Cardiac resynchronization therapy (CRT) device replacement considerations: upgrade or downgrade? A complex decision in the current clinical setting.

There are limited data about the management of patients presenting for elective generator replacements in the setting of previously implanted cardiac resynchronization therapy (CRT) devices that are nearing end-of-life. The individual patient's clinical status and concomitant morbidities may evolve so that considerations may include not only replacement of the pulse generator, but also potentially changing the type of device [e.g. downgrading CRT-defibrillator (CRT-D) to CRT-pacemaker (CRT-P) or ICD or upgrading of CRT-P to CRT-D]. Moreover, the clinical evidence for CRT-D/CRT-P implantation may change over time, with ongoing research and availability of new trial data. In this review we discuss the ethical, clinical and financial implications related to CRT generator replacements and the need for additional clinical trials to better understand which patients should undergo CRT device downgrading or upgrading at the time of battery depletion.

Electrophysiological and Electroanatomical Mapping of the Right Atrium in Persistent Atrial Fibrillation: Relation to Collagen Turnover.

BACKGROUND: Atrial fibrillation (AF) is associated with abnormal atrial substrate. We investigated whether patients with persistent lone AF and patients with persistent AF and nonischemic dilated cardiomyopathy (NIDCM) exhibit any differences in electrophysiological and electroanatomical properties of right atrium (RA) and collagen turnover. We also investigated the relationship between mean RA bipolar voltage and collagen turnover. METHODS: Ten patients with a history of persistent lone AF and eight patients with a history of persistent AF and NIDCM were studied. Sinus node recovery times (SNRTs) and effective refractory periods (ERPs) at 600 ms, 500 ms, and 400 ms from the high (HLRA) and low (LLRA) lateral RA, proximal coronary sinus (pCS), and right atrial appendage (RAA) were evaluated, and RA electroanatomic mapping was created. Serum N-terminal propeptide of collagen type I (PINP), cross-linked C-terminal telopeptide of collagen type I (CTx), matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of matrix metalloproteinases (TIMP-1) were measured as markers of collagen synthesis and degradation. RESULTS: No differences were found in SNRTs, ERPs from the HLRA, LLRA at 600 ms, pCS and RAA, mean RA bipolar voltage, serum PINP, CTx, MMP-1, and TIMP-1 between the two groups. In persistent lone AF, serum levels of TIMP-1 were related with mean HLRA and HPRA bipolar voltage. CONCLUSIONS: Persistent AF patients with or without NIDCM, demonstrate similar changes in electrophysiological and electroanatomical properties of the RA, as well as similar structural changes. Moreover, serum markers of collagen synthesis are correlated with bipolar voltage in specific regions of RA in persistent lone AF.

Sinus rhythm restoration affects collagen turnover in patients with persistent atrial fibrillation.

AIMS: Collagen turnover and atrial fibrosis have been implicated in the generation and perpetuation of atrial fibrillation (AF). We evaluated the importance of serum markers of collagen turnover in predicting the outcome of electrical cardioversion (CV) of persistent AF and the relationship between AF and fibrosis. METHODS AND RESULTS: Serum C-terminal pro-peptide of collagen type-I (CICP) and C-terminal telopeptide of collagen type-I (CITP) were measured in 164 patients with AF before and 2 months after CV. All the patients were successfully cardioverted to sinus rhythm (SR) although in 38 of them AF recurred. Baseline CICP levels were comparable in patients in SR 60 days after CV and in those who experienced a relapse of AF (85.08 ± 16.99 vs. 87.55 ± 10.43 ng/mL, respectively, P = ns). Baseline CITP levels were significantly higher in patients with AF recurrence compared with those who remained in SR (0.48 ± 0.16 vs. 0.32 ± 0.17 ng/mL, respectively, P < 0.0001). In the 126 patients who maintained the SR, CICP levels were significantly lower at the end of the study as compared with the baseline (63.74 ± 15.92 vs. 85.08 ± 16.99 ng/mL P = 0.003), while there was a mild increase in plasma CITP levels (0.36 ± 0.21 vs. 0.32 ± 0.17 ng/mL, respectively, P = 0.03). CONCLUSION: Atrial fibrillation can result in alterations in atrial structure and architecture that make the atrial myocardium more susceptible to the maintenance of the arrhythmia. Sinus rhythm restoration could affect the fibrotic process occurring or exacerbating during AF course.

