Troponin-I levels as a potential prognostic biomarker of sacubitril/valsartan treatment response in heart failure with reduced ejection fraction: Who will benefit most?

BACKGROUND: Despite robust data on the benefits of sacubitril/valsartan (LCZ696) in patients with chronic heart failure with reduced ejection fraction (HFrEF), there is no evidence yet on prespecified predictive markers of its efficacy. Hypothesis The objective of this study was to identify potential prognostic factors of LCZ696 treatment response. METHODS: We included 48 symptomatic patients with chronic HFrEF (left ventricular ejection fraction ≤35%) and New York Heart Association (NYHA) class II/III: Group A (N = 23) received LCZ696 (105 ± 30 mg twice daily), whereas it was not prescribed in group B (N = 25) according to physician's judgment. Analysis of biochemical parameters, cardiopulmonary exercise testing, and echocardiographic evaluation was performed at baseline and 6 months later. RESULTS: The baseline serum troponin-I levels (TnI) and peak oxygen uptake (VO2 max) were positively associated with the increase in VO2 max (ΔVO2 max = +14.11%, P < 0.05 vs group B) after sacubitril/valsartan treatment (r = 0.68, P = 0.001 and r = 0.57, P = 0.004, respectively). Positive correlations were reported between ΔVO2 max and the improvements in the ratio of early diastolic filling to myocardial tissue velocity (ΔE/E') and the tricuspid annular peak systolic velocity (ΔSa) in group A (r = 0.58, P = 0.004 and r = 0.60, P = 0.002, respectively). In multiple regression analysis, ΔVO2 max was correlated significantly with TnI (beta = 0.35, P = 0.048), ΔE/E' (beta = 0.36, P = 0.031) and ΔSa (beta = 0.37, P = 0.035). CONCLUSIONS: TnI levels may be an independent predictive marker of sacubitril/valsartan efficacy in HFrEF.

Recurrence rate of atrial fibrillation after the first clinical episode: A prospective evaluation using continuous cardiac rhythm monitoring.

BACKGROUND: Decision making regarding a patient who has experienced a first clinical episode of atrial fibrillation (AF) is challenging, and the AF recurrences should be a significant consideration. Continuous long-term rhythm monitoring via implantable loop recorders (ILRs) has enabled us to evaluate the AF recurrence profile after the first clinical episode and to investigate clinical parameters associated with the course of the arrhythmia. HYPOTHESIS: Continuous rhythm monitoring via ILRs in AF patients after the first clinical episode is of clinical significance and precisely evaluate the AF recurrence profile. METHODS: Thirty consecutive patients with paroxysmal AF received an ILR after their first symptomatic episode. We evaluated the maximum duration of episodes and the recurrence rate of the arrhythmia during a follow-up period of 3 years. RESULTS: Three patients (10%) had no AF recurrence, whereas 4 patients (13.3%) presented only 1 episode. Almost half of the patients (46.7%) had a low recurrence rate (<5 episodes/year), whereas the majority of patients (19/30) suffered from episodes with maximum duration ≤24 hours. Eleven patients (36.7%) presented either no episode or a low recurrence rate with episodes lasting ≤24 hours. The use of statins was greater in patients with a low recurrence rate (P = 0.025). CONCLUSIONS: A significant percentage of patients either suffer no AF recurrence after their first symptomatic episode or show a low recurrence rate. Most patients present episodes of short duration. If these findings are confirmed in larger studies, they could have clinical implications ensuring individualized management of the arrhythmia in the future.

Long-term clinical outcomes in implantable cardioverter defibrillator recipients on the island of Crete.

PURPOSE: The aim of the current study is to disseminate long-term "real-world" data on mortality and device therapies in primary and secondary prevention implantable cardioverter defibrillator (ICD) recipients on the island of Crete. METHODS: We analyzed data for all consecutive patients who received an ICD in our tertiary university hospital from 1993 until December 2013. Follow-up visits were performed every 6 months or more frequently when indicated. Survival status was recorded, and all stored episodes during interrogation were registered and classified as appropriate or inappropriate. RESULTS: In total, 854 patients received an ICD; 623 (73%) for primary and 231 (27%) for secondary prevention. Most of these patients (490) suffered from ischemic cardiomyopathy. During the mean follow-up of 12.4±7.8 years, 218 (25.5%) patients died; 19.7% in the primary prevention group (p=0.008) and 41.1% in the secondary prevention group. Overall, 248 patients (29%) received appropriate therapy; however, the percentage was significantly higher in the secondary prevention group (44.2%) than in primary prevention group (23.4%). The cumulative incidence of inappropriate therapies during the mean follow-up period was 11.6%. Lead-related complications were noted in 49 patients (5.7%), while only 13 patients (1.5%) suffered device-related infections. CONCLUSIONS: The long-term data related to clinical outcomes in ICD recipients in our center are in accordance with those of other international centers and confirm the high efficacy and safety of these devices in preventing sudden cardiac death.

