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The arrhythmogenic potential of alcohol consumption that leads to cardiac arrhythmia development includes the induction of both atrial and ventricular arrhythmias, with atrial fibrillation (AF) being the commonest alcohol-related arrhythmia, even with low/moderate alcohol consumption. Arrhythmias occur both with acute and chronic alcohol use. The "Holiday Heart Syndrome" relates to the occurrence of AF, most commonly following weekend or public holiday binge drinking; however, other arrhythmias may also occur, including other supraventricular arrhythmias, and occasionally even frequent ventricular premature beats and a rare occurrence of ventricular tachycardia. Arrhythmias in individuals with alcohol use disorder, in addition to AF, may comprise ventricular arrhythmias (VAs) that may be potentially fatal leading to cardiac arrest. The effects of alcohol on triggering VAs appear to be dose-dependent, observed more commonly in heavy drinkers, both in healthy individuals and patients with underlying structural heart disease, including ischemic heart disease and alcoholic cardiomyopathy. Men appear to be affected at higher dosages of alcohol, while women can suffer from arrhythmias at lower dosages. On the other hand, low to moderate consumption of alcohol may confer some protection from serious VAs and cardiac arrest (J- or U-curve phenomenon); however, abstinence is the optimal strategy. These issues as they relate to alcohol-induced proarrhythmia are herein reviewed, with the large studies and meta-analyses tabulated and the arrhythmogenic mechanisms pictorially illustrated.

Lipoprotein(a) or lipoprotein "little a" is an under-recognized causal risk factor for cardiovascular (CV) disease (CVD), including coronary atherosclerosis, aortic valvular stenosis, ischemic stroke, heart failure and peripheral arterial disease. Elevated plasma Lp(a) (≥50 mg/dL or ≥100 nmol/L) is commonly encountered in almost 1 in 5 individuals and confers a higher CV risk compared to those with normal Lp(a) levels, although such normal levels have not been generally agreed upon. Elevated Lp(a) is considered a cause of premature and accelerated atherosclerotic CVD. Thus, in patients with a positive family or personal history of premature coronary artery disease (CAD), Lp(a) should be measured. However, elevated Lp(a) may confer increased risk for incident CAD even in the absence of a family history of CAD, and even in those who have guideline-lowered LDL-cholesterol (

Cilostazol, a phosphodiesterase III inhibitor, has vasodilating and antiplatelet properties with a low rate of bleeding complications. It has been used over the past 25 years for improving intermittent claudication in patients with peripheral artery disease (PAD). Cilostazol also has demonstrated efficacy in patients undergoing percutaneous revascularization procedures for both PAD and coronary artery disease. In addition to its antithrombotic and vasodilating actions, cilostazol also inhibits vascular smooth muscle cell proliferation via phosphodiesterase III inhibition, thus mitigating restenosis. Accumulated evidence has shown that cilostazol, due to its "pleiotropic" effects, is a useful, albeit underutilized, agent for both coronary artery disease and PAD. It is also potentially useful after ischemic stroke and is an alternative in those who are allergic or intolerant to classical antithrombotic agents (eg, aspirin or clopidogrel). These issues are herein reviewed together with the pharmacology and pharmacodynamics of cilostazol. Large studies and meta-analyses are presented and evaluated. Current guidelines are also discussed, and the spectrum of cilostazol's actions and therapeutic applications are illustrated.

Cardiac resynchronization therapy (CRT) has been established as an effective mode of therapy in patients with heart failure and concurrent cardiac dyssynchrony, principally in the form of left bundle branch block (LBBB). The widespread use of CRT has ushered in a new landscape in 12-lead electrocardiography (ECG). ECG readings in these patients are most important to guide troubleshooting and also appropriate device programming, as well as discerning and managing nonresponders. A set of four ECG recordings need to accompany each patient with a CRT device, including a baseline ECG and recordings from monochamber (right and left ventricular) and biventricular pacing, which can be compared against a new recording to facilitate the evaluation of proper versus problematic biventricular pacing. Precordial ECG leads V1/2 acquired at the fourth intercostal space and limb leads, I and III, together with a quick assessment of perpendicular leads I and aVF to determine the quadrant of the QRS axis in the hexaxial diagram, may provide the framework for proper ECG interpretation in these patients. This important issue of 12-lead ECG in CRT patients is herein reviewed, pitfalls are pointed out and practical tips are provided for ECG reading to help recognize and manage problems with CRT device function. Furthermore, several pertinent ECG recordings and tabulated data are provided, and an algorithm is suggested that integrates prior algorithms and relevant information from current literature.

