Effect of Dronedarone on Exercise Capacity and Cardiac Function in Patients With Severe Left Ventricular Dysfunction and Compensated Stable Heart Failure

Purpose

Dronedarone is a novel multichannel blocker with antiadrenergic and vasodilatory properties. The aim of this study was to investigate the effects of dronedarone on functional capacity in patients with severe left ventricular (LV) dysfunction and compensated stable heart failure (HF).

Methods

This was a multicentre, double-blind, randomized, placebo-controlled, dose-escalating study. Patients in sinus rhythm with impaired LV function (LV ejection fraction [LVEF]?≤?30%) and compensated HF (New York Heart Association [NYHA] class I–II), who would continue to receive cardiovascular treatment (excluding antiarrhythmic agents), were eligible. A total of 124 patients were randomized to receive dronedarone (400 mg or 800 mg once daily or 600 mg twice daily) or placebo for 30 days. The primary objective was assessment of the effects of dronedarone on functional capacity, using the 6 min walk test. Secondary objectives included the effects of dronedarone on LVEF, cardiothoracic ratio, NYHA status, and Holter parameters.

Results

A total of 111 patients completed the study. There were no significant differences between dronedarone and placebo with respect to walking distance and LVEF. The cardiothoracic ratio was similar in all treatment groups throughout the study, and the NYHA status did not change in the majority of patients. Dronedarone was well tolerated and, as expected, decreased heart rate. No new arrhythmic events or torsades de pointes were reported.

Conclusions

Short-term treatment with dronedarone did not affect exercise capacity and did not decrease LVEF in patients with severe LV dysfunction and compensated HF.     

Effects of radiofrequency catheter ablation on left ventricular structure and function in patients with atrial fibrillation: a meta-analysis

Introduction

Radiofrequency catheter ablation (RFCA) is an effective therapy for atrial fibrillation (AF). This study was designed to investigate the effects of RFCA on left ventricular (LV) structure and function in AF patients.

Methods and Results

A systematic literature search in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials was performed to identify trials involving changes of LV structure and function in AF patients undergoing RFCA. Effect size was expressed as weighted mean difference (WMD) with 95 % confidence interval (CI). LV end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV ejection fraction (LVEF) were estimated. A total of 21 trials including 1,135 participants were qualified for this meta-analysis. Compared to the baseline values, there were significant decreases in LVEDV (WMD, ?6.39 ml; 95 %CI, ?12.46 to ?0.33) and LVESV (WMD, ?6.39 ml; 95 %CI, ?11.35 to ?1.42) and a significant improvement in LVEF (WMD, 6.23 %; 95 %CI, 3.70 to 8.75), but no significant changes were observed in LVEDD (WMD, ?0.64 mm; 95 %CI, ?2.40 to 1.13) and LVESD (WMD, ?0.38 mm; 95 %CI, ?1.32 to 0.56) after RFCA. Subgroup analysis demonstrated that patients with low LVEF (WMD, 11.90 %; 95 %CI, 9.16 to 14.64) gained more benefits than those with normal LVEF (WMD, 1.56 %; 95 %CI, 0.38 to 2.74). Besides, patients with chronic AF (WMD, 10.96 %; 95 %CI, 4.92 to 17.01) improved more than those with paroxysmal AF (WMD, 1.93 %; 95 %CI, ?0.27 to 4.12).

Conclusions

RFCA in AF patients could reverse LV structural remodeling and improve LV systolic function, especially in patients with low LVEF and chronic AF.     

Rationale and Design of a Randomized, Double-Blind, Placebo Controlled Multicenter Trial to Study Efficacy, Security, and Long Term Effects of Intermittent Repeated Levosimendan Administration in Patients with Advanced Heart Failure: LAICA study

Background

Advanced heart failure (HF) is associated with high morbidity and mortality; it represents a major burden for the health system. Episodes of acute decompensation requiring frequent and prolonged hospitalizations account for most HF-related expenditure. Inotropic drugs are frequently used during hospitalization, but rarely in out-patients. The LAICA clinical trial aims to evaluate the effectiveness and safety of monthly levosimendan infusion in patients with advanced HF to reduce the incidence of hospital admissions for acute HF decompensation.

Methods

The LAICA study is a multicenter, prospective, randomized, double-blind, placebo-controlled, parallel group trial. It aims to recruit 213 out-patients, randomized to receive either a 24-h infusion of levosimendan at 0.1 μg/kg/min dose, without a loading dose, every 30 days, or placebo.

