6.7-10.3 months), and the median OS was 14.4 months (95% CI, 11.9-16.9 months). In a multivariate analysis, the presence of disease symptoms affected both PFS and OS, whereas OS also was independently affected by male gender and disease spread. Age had no independent effect on PFS or OS. Five percent of patients developed Grade > or = 3 hematologic toxicity during treatment, Grade 3 peripheral neuropathy occurred in 8% of patients, and severe hand-foot syndrome in 13% of patients. CONCLUSIONS: Fit elderly patients with MCC showed a good RR to XELOX with only mild toxicity observed in most patients. XELOX, should, therefore be considered as an important therapeutic option for elderly patients with MCC.