Introduction After mitral isthmus (ΜΙ) catheter ablation, perimitral atrial flutter (PMF) circuits can be maintained due to the preservation of residual myocardial connections, even if conventional pacing criteria for complete MI block are apparently met (MI pseudo‐block). We aimed to study the incidence, the electrophysiological characteristics, and the long‐term outcome of these patients. Methods Seventy‐two consecutive patients (mean age 62.4 ± 10.2, 62.5% male) underwent MI ablation, either as part of an atrial fibrillation (AF) ablation strategy (n = 35), or to treat clinical reentrant atrial tachycardia (AT) (n = 32), or to treat AT that occurred during ablation for AF (n = 5). Ιn all patients, the electrophysiological characteristics of PMF circuits were studied by high‐density mapping. Results Mitral isthmus block was successfully achieved in 69/72 patients (95.6%). Five patients developed PMF after confirming MI block. In these patients, high‐density mapping during the PMF showed a breakthrough in MI with extremely low impulse conduction velocity (CV). In contrast, in usual PMF circuits that occurred after AF ablation, the lowest CV of the reentrant circuit was of significantly higher value (0.07 ± 0.02 m/s vs 0.25 ± 0.07 m/s, respectively; P, This is a retrospective clinical study comprising 72 patients who underwent mitral isthmus (MI) ablation either as part of an atrial fibrillation ablation strategy, or to treat reentrant AT. The MI block was acutely achieved in 69/72 patients. However, five patients, despite showing MI block based on conventional pacing maneuvers, developed perimitral atrial flutter through a gap in previous ablation lesions with extremely low impulse conduction velocity as shown by high density mapping.

Objective In 2008, the radiofrequency ablation (RFA) procedures registry of the Hellenic Society of Cardiology was created. This online database allowed electrophysiologists around the country to input data for all performed ablation procedures. The aim of this study is to provide a thorough report and interpretation of the data submitted to the registry between 2008 and 2018. Methods In 2008, a total of 27 centers/medical teams in 24 hospitals were licensed to perform RFA in Greece. By 2018, the number had risen to 31. Each center was tasked with inserting their own data into the registry, which included patient demographics (anonymized), type of procedure and technique, complications, and outcomes. Results A total of 18587 procedures in 17900 patients were recorded in the period of 2008-2018. By 2018, slightly more than 70% of procedures were performed in 7 high-volume centers (>100 cases/year). The most common procedure since 2014 was atrial fibrillation ablation, followed by atrioventricular nodal reentry tachycardia ablation. Complication rates were low, and success rates remained high, whereas the 6-month relapse rates declined steadily. Conclusion This online RFA registry has proved that ablation procedures in Greece have reached a very high standard, with results and complication rates comparable to European and American standards. Ablation procedures for atrial fibrillation are increasing constantly, with it being the most common intervention over the last 6-year period, although the absolute number of procedures still remains low, compared to other European countries.

Myocardial infarction with non-obstructive coronary arteries or any acute coronary syndrome (ACS) with normal or near-normal (non-obstructive) coronary arteries (ACS-NNOCA) is an heterogeneous clinical entity, which includes different pathophysiology mechanisms and is challenging to treat. Sudden cardiac death (SCD) is a catastrophic manifestation of ACS that is crucial to prevent and treat urgently. The concurrence of the two conditions has not been adequately studied. This narrative review focuses on the existing literature concerning ACS-NNOCA pathophysiology, with an emphasis on SCD, together with risk and outcome data from clinical trials. There have been no large-scale studies to investigate the incidence of SCD within ACS-NNOCA patients, both early and late in the disease. Some pathophysiology mechanisms that are known to mediate ACS-NNOCA, such as atheromatous plaque erosion, anomalous coronary arteries, and spontaneous coronary artery dissection are documented causes of SCD. Myocardial ischaemia, inflammation, and fibrosis are probably at the core of the SCD risk in these patients. Effective treatments to reduce the relevant risk are still under research. ACS-NNOCA is generally considered as an ACS with more ‘benign’ outcome compared to ACS with obstructive coronary artery disease, but its relationship with SCD remains obscure, especially until its incidence and effective treatment are evaluated.