Results

The main objective is to assess the incidence of admission for acute HF worsening during 12 months. Secondarily, the trial will assess the effect of intermittent levosimendan on other variables, including the time in days from randomization to first admission for acute HF worsening, mortality and serious adverse events.

Conclusions

The LAICA trial results could allow confirmation of the usefulness of intermittent levosimendan infusion in reducing the rate of hospitalization for HF worsening in advanced HF outpatients.     

Inhibition of atrial fibrillation by low-level vagus nerve stimulation: the role of the nitric oxide signaling pathway

Purpose

We examined the role of the phosphatidylinositol-3 kinase (PI3K)/nitric oxide (NO) signaling pathway in low-level vagus nerve stimulation (LLVNS)-mediated inhibition of atrial fibrillation (AF).

Methods

In 17 pentobarbital anesthetized dogs, bilateral thoracotomies allowed the attachment of electrode catheters to the superior and inferior pulmonary veins and atrial appendages. Rapid atrial pacing (RAP) was maintained for 6 h. Each hour, programmed stimulation was used to determine the window of vulnerability (WOV), a measure of AF inducibility, at all sites. During the last 3 h, RAP was overlapped with right LLVNS (50 % below that which slows the sinus rate). In group 1 (n?=?7), LLVNS was the only intervention, whereas in groups 2 (n?=?6) and 3 (n?=?4), the NO synthase inhibitor N ^G-nitro-l-arginine methyl ester (l-NAME) and the PI3K inhibitor wortmannin, respectively, were injected in the right-sided ganglionated plexi (GP) during the last 3 h. The duration of acetylcholine-induced AF was determined at baseline and at 6 h. Voltage–sinus rate curves were constructed to assess GP function.

Results

LLVNS significantly decreased the acetylcholine-induced AF duration by 8.2?±?0.9 min (p?<?0.0001). Both l-NAME and wortmannin abrogated this effect. The cumulative WOV (the sum of the individual WOVs) decreased toward baseline with LLVNS (p?<?0.0001). l-NAME and wortmannin blunted this effect during the fifth (l-NAME only, p?<?0.05) and the sixth hour (l-NAME and wortmannin, p?<?0.05). LLVNS suppressed the ability of GP stimulation to slow the sinus rate, whereas l-NAME and wortmannin abolished this effect.

Conclusion

The anti-arrhythmic effects of LLVNS involve the PI3K/NO signaling pathway.     

Left atrial reverse remodeling and prevention of progression of atrial fibrillation with atrial resynchronization device therapy utilizing dual-site right atrial pacing in patients with atrial fibrillation refractory to antiarrhythmic drugs or catheter ablation

Introduction

Dual-site right atrial pacing (DAP) produces electrical atrial resynchronization but its long-term effect on the atrial mechanical function in patients with refractory atrial fibrillation (AF) has not been studied.

Methods

Drug-refractory paroxysmal (PAF) and persistent AF (PRAF) patients previously implanted with a dual-site right atrial pacemaker (DAP) with minimal ventricular pacing modes (AAIR or DDDR mode with long AV delay) were studied. Echocardiographic structural (left atrial diameter [LAD] and left ventricular [LV] end diastolic diameter [EDD], end systolic diameter [ESD]) and functional (ejection fraction [EF]) parameters were serially assessed prior to, after medium-term (n?=?39) and long-term (n?=?34) exposure to DAP.

Results

During medium-term follow-up (n?=?4.5 months), there was improvement in left atrial function. Mean peak A wave flow velocity increased with DAP as compared to baseline (75?±?19 vs. 63?±?23 cm/s, p?=?0.003). The long-term impact of DAP was studied with baseline findings being compared with last follow-up data with a mean interval of 37?±?25 (range 7–145) months. Mean LAD declined from 45?±?5 mm at baseline to 42?±?7 mm (p?=?0.003). Mean LVEF was unchanged from 52?±?9 % at baseline and 54?±?6 % at last follow-up (p?=?0.3). There was no significant change in LV dimensions with mean LVEDD being 51?±?6 mm at baseline and 53?±?5 mm at last follow-up (p?=?0.3). Mean LVESD also remained unchanged from 35?±?6 mm at baseline to 33?±?6 mm at last follow-up (p?=?0.47). During long-term follow-up, 30 patients (89 %) remained in sinus or atrial paced rhythm as assessed by device diagnostics at 3 years.