Extracellular matrix alterations in the atria: insights into the mechanisms and perpetuation of atrial fibrillation.

Atrial fibrillation is the most common arrhythmia in clinical practice and is associated with increased cardiovascular morbidity and mortality. Atrial fibrosis, a detrimental process that causes imbalance in extracellular matrix deposition and degradation, has been implicated as a substrate for atrial fibrillation, but the precise mechanisms of structural remodelling and the relationship between atrial fibrosis and atrial fibrillation are not completely understood. A large number of experimental and clinical studies have shed light on the mechanisms of atrial fibrosis at the molecular and cellular level, including interactions between matrix metalloproteinases and their endogenous tissue inhibitors, and profibrotic signals through specific molecules and mediators such as angiotensin II, transforming growth factor-ß1, connective tissue growth factor, and platelet-derived growth factor. This review focuses on the mechanisms of atrial fibrosis and highlights the relationship between atrial fibrosis and atrial fibrillation.

Mechanisms, risk factors, and management of acquired long QT syndrome: a comprehensive review.

Long QT syndrome is characterized by prolongation of the corrected QT (QTc) interval on the surface electrocardiogram and is associated with precipitation of torsade de pointes (TdP), a polymorphic ventricular tachycardia that may cause sudden death. Acquired long QT syndrome describes pathologic excessive prolongation of the QT interval, upon exposure to an environmental stressor, with reversion back to normal following removal of the stressor. The most common environmental stressor in acquired long QT syndrome is drug therapy. Acquired long QT syndrome is an important issue for clinicians and a significant public health problem concerning the large number of drugs with this adverse effect with a potentially fatal outcome, the large number of patients exposed to these drugs, and our inability to predict the risk for a given individual. In this paper, we focus on mechanisms underlying QT prolongation, risk factors for torsades de pointes and describe the short- and long-term treatment of acquired long QT syndrome.

New-onset atrial fibrillation as first clinical manifestation of latent Brugada syndrome: prevalence and clinical significance.

AIMS: To evaluate the prevalence, clinical significance, and prognosis of latent Brugada syndrome (BrS) in patients with new-onset atrial fibrillation (AF) unmasked by class 1C antiarrhythmic drugs. METHODS AND RESULTS: Between January 2000 and June 2008, all consecutive patients with new-onset AF, who after flecainide exhibited typical Brugada ECG pattern, underwent electrophysiologic, pharmacologic, and genetic testing. Among 346 patients [median age 53 years; interquartile range (IQR), 15], 11 (3.2%; median age 51 years; IQR, 19) diagnosed as lone AF exhibited typical Brugada ECG pattern. Genetic testing was negative. Ventricular tachycardia/ventricular fibrillation (VT/VF) was induced by electrophysiologic testing (five patients) or during flecainide infusion (one patient). Six patients with type 1 ECG pattern and inducible VT/VF underwent ICD implantation. During a median follow-up of 31.5 months (range: 10-85) after ICD implantation, three patients developed BrS and one of them experienced VF. Patients without ICD (five patients) remained asymptomatic during a median follow-up of 74 months. Persistent type 1 pattern occurred only in the three patients who developed BrS. CONCLUSION: This study, for the first time, reveals the prevalence of latent BrS in patients with new-onset lone AF, which may precede VT/VF. Persistence of type 1 and ventricular tachyarrhythmias inducibility represents a marker of electrical instability leading to sudden death.

Evidence of mechanoelectric feedback in the atria of patients with atrioventricular nodal reentrant tachycardia.