Congenital complete heart block (CCHB) occurs in 2-5% of pregnancies with positive anti-Ro/SSA and/or anti-La/SSB antibodies, and has a recurrence rate of 12-25% in a subsequent pregnancy. After trans-placental passage, these autoantibodies attack and destroy the atrioventricular (AV) node in susceptible fetuses with the highest-risk period observed between 16 and 28 weeks' gestational age. Many mothers are asymptomatic carriers, while

Growing evidence suggests that atrial fibrillation (AF), in addition to its thromboembolic risk, is a risk factor for cognitive impairment (CI) via several pathways and mechanisms, further contributing to morbidity/mortality. Prior stroke is a contributor to CI, but AF is also associated with CI independently from prior stroke. Silent brain infarctions, microemboli and microbleeds, brain atrophy, cerebral hypoperfusion from widely fluctuating ventricular rates, altered hemostatic function, vascular oxidative stress, and inflammation may all exacerbate CI, particularly in patients with persistent/permanent rather than paroxysmal AF and with increased duration/burden of the arrhythmia. Brain magnetic resonance imaging is an important screening tool in eliciting and monitoring vascular and nonvascular lesions contributing to CI. Evidence is also emerging about the role of genetics in CI development. Anticoagulation and rhythm/rate control strategies may protect against CI preventing or slowing its progression or conversion to dementia, particularly at the early stages when CI may still be a treatable condition. Importantly, AF and CI share many common risk factors. Thus, screening for these 2 conditions and searching for and managing modifiable risk factors and potentially reversible causes for both AF and CI remains an important step toward prevention or amelioration of the impact incurred by these 2 conditions.

Subclinical thyroid dysfunction (STD), presenting as subclinical hypothyroidism (SHypo) or subclinical hyperthyroidism (SHyper), defined as abnormal serum thyrotropin (TSH) and normal free thyroid hormones, is associated with increased cardiovascular (CV) risk and mortality. Depending on the degree of such dysfunction, atherosclerosis, coronary artery disease, heart failure and cardiac arrhythmias, predominantly atrial fibrillation, characterize both disorders and increase CV and total mortality compared to euthyroid persons. There are some differences in the mechanisms involved in the increased CV risk incurred by each type of STD, with more traditional CV risk factors clustered in SHypo than in SHyper, while the role of the TSH or its absence thereof, together with the respective, even subtle, changes incurred in thyroid hormone concentrations, seem to adversely influence the CV system in both types of STD. There is evidence that treatment of STD confers potential benefits by reducing CV events, however, no consensus has been reached due to lack of randomized controlled studies. Nevertheless, due to accumulating evidence from observational studies, many authorities agree that individuals with severe SHypo (TSH 10 mIU/L) or grade 2 SHyper (TSH 0.1 mIU/L) should receive treatment, mostly for the increased risk of CV morbidity and mortality. The evidence reviewed herein should alert and help the clinician to wake up to these two potentially alarming conditions of STD as they may confer serious CV complications, while their treatment appears quite beneficial.

Spironolactone, an antagonist of aldosterone, initially used as a potassium-sparing diuretic, was subsequently shown to be a very effective adjunctive agent in the treatment of patients with heart failure with reduced ejection fraction, by halting the disease progression, with significant beneficial effects on both morbidity and mortality. Other uses comprise resistant hypertension, edema in patients with cirrhosis, and other on- and off-label uses. Recent data indicate that spironolactone also may offer some symptomatic relief in patients with heart failure and preserved ejection fraction. However, a variable percentage of patients, particularly among the aged group, may have difficulty in swallowing or may be unable to swallow tablets and thus are deprived of the benefits of such therapy. In 2017, the FDA approved a liquid suspension formulation of spironolactone, CaroSpir®, which will enable more heart failure and other patients in need of aldosterone inhibition to avail themselves of the protective and beneficial effects of spironolactone. The new drug formulation comes as a banana-flavored oral suspension that contains 25 mg/5 mL of spironolactone, supplied in 4-ounce (118 mL) and 16-ounce (473 mL) bottles. The details of this drug formulation development and the benefits of spironolactone use in patients with heart failure with a focus on patient selection are herein reviewed.

Pulmonary vein (PV) isolation (PVI) remains cornerstone to ablation of atrial fibrillation (AF). For effective and durable PVI and thus fewer AF recurrences, lesion gaps in transmurality and contiguity responsible for PV reconnection (PVR) could only be addressed when one is cognizant of the potential location and sites where these lesion characteristics may be more prevalent and responsible for PVR. In the case of RF ablation, newer technologies incorporating contact force, time and power with automated monitoring of lesion formation, paying attention to difficult areas (carinae, left superior PV-LAA ridge, right inferior PV) and measuring inter-lesion distance may provide the tools to reduce PVR. On the other hand, the improved thermodynamic characteristics of the latest generation of cryoballloons and operator dexterity to achieve better PV occlusion, may be crucial determinants towards the direction of reduced PVR. Whether newer visualization tools, more vigilant testing during the index ablation procedure in these particular regions, prolonging or adding cryothermic applications, waiting longer to test for entrance and exit block, and/or use of provocative drug testing (isoproterenol/adenosine challenge) might help prevent future PVRs awaits further studies. Keywords: Atrial fibrillation, Catheter ablation, Radiofrequency ablation, Pulmonary veins, Pulmonary vein isolation, Pulmonary vein reconnection, Carina, Cryoballoon, Cryothermic ablation