Conclusions

DAP can achieve long-term atrial reverse remodeling and preserve LV systolic function. DAP when added to antiarrhythmic drug (AAD) and/or catheter ablation (ABL) maintains long-term rhythm control and prevents AF progression in elderly refractory AF patients. Reverse remodeling with DAP may contribute to long-term rhythm control.     

The impact of age on clinical outcomes following cardiac resynchronisation therapy

Background

Cardiac resynchronisation therapy (CRT) is an established treatment for selected patients with symptomatic left ventricular (LV) systolic dysfunction. Heart failure (HF) is primarily a disease of the elderly; however, these patients are underrepresented in CRT trials. Our aim was to evaluate the impact of age on clinical outcomes following CRT.

Methods

A consecutive series of 177 patients was identified and divided into those aged ≤75 years (n?=?131, mean ± SD 62.1?±?11.2 years) and those aged >75 years (n?=?46, mean ± SD 80.7?±?4.1 years). The primary end point was a composite of all-cause mortality or HF hospitalisation.

Results

During a median ± IQR follow up of 28.5?±?33.7 months, the event rate for the primary end point was significantly higher in the elderly compared to younger patients (20.1 vs. 11.1 %, respectively, logrank p?=?0.020). This was mainly driven by an excess mortality rate among those aged >75 years (10 vs. 4.7 %, respectively, logrank p?=?0.018) whereas HF hospitalisation rates were similar between groups (10 vs. 6.4 %, respectively, logrank p?=?0.301). After adjusting for comorbidities and ICD status, the difference in the composite end point rates was attenuated and no longer significant (HR 1.580, 95 % CI 0.899–2.778; p?=?0.112 for >75 vs. ≤75 years). Notably, both groups demonstrated similar response rates to CRT in terms of symptomatic improvement, reverse LV remodelling and neurohormonal activation.

Conclusions

CRT is equally effective in the elderly as in younger patients to reduce adverse clinical outcomes. For those who fulfil the prerequisite selection criteria, it should be considered as a valid therapeutic option.     

Dipeptidyl peptidase-4 inhibitors do not increase the risk of cardiovascular events in type 2 diabetes: a cohort study

Aims

Two recent randomized controlled trials of type 2 diabetes mellitus (T2DM) patients with history of, or at high risk of, cardiovascular disease (CVD) showed no risk of ischemic cardiovascular events associated with dipeptidyl peptidase-4 inhibitors (DPP4i), but an increased risk of heart failure (HF) with saxagliptin. We evaluated the risk of CVD including myocardial infarction (MI), stroke, coronary revascularization, and HF associated with DPP4i in T2DM patients with and without baseline CVD as used in the community.

Methods

Using US commercial insurance claims data (2005–2012), we conducted a cohort study that included initiators of DPP4i and non-DPP4i treatments. Composite CVD endpoints including MI, stroke, coronary revascularization, and HF were defined with a hospital discharge diagnosis or procedure code. Cox proportional hazards models compared the risk of composite and individual CVD endpoints in propensity score (PS)-matched initiators of DPP4 versus non-DPP4i.

Results

We included 79,538 (18 % with baseline CVD) persons in PS-matched pairs of DPP4i and non-DPP4i initiators. The incidence rate per 1,000 person-years for composite CVD was 30.30 (95 % CI 28.24–32.51) in DPP4i and 34.76 (95 % CI 32.34–37.36) in non-DPP4i. The PS-matched hazard ratio (HR) for composite CVD was 0.87 (95 % CI 0.79–0.96) in DPP4i versus non-DPP4i. The PS-matched HR for HF was 0.81 (95 % CI 0.70–0.94) in DPP4i versus non-DPP4i. Among patients with baseline CVD, there was no increased risk of CVD or HF associated with DPP4i use.

Conclusions

Among T2DM patients, initiating DPP4i was not associated with a greater risk of CVD or HF compared to non-DPP4i initiators.     

Recently introduced biomarkers for screening of hepatocellular carcinoma: a systematic review and meta-analysis

Purpose

Early detection of hepatocellular carcinoma (HCC) is essential for improved prognosis and long-term survival. To date, screening for HCC depends on serological testing (alpha-fetoprotein, AFP) and imaging (ultrasonography), both of which are not highly sensitive. A meta-analysis was performed to discuss recent developments in biomarkers that may be effective in screening for HCC.

Methods

A systematic search of PubMed, Embase, and Web of Science was performed for articles published between January 2005 and October 2010, and focusing on biomarkers for HCC in urine, serum, or saliva. Data on sensitivity and specificity of tests were extracted from each included article and displayed with a summary ROC. A meta-analysis was carried out in which the area under the curve for each biomarker was used to compare the accuracy of different tests.