Alterations in the expression of genes related to contractile function and hypertrophy of the left ventricle in chronically paced patients from the right ventricular apex.

AIM: Long-term right ventricular apical (RVA) pacing may lead to left ventricular (LV) remodelling and heart failure. This study assessed changes in the expression of genes regulating LV contractile function and hypertrophy, after permanent RVA pacing and investigated whether such changes proceed or even predict LV remodelling. METHODS AND RESULTS: We enrolled 52 consecutive patients (age 79.1 ± 7.7 years, 34 males) who underwent pacemaker implantation for bradycardic indications: Group A, 24 individuals with atrioventricular conduction disturbances and group B, 28 patients with sinus node disease. In group A, peripheral blood mRNA levels of gene sarcoplasmic reticulum calcium ATPase decreased at 3, 6, and 12 months' follow-up, while α-myosin heavy chain (MHC) decreased and ß-MHC increased until 6 months follow-up. In this group, 25% of patients demonstrated significant LV remodelling. At 4 years, LV end-systolic diameter increased from 29.67 ± 3.39 mm at baseline to 35.38 ± 4.22 mm, LV end-diastolic diameter increased from 50 ± 4.95 to 56.71 ± 5.52 mm, and ejection fraction declined from 63.04 ± 10.22 to 52.83 ± 10.81%. Early alterations in gene expression were associated with a deterioration in LV function and geometry that became apparent months later. In group B, echocardiographic indexes and mRNA levels of the evaluated genes demonstrated no statistically significant changes. CONCLUSIONS: Permanent RVA pacing in patients with preserved ejection fraction is associated with alterations in the expression of genes regulating LV contractile function and hypertrophy, measured in the peripheral blood. These alterations are traceable at an early stage, before echocardiographic changes are apparent and are associated with LV remodelling that becomes evident in the long term.

Validity of the cohort of Crete in the Seven Countries Study: A time-series study applied to the cancer mortality trend between 1960 and 2011.

We examined whether the Cretan cohort of the Seven Countries Study (SCS) is representative for the entire population in the island using cancer mortality registries. The analysis was carried out on the Cretan cohort of the SCS cancer mortality data and a similar cancer registry for the general population during a 51-year follow-up (1960-2011). Information about the causes of mortality was obtained from official death certificates and classified according to the International Classification of Diseases, 9th Revision (ICD-9). Two time-series models of mortalities from cancer, using data from the Cretan cohort and the Hellenic Statistical Office (EL. STAT), were developed using Matlab software. The existence of long-term memory in the data was tested by rescaled range analysis (Hurst-Mandelbrot). State-space reconstruction was applied to identify the simplest system that was able to re-create the present time-series. In the cohort, cancer mortalities accounted for 18.9% of total mortalities. The EL.STAT time-series analysis generated mean V statistics (95%CI) of 0.69815 (0.398-0.999) and 0.677143 (0.301-0.897) for the general population and the seven countries cohort, respectively. The embedding dimension for the EL.STAT data was equal to 1 for the general population and for the Cretan cohort (m=1). The exponent H values for the two time-series were almost equal. In the two time-series the proposed time delay of cancer mortalities was 2. The Cretan cohort of the SCS and the entire population of the island followed similar patterns of cancer mortality over time.

Evaluating the outcome of phonosurgery: comparing the role of VHI and VoiSS questionnaires in the Greek language.

OBJECTIVES/HYPOTHESIS: The objective was to study the role of the Greek version of Voice Handicap Index (VHI) in comparison with Voice Symptom Scale (VoiSS) in terms of measuring voice surgery outcome in patients with benign laryngeal lesions. STUDY DESIGN: Nonrandomized prospective. METHODS: Forty-six patients operated for benign laryngeal lesions were enrolled in the present study. All patients were assessed according to the European Laryngological Society guidelines. In terms of self-evaluation, patients answered the Greek versions of both VHI and VoiSS, preoperatively and 6 weeks postoperatively, and the results were statistically analyzed. RESULTS: The strongest correlation was observed between the functional subscale of VHI and the impairment subscale of VoiSS, as well as, between the emotional subscales of both VHI and VoiSS, pre- and postoperatively. A statistically significant change in subscale and total scores was found. VHI and VoiSS subscales and total scores correlated with the stroboscopic and aerodynamic measurements in a variable manner. Perceptual measurements, as well as shimmer and harmonic-to-noise ratio showed significant correlation with both VHI and VoiSS subscale and total scores postoperatively. CONCLUSION: VHI and VoiSS are considered useful tools in evaluating voice surgery outcome, in the Greek language.