Aims Per standard of care, dual-chamber pacemakers are programmed in DDDR mode with fixed atrioventricular (AV) delay or with long AV delay to minimize ventricular pacing. We aimed to evaluate whether the PR interval may be a specific criterion of choice between standard DDDR, to preserve AV synchrony in long PR patients, and managed ventricular pacing (MVP), to avoid ventricular desynchronization imposed by right ventricle apical pacing, in short PR patients. Methods and results In the MINERVA trial, 1166 patients were randomized to Control DDDR, MVP, or atrial anti-tachycardia pacing plus MVP (DDDRP + MVP). We evaluated the interaction of PR interval with pacing mode by comparing the risk of atrial fibrillation (AF) longer than 7 consecutive days as a function of PR interval. Out of 906 patients with available data, the median PR interval was 180 ms. The PR interval was found to significantly (P = 0.012) interact with pacing mode for AF incidence: the risk of AF > 7 days was lower [hazard ratio (HR) 0.58, 95% confidence interval (95% CI) 0.34-0.99; P = 0.047] in patients with short PR (shorter than median PR) if programmed in MVP mode compared with DDDR mode and it was lower (HR 0.65, 95% CI 0.43-0.99; P = 0.049) in patients with long PR (equal to or longer than median PR) if programmed in DDDR mode compared with MVP. Conclusion Our data show that PR interval may be used as a selection criterion to identify the optimal physiological pacing mode. Persistent AF incidence was lower in short PR patients treated by right ventricular pacing minimization and in long PR patients treated by standard dual-chamber pacing.

Background: Intracoronary thrombus in acute Myocardial Infarction (MI) confers higher rates of no-reflow with attendant adverse consequences. Earlier Randomized-Controlled-Trials (RCTs) of routine thromboaspiration during Percutaneous Coronary Intervention (PCI) indicated a clinical benefit, but more recent RCTs were negative. However, data of selective use of this adjunctive approach remain scarce. Objective: The aim of this single-centre prospective study was to report the results of selective thromboaspiration during PCI in patients with intracoronary thrombi, and also to provide an extensive literature review on current status of thromboaspiration. Methods: The study included 90 patients (77 men; aged 59.3±12.7 years) presenting with acute MI (STElevation MI (STEMI) in 74, non-STEMI in 16) who had intracoronary thrombi and were submitted to thromboaspiration. Results: Total (n=67) or subtotal (n=18) vessel occlusions were present in 85 (94%) patients. Thromboaspiration and subsequent PCI were successful in 89/90 (98.9%) patients, with coronary stenting in 86 (96.6%). In 4 patients with residual thrombus, a mesh-covered stent was implanted. IIb/IIIa-inhibitors were administered in 57 (63.3%) patients. No-reflow occurred in only 1 (1.1%) patient. The postprocedural course was uneventful. Review of the literature revealed several early observational and RCTs and meta-analyses favouring manual, not mechanical, thrombectomy. However, newer RCTs and meta-analyses significantly curtailed the initial enthusiasm for the clinical benefits of routine use of thromboaspiration. Conclusion: Selective thromboaspiration for angiographically visible thrombi in MI patients undergoing PCI, as an adjunct to mechanical reperfusion and to IIb/IIIa-inhibitors, may be an option since this manoeuvre may improve procedural and clinical outcome.

In the era of the coronavirus disease 2019 (COVID-19) pandemic, acute cardiac injury (ACI), as reflected by elevated cardiac troponin above the 99th percentile, has been observed in 8%-62% of patients with COVID-19 infection with highest incidence and mortality recorded in patients with severe infection. Apart from the clinically and electrocardiographically discernible causes of ACI, such as acute myocardial infarction (MI), other cardiac causes need to be considered such as myocarditis, Takotsubo syndrome, and direct injury from COVID-19, together with noncardiac conditions, such as pulmonary embolism, critical illness, and sepsis. Acute coronary syndromes (ACS) with normal or near-normal coronary arteries (ACS-NNOCA) appear to have a higher prevalence in both COVID-19 positive and negative patients in the pandemic compared to the pre-pandemic era. Echocardiography, coronary angiography, chest computed tomography and/or cardiac magnetic resonance imaging may render a correct diagnosis, obviating the need for endomyocardial biopsy. Importantly, a significant delay has been recorded in patients with ACS seeking advice for their symptoms, while their routine care has been sharply disrupted with fewer urgent coronary angiographies and/or primary percutaneous coronary interventions performed in the case of ST-elevation MI (STEMI) with an inappropriate shift toward thrombolysis, all contributing to a higher complication rate in these patients. Thus, new challenges have emerged in rendering a diagnosis and delivering treatment in patients with ACI/ACS in the pandemic era. These issues, the various mechanisms involved in the development of ACI/ACS, and relevant current guidelines are herein reviewed.