Results

In seven well-defined studies, three biomarkers were identified for potential use, namely, Golgi protein 73 (GP73), interleukin-6 (IL-6), and squamous cell carcinoma antigen (SCCA). Comparison with AFP showed that GP73 was superior (p = 0.006; 95 % CL ?0.23, ?0.12), IL-6 was similar (p = 0.66; 95 % CL ?0.31, 0.25), and SCCA was inferior to AFP (p = 0.001; 95 % CL 0.12, 0.23).

Conclusion

GP73 is a valuable serum marker that seems to be superior to AFP and can be useful in the diagnosis and screening of HCC. Although GP73 may improve the detection and treatment of one of the most common malignancies worldwide, additional research is required.     

Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study

Background

Cardiotoxicity associated with 5-Fluorouracil (5FU) administration has been infrequently reported in literature, albeit various series of acute coronary syndromes have recorded a low but definite incidence of the above toxicity. In the present study, patients undergoing 5FU-based and oral capecitabine (Xeloda^®)-based chemotherapy were tested for the potential development of cardiac-related symptoms during their administration.

Patients and methods

Six hundred and forty-four patients entered the study. Those experiencing any cardiac-related symptoms during 5FU infusion or oral capecitabine were subjected to ECG and serum cardiac enzymes determination. If cardiotoxicity was confirmed, 5FU infusion or oral capecitabine were interrupted, sublingual nitrates administered and cardiac monitoring initiated, while patients with >two-fold enzyme elevation were followed in a coronary care unit for at least 72 h. Cases with acute myocardial infarction were excluded from further 5FU or oral capecitabine treatment.

Results

Overall 26 patients (4.03%) developed symptoms and/or ECG abnormalities due to 5FU and capecitabine. Patients with continuous 5FU infusion presented a higher incidence of cardiotoxicity [14/209; 6.7%, 95% confidence interval (CI) = 3.3–10.1%] than the remaining (7/317; 2.3%, 95% CI = 0.8–3.3%) (P < 0.012). Specifically, an increased incidence of cardiac-related events was encountered in patients with continuous 24-h 5FU + LV infusion for 5 days (12.5%, 95% CI = 2.3–22.7%) rather than in patients with the same schedule without LV (5.3%, 95% CI = 1.95–8.67%) (P < 0.027), as well as in patients with short 5FU + LV administration (2.4%, 95% CI = 0.9–3.9%) (P < 0.019). Overall, 3/54 patients (5.5%, 95% CI = ?0.6–11.1%) on oral capecitabine developed cardiac-related events. Seven out of the 20 patients suffered an acute myocardial infarction, 6 developed ischemia only, while 4 more patients had ECG consistent with coronary vasospasm and 3 with conduction disturbances, of which one subsequently died. Patients administered oral capecitabine had a similar incidence of cardiac-related events; 1/22 (4.5%) patients with advanced breast cancer and 2/32 (6.2%) with colorectal cancer.

Conclusions

The present study supports the toxic effect of 5-FU on the myocardium, which is largely schedule-dependent, whereas a low but finite risk of such toxicity has been observed with oral capecitabine. A high level of alertness is required when using fluoropyrimidines (i.v. 5FU or oral capecitabine), while their toxic effect on the coronary endothelium and myocardium merits further investigation.     

Influence of Intraluminal Acidification on Esophageal Secondary Peristalsis in Humans

Background

Secondary peristalsis contributes to clearance of retained refluxate or material from the esophagus.

Aim

The goal of our study was to investigate the effects of hydrochloric acid (HCl) on physiological characteristics of esophageal secondary peristalsis in healthy adults.

Methods

After recording esophageal motility baseline for primary peristalsis, secondary peristalsis was stimulated with slow and rapid air injections in the mid-esophageal in 16 healthy subjects. Normal saline and HCl (0.1 N) were separately infused into the esophagus to test whether they had effects on secondary peristalsis.

Results

After infusion of HCl, the threshold volume to generate secondary peristalsis was significantly decreased during rapid and slow air infusions (both P < 0.05). The frequency of secondary peristalsis was increased after HCl infusion (90 % [72.5–100 %] versus 85 % [72.5–90 %], P = 0.002). Infusion of HCl significantly increased pressure wave amplitude during rapid and slow air infusions (both P < 0.05). Infusion of saline did not affect any parameters of secondary peristalsis. The occurrence of heartburn was generated in 7 of 16 subjects after infusion of HCl with an increase in visual analogue scale score (12.5).