Serum markers of collagen turnover predict future shocks in implantable cardioverter-defibrillator recipients with dilated cardiomyopathy on optimal treatment.

OBJECTIVES: We investigated prospectively whether serum markers of collagen turnover could be used as predictors for the occurrence of malignant ventricular arrhythmias in patients with nonischemic dilated cardiomyopathy (NIDC) who had received an implantable cardioverter-defibrillator (ICD) for primary prevention. BACKGROUND: Extracellular matrix alterations in NIDC might provide electrical heterogeneity, thus potentially contributing to the occurrence of ventricular arrhythmia and subsequent sudden cardiac death (SCD). METHODS: Serum C-terminal propeptide of collagen type-I, C-terminal telopeptide of collagen type-I, matrix metalloproteinase (MMP)-1, and tissue inhibitor of MMP-1 were measured as markers of collagen synthesis and degradation in 70 patients with mild to moderate symptomatic heart failure due to NIDC with left ventricular ejection fraction <35%, who received an ICD for primary prevention of SCD. Patients were evaluated for any appropriate ICD delivered therapy, whether shock or antitachycardia pacing, during a 1-year follow-up period. RESULTS: Appropriate device therapies were delivered in 14 of the 70 patients during the follow-up period, with antitachycardia pacing in 2, antitachycardia pacing with shocks in 4, and shocks in 8. Pre-implantation serum concentrations of C-terminal telopeptide of collagen type-I levels were significantly higher in patients who had appropriate ICD-delivered therapy than in those who did not have any therapy (0.46 +/- 0.19 ng/ml vs. 0.19 +/- 0.07 ng/ml, p < 0.001, respectively). The same was true for baseline MMP-1 and tissue inhibitor of MMP-1 (27.7 +/- 1.6 ng/ml vs. 24.1 +/- 2.5 ng/ml, p < 0.001, and 89 +/- 14 ng/ml vs. 58 +/- 18 ng/ml, p = 0.008, respectively). CONCLUSIONS: If the maximum benefit is to be achieved from ICD therapy in NIDC patients for the primary prevention of SCD, a more precise risk stratification is required. As extracellular matrix alterations affect the arrhythmogenic substrate in NIDC, we observed that serum markers of collagen turnover could predict arrhythmic events in ICD recipients.

Effect of sinus rhythm restoration after electrical cardioversion on apelin and brain natriuretic Peptide prohormone levels in patients with persistent atrial fibrillation.

Because humoral alterations have been implicated in the generation and perpetuation of atrial fibrillation (AF), we aimed to elucidate possible abnormalities in atrial endocrine function in the setting of lone AF. Levels of plasma apelin and amino terminal fragment of the brain natriuretic peptide prohormone (NT-pro-BNP) were measured in 40 patients with persistent AF, before and 1 month after electrical cardioversion, and in 15 controls in sinus rhythm (SR). All patients were successfully cardioverted to SR, although in 9 of them AF recurred. Baseline apelin levels were lower and NT-pro-BNP levels higher in patients with AF compared to controls (380 +/- 186 vs 700 +/- 151 pg/ml, p <0.001, and 615 +/- 611 vs 50 +/- 28 pg/ml, p <0.001, respectively). Maintenance of SR resulted in an increase of apelin and a decrease of NT-pro-BNP levels during the postcardioversion follow-up period compared to baseline (497 +/- 170 vs 368 +/- 178 pg/ml, p <0.001, and 206 +/- 106 vs 398 +/- 269 pg/ml, p <0.001 respectively). Patients who developed AF recurrence by the end of the follow-up period had similar values of apelin and NT-pro-BNP on final and initial evaluations (444 +/- 142 vs 422 +/- 217 pg/ml, p = 0.62, and 1,328 +/- 714 vs 1,362 +/- 862 pg/ml, p = 0.74, respectively). Stepwise logistic regression analysis showed that left atrial diameter (b =-0.49, p = 0.05), and baseline NT-pro-BNP (b = 0.006, p = 0.022), but not apelin, were independent predictors for AF recurrence. In conclusion, this study suggests that endocrine heart function, as judged from apelin and NT-pro-BNP levels, is reversibly modified in the setting of lone AF. This could influence systemic hemodynamics and pharmacologic measures designed to treat this arrhythmia.