Coronavirus-2019 (COVID-19) predisposes patients to arterial and venous thrombosis commonly complicating the clinical course of hospitalized patients and attributed to the inflammatory state, endothelial dysfunction, platelet activation and blood stasis. This viral coagulopathy may occur despite thromboprophylaxis and raises mortality; the risk appears highest among critically ill inpatients monitored in the intensive care unit. The prevalence of venous thromboembolism in COVID-19 patients has been reported to reach ∼10-35%, while autopsies raise it to nearly 60%. The most common thrombotic complication is pulmonary embolism, which though may occur in the absence of a recognizable deep venous thrombosis and may be due to pulmonary arterial thrombosis rather than embolism, resulting in thrombotic occlusion of small- to mid-sized pulmonary arteries and subsequent infarction of lung parenchyma. This micro-thrombotic pattern seems more specific for COVID-19 and is associated with an intense immuno-inflammatory reaction that results in diffuse occlusive thrombotic micro-angiopathy with alveolar damage and vascular angiogenesis. Furthermore, thrombosis has also been observed in various arterial sites, including coronary, cerebral and peripheral arteries. Biomarkers related to coagulation, platelet activation and inflammation have been suggested as useful diagnostic and prognostic tools for COVID-19-associated coagulopathy; among them, D-dimer remains a key biomarker employed in clinical practice. Various medical societies have issued guidelines or consensus statements regarding thromboprophylaxis and treatment of these thrombotic complications specifically adapted to COVID-19 patients. All these issues are detailed in this review, data from meta-analyses and current guidelines are tabulated, while the relevant mechanisms of this virus-associated coagulopathy are pictorially illustrated.

In Part 1 of this Thematic Issue entitled “Systemic Autoimmune Rheumatic Diseases and Cardiology”, a panel of specialists and experts in cardiology, rheumatology, immunology and related fields discussed the cardiovascular complications of spondyloarthritides, rheumatoid arthritis, Sjogren’s syndrome and vasculitides, as well as relevant cardiovascular issues related to non-biologic and biologic disease-modifying anti-rheumatic drugs (DMARDs), and provided their recommendations for prevention and management of these complications. In part 2 of this Thematic Issue, experts discuss the enhanced cardiovascular risk conferred by additional autoimmune rheumatic diseases (ARDs), including systemic lupus erythematosus, the antiphospholipid syndrome, psoriasis and psoriatic arthritis and juvenile idiopathic arthritis. These, and the previous articles, place inflammation as the key common link to explain the enhanced risk of cardiovascular complications in patients with ARDs. It follows that treatment should probably target inflammation. From all these contemporary reviews, the conclusion that is derived further supports the notion of the emerging field of Cardio- Rheumatology where physicians and experts from these two disciplines collaborate in risk stratification and optimization of preventive strategies and drug therapies in patients with ARDs.

The autonomic nervous system (ANS) with its two limbs, the sympathetic (SNS) and parasympathetic nervous system (PSNS), plays a critical role in the modulation of cardiac arrhythmogenesis. It can be both pro- and/or anti-arrhythmic at both the atrial and ventricular level of the myocardium. Intricate mechanisms, different for specific cardiac arrhythmias, are involved in this modulatory process. More data are available for the arrhythmogenic effects of the SNS, which, when overactive, can trigger atrial and/or ventricular "adrenergic" arrhythmias in susceptible individuals (e.g. in patients with paroxysmal atrial fibrillation-PAF, ventricular pre-excitation, specific channelopathies, ischemic heart disease or cardiomyopathies), while it can also negate the protective anti-arrhythmic drug effects. However, there is also evidence that PSNS overactivity may be responsible for triggering "vagotonic" arrhythmias (e.g. PAF, Brugada syndrome, idiopathic ventricular fibrillation). Thus, a fine balance is necessary to attain in these two limbs of the ANS in order to maintain eurhythmia, which is a difficult task to accomplish. Over the years, in addition to classical drug therapies, where beta-blockers prevail, several ANS-modulating interventions have been developed aiming at prevention and management of arrhythmias. Among them, techniques of cardiac sympathetic denervation, renal denervation, vagal stimulation, ganglionated plexi ablation and the newer experimental method of optogenetics have been employed. However, in many arrhythmogenic diseases, ANS modulation is still an investigative tool. Initial data are encouraging; however, further studies are needed to explore the efficacy of such interventions. These issues are herein reviewed and old and recent literature data are discussed, tabulated and pictorially illustrated.