OBJECTIVE: Patients with atrioventricular nodal reentrant tachycardia (AVNRT) could serve as a clinical model to study the effects of mechanical stretch in the electrical properties of atrial myocardium. MATERIALS AND METHODS: We studied 14 patients with AVNRT. Peak, mean and minimal atrial pressures, atrial refractoriness (ERP) in the right atrial appendage and high right atrial lateral wall and monophasic action potential duration at 90% of repolarisation (MAPd90) in the right atrial appendage were assessed during atrial pacing at 500 and 400 ms and after 2 min of pacing at the tachycardia cycle length. Measurements were repeated from the same positions after ventricular pacing at the same cycle lengths and after 2 min of tachycardia. Susceptibility to atrial fibrillation (AF) was assessed by noting whether AF was induced during ERP evaluation. RESULTS: Atrial pressure showed a statistically significant increase during ventricular pacing compared to baseline. This increase remained substantially unchanged when the tachycardia was induced. A significant reduction in atrial ERP and MAPd90 was also observed during ventricular pacing at all cycle lengths compared to atrial pacing. Two minutes of spontaneous tachycardia were enough to change the atrial ERP and MAPd90 to values significantly lower than those during atrial pacing at the cycle length of tachycardia. During the ERP evaluation AF was induced more often during the tachycardia (28%) than during ventricular (14%) and atrial pacing (0%). CONCLUSION: In AVNRT patients, ventricular pacing and reentrant tachycardia significantly increase right atrial pressures and subsequently shorten ERP and MAPd90, leading to an enhanced propensity for AF.

Amino-terminal pro-brain natriuretic peptide predicts ventricular arrhythmogenesis in patients with ischemic cardiomyopathy and implantable cardioverter-defibrillators.

STUDY OBJECTIVES: Even in high-risk population groups, not all patients have the same risk of sudden cardiac death (SCD). Given the emerging data about the amino-terminal fragment of the brain natriuretic peptide prohormone (NT-proBNP) value in heart failure, we planned to evaluate the importance of NT-proBNP levels in predicting the occurrence of malignant arrhythmias in patients with ischemic cardiomyopathy and implantable cardioverter-defibrillators (ICDs). DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Thirty five ambulatory patients with previous myocardial infarction, left ventricular ejection fraction < 35%, and ICDs for primary prevention of SCD according to Multicenter Automatic Defibrillator Implantation Trial I criteria. INTERVENTIONS: Venous blood samples for plasma NT-proBNP measurement were obtained after 30 min of supine rest from all patients at the beginning of the study. Patients were evaluated every 2 months, or sooner in cases of device discharges, during a 1-year follow-up period. Data concerning arrhythmias and device therapy were stored at the time of device interrogation on each follow-up visit. MEASUREMENTS AND RESULTS: During 1-year follow-up, 11 of 35 patients (31.4%) received 18 antiarrhythmic device therapies for ventricular tachyarrhythmia (VT). Patients who experienced such arrhythmias had NT-proBNP levels of 997.27 +/- 335.14 pmol/L (mean +/- SD), whereas those without VT had NT-proBNP levels of 654.87 +/- 237.87 pmol/L (p = 0.001). An NT-proBNP cutoff value of 880 pmol/L had a sensitivity of 73%, a specificity of 88%, a positive predictive value of 80%, and a negative predictive value of 88% for the prediction of occurrence-sustained VT events. CONCLUSION: To achieve the maximum benefit by ICD therapy, more precise risk stratification is required, even in high-risk, post-myocardial infarction patients. Plasma NT-proBNP levels comprise a promising method that could help in the better identification of a patient group with an even higher risk of sudden death.

Acute electrophysiologic effects of inhaled salbutamol in humans.