Extracellular matrix alterations in patients with paroxysmal and persistent atrial fibrillation: biochemical assessment of collagen type-I turnover.

OBJECTIVES: We investigated whether the serum markers of collagen turnover differed in various forms of atrial fibrillation (AF) and in sinus rhythm (SR) in humans. BACKGROUND: Structural alterations and fibrosis have been implicated in the generation and perpetuation of AF. METHODS: Serum C-terminal propeptide of collagen type-I (CICP), C-terminal telopeptide of collagen type-I (CITP), matrix metalloproteinase-1, and tissue inhibitor of matrix metalloproteinases-1 were measured as markers of collagen synthesis and degradation in 70 patients with AF and 20 healthy control subjects in SR. RESULTS: C-terminal propeptide of collagen type-I and CITP were significantly higher in AF patients than in control subjects (91 +/- 27 ng/ml vs. 67 +/- 11 ng/ml, p < 0.001 and 0.38 +/- 0.20 ng/ml vs. 0.25 +/- 0.08 ng/ml, p < 0.001, respectively). Persistent AF patients had higher levels of CICP (105 +/- 28 ng/ml vs. 80 +/- 21 ng/ml, p < 0.001), but not CITP, compared with those with paroxysmal AF. Patients with persistent AF had lower levels of matrix metalloproteinase-1 but increased levels of tissue inhibitor of matrix metalloproteinases-1 compared with patients with paroxysmal AF (11.90 +/- 4.79 ng/ml vs. 14.98 +/- 6.28 ng/ml, p = 0.03 and 155 +/- 45 ng/ml vs. 130 +/- 38 ng/ml, p < 0.001, respectively). Tissue inhibitor of matrix metalloproteinases-1 levels were significantly lower in control subjects compared with those in both paroxysmal and persistent AF patients (102 +/- 15 ng/ml vs. 130 +/- 38 ng/ml vs. 155 +/- 45 ng/ml, respectively, p < 0.001). CONCLUSIONS: Serum markers of collagen type-I turnover differed significantly between patients with AF and SR. Furthermore, these markers also differed significantly between paroxysmal and persistent AF patients, suggesting that the intensity of the extracellular synthesis and degradation of collagen type-I may be related to the burden or type of AF.

Angiotensin II type 1 receptor inhibition is associated with reduced tachyarrhythmia-induced ventricular interstitial fibrosis in a goat atrial fibrillation model.

BACKGROUND: Using a goat animal model, we tested the hypothesis that angiotensin-II inhibition reduces fibrotic degeneration of both the atrial and ventricular myocardium as well as AF induction susceptibility. METHODS: We studied three groups of five goats over a 6-month period. The study animals in the first two groups were implanted with a pacemaker capable of maintaining AF with burst pacing. Additionally, in one group, goats were administered candesartan (AF+candesartan group). The third group (SR group) of animals served as control. Animals were tested for AF induction on day 0, 1, 30, 90 and 180. A "Vulnerability Index" (VI) for AF induction was calculated, defined as the ratio of total time in AF per number of bursts needed to induce sustained AF, in each session. At the end of the study, all four heart chambers were examined and fibrosis quantified. RESULTS: Both AF goat groups developed cardiomegaly due to tachy-cardiomyopathy. Although, the VI was significantly increased in AF group over time (28.8+/-43 to 284.7+/-291, p=0.045), this was not the case for AF+candesartan group (30.3+/-40 to 170.8+/-243, p=0.23). Histology revealed a significant increase of fibrous tissue in goats with induced AF, noticeable in all four heart chambers, compared to controls. However, the degree of fibrosis was significantly lower in AF animals on candesartan. CONCLUSIONS: Our study demonstrated a beneficial effect of angiotensin II inhibition on tachyarrhythmia-induced ventricular fibrosis. It is also consistent with previous studies indicating a reduction in burst-induced AF susceptibility in goats and confirms the favorable effects in atrial structural remodeling.

A comparative study of the efficacy and safety of procainamide versus propafenone versus amiodarone for the conversion of recent-onset atrial fibrillation.