Patients with acute coronary syndrome (ACS) with normal or near-normal (non-obstructive) coronary arteries (ACSNNOCA) constitute an important, albeit heterogeneous, patient subset of younger patients, more commonly females, who may have lower risk of cardiovascular events compared to patients with obstructive coronary artery disease; however this risk remains substantial, hence needing further investigation to identify the underlying cause and devise a proper therapeutic strategy. A diagnostic algorithm starts during coronary angiography with some essential additional diagnostic steps, such as a left ventricular angiogram that may readily identify the underlying cause, e.g. Takotsubo syndrome, while intravascular imaging and vascular reactivity testing may need to be considered for assessing other diagnostic possibilities (e.g. occult atherosclerotic plaque rupture, spontaneous coronary dissection or microvascular dysfunction). Nevertheless, pursuing further investigation with less risky noninvasive tests, such as echocardiography and cardiac magnetic resonance imaging, may effectively identify the cause of ACSNNOCA (e.g. myocarditis or Takotsubo syndrome), and guide management.

Cardiac resynchronization therapy (CRT) is an established therapeutic option for the subset of patients with heart failure (HF), reduced ejection fraction (EF), and dyssynchrony evidenced by electrocardiography. Benefit from CRT has been proven in many clinical trials, yet a sizeable proportion of these patients with wide QRS do not respond to this intervention, despite the updated practice guidelines. Several echocardiographic indices, targeting mechanical rather than electrical dyssynchrony, have been suggested to address this issue, but research so far has not succeeded in providing a single and simple measurement with adequate sensitivity and specificity for identification of responders. While there is still ongoing research in this field, echocardiography proves helpful in other aspects of CRT implementation, such as site selection for left ventricular (LV) lead pacing and optimization of pacing parameters during follow-up visits. Keywords: Heart failure, cardiac resynchronization therapy, biventricular pacing, echocardiography

Background: The mitochondrial Na+/Ca2+ exchanger (mNCX) has been implicated in the pathogenesis of arrhythmogenicity and myocardial reperfusion injury, rendering its inhibition a potential therapeutic strategy. We examined the effects of CGP-37157, a selective mNCX inhibitor, on arrhythmogenesis, infarct size (IS), and no reflow area (NRA) in a porcine model of ischemia-reperfusion. Methods: Forty pigs underwent myocardial ischemia for 60 minutes, followed by 2 hours of reperfusion. Animals were randomized to receive intracoronary infusion of 0.02 mg/kg CGP-37157 or vehicle, either before ischemia (n=17) or before reperfusion (n=17). Animals were monitored for arrhythmias. Myocardial area at risk (AR), IS, and NRA were measured by histopathology. Results: AR, NRA, and IS were comparable between groups. Administration of CGP-37157 before ischemia resulted in the following: (a) suppression of ventricular tachyarrhythmias (events/pig: 1.5±1.1 vs 3.5±1.9, p=0.014), (b) easier cardioversion of ventricular tachyarrhythmias (defibrillations required for cardioversion of each episode: 2.6±2.3 vs 6.2±2.1, p=0.006), and (c) decreased maximal depression of the J point (0.75±0.27 mm vs 1.75±0.82 mm, p=0.007), compared to controls. Administration of CGP-37157 before reperfusion expedited ST-segment resolution; complete ST-segment resolution within 30 minutes of reperfusion was observed in 7/8 CGP-37157-treated animals versus 1/9 controls (p=0.003). Conclusions: In a porcine model of myocardial infarction, intracoronary administration of CGP-37157 did not decrease IS or NRA. However, it suppressed ventricular arrhythmias, decreased depression of the J point during ischemia and expedited ST-segment resolution after reperfusion. These findings motivate further investigation of pharmacologic mNCX inhibition as a potential therapeutic strategy to suppress arrhythmias in the injured heart. Keywords: Ischemia-reperfusion injury, Myocardial infarction, Arrhythmias, Mitochondrial Na+/Ca2+ exchanger, CGP-37157