STUDY OBJECTIVES: Although inhaled beta2-agonists are in widespread use, several reports question their potential arrhythmogenic effects. The purpose of this study was to evaluate the cardiac electrophysiologic effects of a single, regular dose of an inhaled beta2-agonist in humans. DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Six patients with bronchial asthma and 12 patients with mild COPD. INTERVENTIONS: All patients underwent an electrophysiologic study before and after the administration of salbutamol solution (5 mg in a single dose). MEASUREMENTS AND RESULTS: Sinus cycle length, sinus node recovery time (SNRT), interval from the earliest reproducible rapid deflection of the atrial electrogram in the His bundle recording to the onset of the His deflection (AH), interval from the His deflection to the onset of ventricular depolarization (HV), Wenckebach cycle length (WCL), atrial effective refractory period (AERP), and ventricular effective refractory period (VERP) were evaluated just before and 30 min after the scheduled intervention. Salbutamol, a selective beta2-agonist, administered by nebulizer had significant electrophysiologic effects on the atrium, nodes, and ventricle. The AH length decreased from 86.1 +/- 19.5 ms at baseline to 78.8 +/- 18.4 ms (p < 0.001), and the WCL decreased from 354.4 +/- 44.2 to 336.6 +/- 41.7 ms (p = 0.001). Salbutamol significantly decreased the AERP and VERP too while leaving the HV unchanged. Additionally, inhaled salbutamol increased heart rate (from 75.5 +/- 12.8 beats/min at baseline to 93.1 +/- 16 beats/min, p < 0.001) and shortened the SNRT (from 1,073.5 +/- 178.7 to 925.2 +/- 204.9 ms, p = 0.001). CONCLUSION: Inhaled salbutamol results in significant changes of cardiac electrophysiologic properties. Salbutamol enhances atrioventricular (AV) nodal conduction and decreases AV nodal, atrial, and ventricular refractoriness in addition to its positive chronotropic effects. These alterations could contribute to the generation of spontaneous arrhythmias.

Obstructive sleep apnea syndrome and cardiovascular disease: The influence of C-reactive protein.

Obstructive sleep apnea syndrome (OSAS) is a common medical condition, associated with atherosclerosis and cardiovascular disease (CVD). The underlying pathophysiologic mechanisms of this association have not been completely understood and may be multifactorial in origin. A number of studies suggest that inflammatory processes have emerged critical in the pathogenesis of CVD in OSAS. A range of circulating inflammatory molecules has been identified and measured, with a view to assess inflammation and predict vascular damage risk, such as plasma cytokines, adhesion molecules, and C-reactive protein (CRP). CRP is a relevant marker worthy of further study, because not only is elevated in patients with OSAS, but also is rapidly becoming a risk factor for cardiac disease. Furthermore, in selected OSAS patients, aggressive treatment of the disorder may lead to retarding or even improvement of CVD progression. However, still there is a debate on the true correlation between CRP and OSAS, as well as the clinical effect of any reduction after OSAS treatment. Further research is required to define those OSAS patients who will have a considerable reduction with treatment, as well as to understand the significance of the interaction between cardiovascular risk factor and CRP reduction in patients with OSAS.

Obesity and atrial fibrillation: A comprehensive review of the pathophysiological mechanisms and links.

Obesity is a worldwide health problem with epidemic proportions that has been associated with atrial fibrillation (AF). Even though the underlying pathophysiological mechanisms have not been completely elucidated, several experimental and clinical studies implicate obesity in the initiation and perpetuation of AF. Of note, hypertension, diabetes mellitus, metabolic syndrome, coronary artery disease, and obstructive sleep apnea, represent clinical correlates between obesity and AF. In addition, ventricular adaptation, diastolic dysfunction, and epicardial adipose tissue appear to be implicated in atrial electrical and structural remodeling, thereby promoting the arrhythmia in obese subjects. The present article provides a concise overview of the association between obesity and AF, and highlights the underlying pathophysiological mechanisms.

Diabetes mellitus and atrial fibrillation: Pathophysiological mechanisms and potential upstream therapies.

Diabetes mellitus (DM) represents one of the most important risk factors for atrial fibrillation (AF) while AF is a strong and independent marker of overall mortality and cardiovascular morbidity in diabetic patients. Autonomic, electrical, electromechanical, and structural remodeling, including oxidative stress, connexin remodeling and glycemic fluctuations seem to be implicated in AF pathophysiology in the setting of DM. The present review highlights the association between DM and AF, provides a comprehensive overview of the responsible pathophysiological mechanisms and briefly discusses potential upstream therapies for DM-related atrial remodeling.

Atrial fibrillation: a progressive atrial myopathy or a distinct disease?