Conclusions

Our data show that acute esophageal acid infusion enhances sensitivity of distension-induced secondary peristalsis and enhances secondary peristaltic activity. The study supports the evidence of the presence of acid-sensitive afferents in the modulation of distension-induced secondary peristalsis in humans.     

Reversal of cardiomyopathy in patients with congestive heart failure secondary to tachycardia

Objectives

Tachycardia-induced cardiomyopathy (TCM) is a reversible cause of heart failure. Little is known of the characteristics of tachycardia associated with the development of left ventricular (LV) dysfunction and the reversal of cardiomyopathy after cure of tachycardia. This study aimed to examine the reversal of cardiomyopathy in patients undergoing ablation with congestive heart failure secondary to tachycardia.

Methods

A total of 625 patients underwent radiofrequency ablation for tachycardiarrhymias between January 2009 and July 2011. Echocardiography analysis was performed to identify patients with depressed LV function, defined as a left ventricular ejection fraction <50 %. Patients with preexisting structural heart disease (n?=?10) were excluded. NT-pro-B-type natriuretic peptide (NT-proBNP) assessment was performed before ablation in patients considered to have TCM (n?=?17). Repeated echocardiography study and NT-proBNP assessment were measured after a mean follow-up of 3 months. Levels of NT-proBNP before and after ablation were compared. Reversal of cardiomyopathy was also assessed.

Results

The incidence of TCM was 2.7 % (12 males; age, 35.8?±?17.1 years). Successful ablation was performed in 16 of 17 patients (94.1 %). There was a significant improvement in left ventricular ejection fraction (36.7?±?7.5 vs. 59.4?±?9.7 %; P?<?0.001). The mean left ventricular end-diastolic diameter before treatment was 59.5?±?8.3 mm (range, 43 to 70), compared with 51.9?±?7.4 mm (range, 40 to 67) (P?=?0.009) after 3 months follow-up. The levels of NT-proBNP decreased after ablation procedure, from 4,092.6?±?3,916.6 to 478.9?±?881.9 pg/ml (P?<?0.001). After successful ablation, ventricular function normalized in 15 of 17 (88.2 %) patients at a mean of 3 months.

Conclusions

Restoration of LV function and reversal of LV remodeling can be achieved with successful elimination of tachycardia in the majority of patients. NT-proBNP level elevates in subjects with TCM and decreases sharply after ablation.     

Effects of Candesartan on Left Ventricular Function, Aldosterone and BNP in Chronic Heart Failure

Purpose

Heart failure (HF) is characterized by activation of neurohormonal systems such as aldosterone and natriuretic peptides. In the absence of published data, CandHeart trial was designed to assess the effects on left ventricular (LV) function, aldosterone and brain natriuretic peptide (BNP) of candesartan in patients with HF and preserved (LVEF ?? 40%) or depressed (LVEF <40%) LV systolic function.

Methods

A total of 514 patients with stable symptomatic NYHA II-IV HF and any left ventricular ejection fraction (LVEF)were randomized to candesartan (target dose 32?mg once daily) as add-on therapy or standard medical therapy alone. Standardized echocardiographic exams were performed locally under central quality control, whereas biomarkers were assayed in a core laboratory.

Results

The majority of patients (73.3%) were NYHA II and on ACE inhibitors (91.8%) and beta-blockers (85.4%). Mean age was 66?±?11?years. Mean LVEF was 36.2?±?9.7% and 24.9% of patients had LVEF ?? 40%. LVEF increased significantly more in the candesartan group (p?=?0.09 at 12?weeks and p?=?0.01 at 48?weeks) and left ventricular end-diastolic diameter decreased in candesartan group (p?=?0.05 at 12?weeks). Candesartan significantly reduced aldosterone at 48?weeks (p?=?0.009). BNP was reduced similarly over time in both study groups (p?=?0.35 and p?=?0.98 at 12 and 48?weeks, respectively). There were 6.6% of discontinuations of candesartan for adverse events.

Conclusions

In CandHeart, the addition of candesartan to standard medical treatment did not reduce circulating BNP more than standard therapy (primary endpoint), but it significantly improved LV function and produced a marked decrease in aldosterone levels at study end.     