Background: Cardiac resynchronization therapy (CRT) device implantation is hampered by difficult placement of the left ventricular (LV) lead. We have routinely used a steerable electrophysiology catheter to guide coronary sinus (CS) cannulation and facilitate LV lead positioning. The aim of this prospective study is to present our results with this approach in 138 consecutive patients receiving a CRT device over 10 years. Methods: The study included 120 men and 18 women, aged 64.8±11.4 years, with coronary disease (n=63), cardiomyopathy (n=72), or other disease (n=3), and mean ejection fraction of 24.5±4.5%. Devices were implanted for refractory heart failure and dyssynchrony, all but 2 in the presence of left bundle branch block. Implanted devices included biventricular pacemakers (CRT-P) (n=33) and cardioverter defibrillators (CRT-D) (n=105). Results: Using the electrophysiology catheter, the CS could be engaged in 134 (97.1%) patients. In 4 patients failing CS cannulation, a dual-chamber device was implanted in 2, and bifocal right ventricular pacing was effected in 2. Bifocal (n=2) or conventional (n=1) systems were implanted in another 3 patients, in whom the LV lead got dislodged (n=2) or removed because of local dissection (n=1). Thus, finally, a CRT system was successfully established in 131 (94.9%) patients. There were 3 patients with CS dissection, of whom 1 was complicated by cardiac tamponade managed with pericardiocentesis. There were no perioperative deaths. During follow-up (31.0±21.2 months), clinical improvement was reported by 108 (82.4%) patients. Conclusion: Routine use of an electrophysiology catheter greatly facilitated CS cannulation and successful LV lead placement in ∼95% of patients undergoing CRT system implantation. Keywords: heart failure, cardiac resynchronization therapy, implantable cardioverter defibrillator, coronary sinus, left ventricular lead

The Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC Endorsed by the European Stroke Organisation (ESO)

Medical management of atrial fibrillation (AF), the most common arrhythmia in the general population, has had modest efficacy in controlling symptoms and restoring and maintaining sinus rhythm. Since the seminal observation in 1998 that pulmonary veins host the triggers of AF in the majority of cases, electrical isolation of all pulmonary veins constitutes the cornerstone of ablation in patients with symptomatic AF. However, due to the elaborate and tedious technique of the conventional point-by-point method with radiofrequency ablation guided by electroanatomical mapping, newer, more versatile single-shot techniques, such as cryoballoon ablation, have been sought and developed over recent years and are progressively prevailing. Cryoballoon ablation appears to be the most promising practical and effective approach, and we review it here by presenting all available relevant data from the literature as well as from our own experience in an attempt to apprise colleagues of the significant progress made over the last several years in this important field of electrophysiology.

Heart failure (HF) with preserved ejection fraction (HFpEF) represents half of HF patients, who are more likely older, women, and hypertensive. Mortality rates in HFpEF are higher compared with age- and comorbidity-matched non-HF controls and lower than in HF with reduced ejection fraction (HFrEF); the majority (50–70%) are cardiovascular (CV) deaths. Among CV deaths, sudden death (SD) (~ 35%) and HF-death (~ 20%) are the leading cardiac modes of death; however, proportionally, CV deaths, SD, and HF-deaths are lower in HFpEF, while non-CV deaths constitute a higher proportion of deaths in HFpEF (30–40%) than in HFrEF (~ 15%). Importantly, the underlying mechanism of SD has not been clearly elucidated and non-arrhythmic SD may be more prominent in HFpEF than in HFrEF. Furthermore, there is no specific strategy for identifying high-risk patients, probably due to wide heterogeneity in presentation and pathophysiology of HFpEF and a plethora of comorbidities in this population. Thus, the management of HFpEF remains problematic due to paucity of data on the clinical benefits of current therapies, which focus on symptom relief and reduction of HF-hospitalization by controlling fluid retention and managing risk-factors and comorbidities. Matching a specific pathophysiology or mode of death with available and novel therapies may improve outcomes in HFpEF. However, this still remains an elusive target, as we need more information on determinants of SD. Implantable cardioverter-defibrillators (ICDs) have changed the landscape of SD prevention in HFrEF; if ICDs are to be applied to HFpEF, there must be a coordinated effort to identify and select high-risk patients.