The appropriate treatment for the restoration of sinus rhythm in patients with atrial fibrillation (AF) of recent onset is still the subject of controversy. In this prospective, randomized, single-blind, placebo-controlled clinical study, we investigated the effectiveness and safety of procainamide, propafenone, and amiodarone, administered intravenously, for the conversion of recent-onset AF. We enrolled 362 consecutive patients (183 men; age 34 to 86 years; mean 65+/-10) with AF duration of no >48 hours. Of these patients, 89 were given procainamide, 91 propafenone, 92 amiodarone, and 90 placebo. Treatment was considered successful if conversion to sinus rhythm was achieved within the 24-hour study period. Baseline clinical characteristics were similar in the 4 groups. The treatment was successful in 61 of the 89 patients who received procainamide (68.53%; median time 3 hours), 73 of the 91 patients who received propafenone (80.21%; median time 1 hour), 82 of the 92 patients who received amiodarone (89.13%; median time 9 hours), and 55 of the 90 patients who received placebo (61.11%; median time 17 hours; p<0.05 for all medicated groups vs placebo; p<0.05 for amiodarone and propafenone vs procainamide). In conclusion, all 3 medications, when administered intravenously, are effective in the restoration of sinus rhythm in recent-onset AF. Amiodarone and propafenone are more effective whereas procainamide and propafenone are faster.

Atrial overdrive pacing for the obstructive sleep apnea-hypopnea syndrome.

BACKGROUND: The role of atrial overdrive pacing (AOP) in sleep apnea remains uncertain. We prospectively evaluated the effect of AOP after 24 hours and after one month in patients with the obstructive sleep apnea-hypopnea syndrome and compared it with the use of nasal continuous positive airway pressure (n-CPAP). METHODS: We studied 16 patients with a moderate or severe case of the obstructive sleep apnea-hypopnea syndrome (baseline mean apnea-hypopnea index, 49) and normal left ventricular systolic function in whom a dual-chamber pacemaker had been implanted. After 48 hours, the patients were randomly assigned to AOP (pacing at 15 bpm above the spontaneous mean nocturnal heart rate) or backup atrial pacing (pacing at a heart rate below 40 bpm); the latter group began n-CPAP therapy one day later. After one month, the two groups switched therapies and were followed for an additional month. Polysomnographic studies were performed at baseline, on the first night after randomization, at crossover, and at the end of the study. RESULTS: During AOP, no significant changes were observed in any of the respiratory variables measured. The change in the apnea-hypopnea index at one month with AOP was +0.2 (95 percent confidence interval, -2.7 to +2.3; P=0.87). In contrast, all variables improved significantly after one month of n-CPAP (change in the apnea-hypopnea index, -46.3; 95 percent confidence interval, -56.2 to -36.5; P<0.001). CONCLUSIONS: Nasal continuous positive airway pressure therapy is highly effective for the treatment of the obstructive sleep apnea-hypopnea syndrome, whereas AOP has no significant effect.

Sotalol versus propafenone for long-term maintenance of normal sinus rhythm in patients with recurrent symptomatic atrial fibrillation.

This prospective, randomized, single-blinded, placebo-controlled study compared the efficacy and safety of sotalol and propafenone when used for long-term prevention of atrial fibrillation. For the long-term maintenance of normal sinus rhythm, propafenone seems to be more effective than sotalol.

Severe bradyarrhythmias in patients with sleep apnoea: the effect of continuous positive airway pressure treatment: a long-term evaluation using an insertable loop recorder.

AIM: In this new era of insertable loop recorders, we studied obstructive sleep apnoea-hypopnoea syndrome (OSAHS) patients in order to evaluate their arrhythmias and the beneficial effect of Continuous Positive Airway Pressure treatment (CPAP), over a long-term period. METHODS AND RESULTS: We enrolled 23 patients (16 men, 50 +/- 11 years) with moderate and severe OSAHS. In all patients, an insertable loop recorder capable of monitoring the heart rhythm for 16 months was implanted. Cardiac pauses >3 s and bradycardic episodes <40 bpm during a 2-month period before, and for 14 months after, the CPAP application, were noted. In each period, the patients underwent two 24-h Holter recordings. Before treatment, 11 patients (47%) revealed severe cardiac rhythm disturbances, mostly nocturnal. Holter recordings showed disturbances in only 3 (13%) patients (P=0.039), those in whom the insertable loop device had recorded frequent episodes. Eight weeks after the initiation of treatment, the total number of the recorded episodes tended to decrease while, during the last 6 months of the follow-up, no episodes were recorded. CONCLUSION: Approximately half of OSAHS patients evidence severe cardiac rhythm disturbances, which are significantly reduced by CPAP. Holter recordings seem unable to precisely describe the incidence of severe brady-arrhythmias and the effect of treatment.