Enhanced inotropic state of the failing left ventricle by cardiac contractility modulation electrical signals is not associated with increased myocardial oxygen consumption

BackgroundPrevious studies in patients and in dogs with experimentally induced heart failure (HF) showed that electrical signals applied to the failing myocardium during the absolute refractory period improved left ventricular (LV) function. We examined the effects these same cardiac contractility modulating (CCM) electrical signals on myocardial oxygen consumption (MVO₂) in both patients and dogs with chronic HF.Methods and ResultsSix dogs with microembolizations-induced HF and 9 HF patients underwent CCM leads and generator (OPTIMIZER II) implantation. After baseline measurements, CCM signals were delivered continuously for 2 hours in dogs and for 30 minutes in patients. MVO₂ was measured before and after CCM therapy. In dogs, CCM therapy increased LV ejection fraction at 2 hours (26 ± 1 versus 31 ± 2 %, P = .001) without increasing MVO₂ (257 ± 41 versus 180 ± 34 μmol/min). In patients, CCM therapy increased LV peak +dP/dt by 10.1 ± 1.5 %. As with dogs, the increase in LV function after 30 minutes of CCM therapy was not associated with increased MVO₂ (13.6 ± 9.7 versus 12.5 ± 7.2 mL O₂/min).ConclusionsThe study results suggest that unlike cAMP-dependent positive inotropic drugs, the increase in LV function during CCM therapy is elicited without increasing MVO₂.     

A Novel Adenosine Precursor 2′,3′-Cyclic Adenosine Monophosphate Inhibits Formation of Post-surgical Adhesions

Background

Intraperitoneal adenosine reduces abdominal adhesions. However, because of the ultra-short half-life and low solubility of adenosine, optimal efficacy requires multiple dosing.

Aim

Here, we compared the ability of potential adenosine prodrugs to inhibit post-surgical abdominal adhesions after a single intraperitoneal dose.

Methods

Abdominal adhesions were induced in mice using an electric toothbrush to damage the cecum. Also, 20 μL of 95 % ethanol was applied to the cecum to cause chemically induced injury. After injury, mice received intraperitoneally either saline (n = 18) or near-solubility limit of adenosine (23 mmol/L; n = 12); 5′-adenosine monophosphate (75 mmol/L; n = 11); 3′-adenosine monophosphate (75 mmol/L; n = 12); 2′-adenosine monophosphate (75 mmol/L; n = 12); 3′,5′-cyclic adenosine monophosphate (75 mmol/L; n = 19); or 2′,3′-cyclic adenosine monophosphate (75 mmol/L; n = 20). After 2 weeks, adhesion formation was scored by an observer blinded to the treatments. In a second study, intraperitoneal adenosine levels were measured using tandem mass spectrometry for 3 h after instillation of 2′,3′-cyclic adenosine monophosphate (75 mmol/L) into the abdomen.

Results

The order of efficacy for attenuating adhesion formation was: 2′,3′-cyclic adenosine monophosphate > 3′,5′-cyclic adenosine monophosphate ≈ adenosine > 5′-adenosine monophosphate ≈ 3′-adenosine monophosphate ≈ 2′-adenosine monophosphate. The groups were compared using a one-factor analysis of variance, and the overall p value for differences between groups was p < 0.000001. Intraperitoneal administration of 2′,3′-cAMP yielded pharmacologically relevant levels of adenosine in the abdominal cavity for >3 h.

Conclusion

Administration of 2′,3′-cyclic adenosine monophosphate into the surgical field is a unique, convenient and effective method of preventing post-surgical adhesions by acting as an adenosine prodrug.     

Role of Heart Rate Variability in Predicting the Severity of Severe Acute Pancreatitis

Background

Infected pancreatic necrosis (IPN) and multiple organ dysfunction syndrome (MODS) are major complications of acute pancreatitis which determine disease severity and outcome.

Aims

The aim of this study is to investigate the value of admission heart rate variability as a marker of IPN or MODS in severe acute pancreatitis (SAP) patients.

Methods

Forty-one SAP patients within 72 h of symptoms onset were included in this prospective observational study. General demographics, laboratory data and the acute physiology and chronic health evaluation (APACHE) II scores were recorded at admission. 5-minute ECG signals were obtained at the same time for heart rate variability analyses to assess SAP severity.

Results

The baseline heart rate variability measurements, levels of low frequency/high frequency (LF/HF) were significantly lower whereas high frequency norm (nHF) levels were significantly higher in patients who present with IPN and MODS or died (P < 0.01). Low frequency (LF) levels were lower in patients who present with IPN or MODS as compared to patients without these complications. Levels of low frequency norm (nLF) were lower in MODS and non-survival patients. nHF and LF/HF were good predictors of IPN and MODS, superior to procalcitonin. nHF and LF/HF were better than APACHE II in predicting IPN and LF/HF showed superiority over APACHE II in the prediction of MODS.