Atrial fibrillation is a complex arrhythmia with multiple possible mechanisms. A lot of experimental and clinical studies have shed light on the pathophysiological mechanisms of arrhythmia, especially on molecular basis. Electrical, contractile and structural remodeling, calcium handling abnormalities, autonomic imbalance and genetic factors seem to play a crucial role in atrial fibrillation initiation and maintenance. However, the exact pathophysiological mechanisms of atrial fibrillation are not completely understood and whether atrial fibrillation is an unclassified cardiomyopathy or a distinct disease still remains to be answered. This review highlights proarrhythmic and pathophysiological mechanisms of atrial fibrillation and approaches the molecular basis underlying atrial fibrillation susceptibility.

Impact of Atrial Fibrillation on Coronary Blood Flow: A Systematic Review.

Patients with atrial fibrillation (AF) frequently present with symptoms suggestive of myocardial isch- aemia, even in the absence of significant CAD, that seem to be attributable to abnormalities of myocardial perfusion and perfusion reserve. According to the results of recent human and previous experimen- tal studies the increase in coronary artery blood flow during AF is smaller, while the coronary vascular resistance during the arrhythmia does not decrease as much as we would expect, suggesting a mismatch between coronary blood flow and myocardial metabolic demand. AF itself diminishes coronary flow reserve, especially in the subendocardial layer, partly as a result of the increase in the myocardial com- ponent of coronary vascular resistance, and it is possible that irregular ventricular rhythm may play an important role. The mismatch of coronary blood flow and myocardial metabolic demand, especially in view of the severe reduction in coronary flow reserve, may have deleterious consequences that are not limited to patients with CAD.

Sleep disordered breathing in patients with acute coronary syndromes.

STUDY OBJECTIVES: Although the prevalence of obstructive sleep apnea/hypopnea syndrome (OSAHS) is high in patients with acute coronary syndromes (ACS), there is little knowledge about the persistence of OSAHS in ACS patients after the acute event. We aimed to assess the prevalence and time course of OSAHS in patients with ACS during and after the acute cardiac event. METHODS: Fifty-two patients with first-ever ACS, underwent attended overnight polysomnography (PSG) in our sleep center on the third day after the acute event. In patients with an apnea hypopnea index (AHI) > 10/h, we performed a follow up PSG 1 and 6 months later. RESULTS: Twenty-eight patients (54%) had an AHI > 10/h. There was a significant decrease in AHI 1 month after the acute event (13.9 vs. 19.7, p = 0.001), confirming the diagnosis of OSAHS in 22 of 28 patients (79%). At 6-month follow-up, the AHI had decreased further (7.5 vs. 19.7, p < 0.05), and at that time only 6 of the 28 patients (21%) were diagnosed as having OSAHS. Twelve of the 16 current smokers stopped smoking after the acute event. CONCLUSIONS: We have demonstrated a high prevalence of OSAHS in ACS patients, which did not persist 6 months later, indicating that, to some degree, OSAHS may be transient and related with the acute phase of the underlying disease or the reduction in the deleterious smoking habit.

Sleep patterns in patients with acute coronary syndromes.

BACKGROUND: Little is known about sleep quality in patients with acute coronary syndromes (ACS) admitted to the coronary care unit (CCU). The aim of this study was to assess nocturnal sleep in these patients, away from the CCU environment, and to evaluate potential connections with the disease process. METHODS: Twenty-two patients with first ever ACS, who were not on sedation or inotropes, underwent a full-night polysomnography (PSG) in our sleep disorders unit within 3 days of the ACS and follow-up PSGs 1 and 6 months later. RESULTS: PSG parameters showed a progressive improvement over the study period. There was a statistically significant increase in total sleep time (TST), sleep efficiency, slow wave sleep (SWS), and rapid eye movement (REM) sleep, while arousal index, wake after sleep onset (WASO) and sleep latency decreased. Six months after the acute event, sleep architecture was within the normal range. CONCLUSIONS: Patients with ACS have marked alterations in sleep macro- and micro-architecture, which have a negative influence on sleep quality. The changes tend to disappear over time, suggesting a relationship with the acute phase of the underlying disease.

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.