Conclusions

Admission heart rate variability is a good marker of IPN and MODS in SAP patients.     

Delayed neutrophil apoptosis mediates intermittent hypoxia-induced progressive heart failure in pressure-overloaded rats

Background and objective

Obstructive sleep apnea (OSA) and heart failure (HF) are common coexisting diseases. Intermittent hypoxia (IH), caused by repeated apnea/hypopnea events, accompanied by increased systemic inflammation, might contribute to the promotion of HF.

Methods

To assess the hypothesis, rats were exposed to IH or normal air condition 4 weeks on the basis of normal heart function or pre-existing HF, which was induced by pressure overload caused by abdominal aortic constriction surgery performed 12 weeks earlier. Echocardiography was performed before and after IH exposure to evaluate left ventricular (LV) function. Serum concentrations of pro-inflammatory cytokines TNF-α and IL-6 were detected by enzyme-linked immunosorbent assay. Flow cytometric analysis was used to determine the apoptotic rate of polymorphonuclear neutrophils (PMNs).

Results

The echocardiographic study showed a significant decrease in LV fractional shortening (FS) and ejection fraction (EF) as well as an increase in the LV relative wall thickness (RWT) index in HF rats, which was aggravated by further exposure to IH compared with single-handed HF-only and sham-IH and sham-control groups. A reduced PMN apoptotic rate was observed in HF-IH rats compared with HF-only, sham-IH, and sham-control rats. Serum concentrations of TNF-α and IL-6 were also increased in HF-IH rats, accompanied by delayed PMN apoptosis, indicating significant systemic inflammation induced by IH.

Conclusion

The results of this study demonstrated that IH aggravates LV remodeling and heart dysfunction in rats with pre-existing HF. Delayed neutrophil apoptosis, which was revealed in HF rats following exposure to IH, contributed to the exacerbation of myocardial damage and progression of heart dysfunction.

     

Role of Beta-Adrenergic Receptor Gene Polymorphisms in the Long-Term Effects of Beta-Blockade with Carvedilol in Patients with Chronic Heart Failure

Background

Beta-blockers are mainstay of current treatment of heart failure (HF). Beta-adrenergic receptors (AR) single nucleotide gene polymorphisms (SNPs) may influence the sensitivity and density of beta-AR. We assessed the relation between three common beta-AR SNPs and the response to carvedilol administration.

Methods and Results

We studied 183 consecutive patients with chronic HF due to ischemic or nonischemic cardiomyopathy, a LV ejection fraction (LVEF)?≤?0.35, not previously treated with beta-blockers. Each patient underwent gated-SPECT radionuclide ventriculography, cardiopulmonary exercise testing and invasive hemodynamic monitoring at baseline and after 12 months of carvedilol administration at maintenance dosages. The beta1-AR gene Arg389Gly and the beta2-AR gene Arg16Gly SNPs were not related to the response to carvedilol administration. Homozygotes for the Glu27Glu allele showed a greater increase in the LVEF, compared to the other patients (+13.0?±?12.2% versus +7.1?±?8.1% in the Gln27Gln homozygotes, and 8.3?±?11.4% units in the Gln27Glu heterozygotes; p?=?0.022 by ANOVA). Glu27Glu homozygotes also showed a greater decline in the pulmonary wedge pressure both at rest and at peak exercise. Gln27Glu SNP was selected amongst the determinants of the LVEF response to carvedilol at multivariable analysis, in addition to the cause of cardiomyopathy, baseline systolic blood pressure and the dose of carvedilol administered.

Conclusion

Beta1-AR Arg389Gly and beta2-AR Arg16Gly SNPs are not related to the response to carvedilol therapy. In contrast, the Gln27Glu SNP is a determinant of the LVEF response to this agent in patients with chronic HF.     

Low Literacy Is Associated with Increased Risk of Hospitalization and Death Among Individuals with Heart Failure

BACKGROUND

Low literacy increases the risk for many adverse health outcomes, but the relationship between literacy and adverse outcomes in heart failure (HF) has not been well studied.

METHODS

We studied a cohort of ambulatory patients with symptomatic HF (NYHA Class II-IV within the past 6 months) who were enrolled in a randomized controlled trial of self-care training recruited from internal medicine and cardiology clinics at four academic medical centers in the US. The primary outcome was combined all-cause hospitalization or death, with a secondary outcome of hospitalization for HF. Outcomes were assessed through blinded interviews and subsequent chart reviews, with adjudication of cause by a panel of masked assessors. Literacy was measured using the short Test of Functional Health Literacy in Adults. We used negative binomial regression to examine whether the incidence of the primary and secondary outcomes differed according to literacy.

RESULTS

Of the 595 study participants, 37 % had low literacy. Mean age was 61, 31 % were NYHA class III/IV at baseline, 16 % were Latino, and 38 % were African-American. Those with low literacy were older, had a higher NYHA class, and were more likely to be Latino (all p?<?0.001). Adjusting for site only, participants with low literacy had an incidence rate ratio (IRR) of 1.39 (95 % CI: 0.99, 1.94) for all-cause hospitalization or death and 1.36 (1.11, 1.66) for HF-related hospitalization. After adjusting for demographic, clinical, and self-management factors, the IRRs were 1.31 (1.06, 1.63) for all-cause hospitalization and death and 1.46 (1.20, 1.78) for HF-related hospitalization.

CONCLUSIONS

Low literacy increased the risk of hospitalization for ambulatory patients with heart failure. Interventions designed to mitigate literacy-related disparities in outcomes are warranted.     

Baduanjin Exercise Prevents post-Myocardial Infarction Left Ventricular Remodeling (BE-PREMIER trial): Design and Rationale of a Pragmatic Randomized Controlled Trial

Background

Left ventricular (LV) remodeling following myocardial infarction (MI) is an established prognostic factor for adverse cardiovascular events and the leading cause of heart failure. Empirical observations have suggested that Baduanjin exercise, an important component of traditional Chinese Qigong, may exert potential benefits on cardiopulmonary function. However, the impact of a Baduanjin exercise-based cardiac rehabilitation program for patients recovering from a recent MI has yet to be assessed. The aim of this trial is to evaluate the potential role of Baduanjin exercise in preventing the maladaptive progression to adverse LV remodeling in patients post-MI.

Methods

A total of 110 clinically stable patients following an MI after undergoing successful infarct-related artery reperfusion will be randomly assigned to the Baduanjin exercise group or usual exercise control group. In addition to usual physical activity, participants in the Baduanjin exercise group will participate in a 45 min Baduanjin exercise training session twice a week, for a total of 12 weeks. The primary endpoint will be the percentage change in LV end-diastolic volume index (LVEDVi) assessed using echocardiography from baseline to 6 months.

Conclusion

The results of this study may provide novel evidence on the efficacy of Baduanjin exercise therapy in post-MI patients in reversing adverse LV remodeling and improving clinical outcome.

Trial Registration

Clinical Trials.gov: NCT02693795.

     

Acute changes in electromechanical parameters during different pacing configurations using a quadripolar left ventricular lead

Purpose

Quadripolar left ventricular (LV) leads allow for several pacing configurations in candidates for cardiac resynchronization therapy (CRT). Whether different pacing configurations may affect LV dyssynchrony and systolic function is not completely known. We aimed to evaluate the acute effects of different pacing vectors on LV electromechanical parameters in patients implanted with a quadripolar LV lead.

Methods

In this two-centre study, within 1 month of implantation 21 CRT patients (65?±?8 years, 76 % men, 38 % ischemic) receiving a quadripolar LV lead (Quartet 1458Q, St Jude Medical) underwent LV capture threshold assessment, intracardiac electrogram optimization, and two-dimensional echocardiography during four pacing configurations: D1-P4, P4-RV coil, D1-RV coil, and P4-M2. LV dyssynchrony and contractile function were expressed by septal-to-lateral delay and global longitudinal strain (GLS).

Results

LV capture threshold varied between the configurations (P?P?=?0.003 and P?=?0.033 vs. spontaneous rhythm, respectively). GLS improved significantly vs. spontaneous rhythm only in the configuration D1-P4 (from ?8.6?±?3.5 to ?11.0?±?3.2 %, P?=?0.001). Accordingly, an increase in stroke volume and a decrease in mitral regurgitation were observed in the configuration D1-P4 (P?≤?0.001 vs. spontaneous rhythm).

Conclusions

In CRT patients receiving a quadripolar LV lead, significant variations in electromechanical parameters were observed by changing pacing vector. Individually targeting the optimal pacing site may enhance the acute haemodynamic response to CRT.