Cardiac amyloidosis or amyloid cardiomyopathy (ACM), commonly resulting from extracellular deposition of amyloid fibrils consisted of misfolded immunoglobulin light chain (AL) or transthyretin (TTR) protein, is an underestimated cause of heart failure and cardiac arrhythmias. Among the three types of cardiac amyloidosis (wild-type or familial TTR and light-chain), the wild-type (Wt) TTR-related amyloidosis (ATTR) is an increasingly recognized cause of heart failure with preserved ejection fraction (HFpEF), and amyloidosis should be considered in the differential diagnosis of this heart failure group of patients. Recent advances in the diagnosis and drug treatment of ACM have ushered in a new era in early disease detection and better management of these patients. Certain clues in cardiac and extracardiac manifestations of ACM may heighten clinical suspicion and guide further confirmatory testing. Newer noninvasive imaging methods (strain echocardiography, cardiac magnetic resonance and bone scintigraphy) may obviate the need for endomyocardial biopsy in ATTR patients, while newer targeted therapies may alter the adverse prognosis in these patients. Early recognition of ACM is crucial in halting the disease process before irreversible organ damage occurs. Chemotherapy and stem-cell transplantation combined with immunomodulatory therapy may also favorably affect the course and prognosis of light chain ACM. Finally, in select patients with end-stage disease, heart transplantation may render results comparable to non-ACM patients. All these issues are herein reviewed.

To review comparative efficacy and tolerability data between the two main mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, in patients with resistant hypertension (HTN). The focus was whether spironolactone, being the classical non-selective agent that has been used for years, albeit with several anti-androgenic side effects, can be rivaled by eplerenone, an apparently weaker, but better tolerated, more selective MRA. Evidence has accumulated that resistant HTN is generally volume-dependent, attributable to varying degrees of aldosterone excess with its attendant renal effects of sodium and fluid retention. Such aldosteronism may be due to an underestimated occurrence of primary aldosteronism; however, it more commonly occurs separately from it and independent from angiotensin II. The aldosterone-induced volume excess placed at the root of the development of resistant HTN in a large number of patients, together with the extrarenal deleterious effects of aldosterone, such as endothelial dysfunction, vascular remodeling and increased arterial stiffness, cardiac hypertrophy, and fibrosis can all be counterbalanced by the administration of MRAs. In the absence of a direct comparison between spironolactone and eplerenone, and in light of compelling evidence provided by the recently reported results of the PATHWAY-2 and ReHOT studies, spironolactone has been established as the most effective add-on anti-aldosterone therapy in resistant HTN. The data on use of eplerenone continue to emerge and are quite encouraging. Despite the lack of direct comparative data, the weight of evidence regarding efficacy is currently in favor of spironolactone. However, the data on the efficacy of eplerenone are promising but still being accumulated suggesting this agent as an alternative to spironolactone and certainly as the preferred choice for those not tolerating spironolactone, especially for patients developing anti-androgenic side effects like breast tenderness, gynecomastia/mastodynia, and/or sexual dysfunction. Both these agents appear to have several other pleiotropic effects that confer cardioprotection and renoprotection beyond their antihypertensive effect. Potassium levels and renal function need to be closely monitored during administration of these therapies. Future comparative studies may shed more light on these issues, while emerging newer agents may offer better and safer therapeutic options.

Right ventricular (RV) myocardial infarction (MI) usually occurs in the setting of an inferior MI (IMI) when the acute occlusion of the right coronary artery (RCA) is located proximally to the acute RV marginal branches, which commonly provide blood supply to the RV. RV MI may result in severe right heart failure with hemodynamic compromise and cardiogenic shock which distinctly differs from the cardiogenic shock secondary to left ventricular (LV) dysfunction, presenting with the clinical triad of low-output hypotension, clear lungs, and jugular venous distention despite intact global LV systolic function. The ECG provides further confirmation by examining the right precordial leads, V1 and more specifically V4R displaying ST elevation. Management of this type of cardiogenic shock is also grossly different from the management of LV shock requiring fluid resuscitation and/or vasopressors as the most important initial approach; however more definitive treatment is similar to any type of acute MI with prompt mechanical reperfusion therapy, most effectively achieved via primary percutaneous coronary intervention (PCI) of the culprit coronary artery occlusion.

The right ventricle (RV) responds differently to prolonged exhaustive and competitive exercise, usually with enlargement, than does the left ventricle. Evidence has accumulated indicating that regular intense endurance exercise and sporting can promote electrical and structural remodeling of the RV, leading to fibrosis. This “exercise-induced cardiomyopathy” mimics features observed in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). In addition, exercise-induced impairment in atrial function (atrial remodeling), mostly in the right atrium related to RV systolic dysfunction, has also been suggested which favors the development of atrial arrhythmias. It should be noted that these adverse effects seem to be limited to extreme intensity levels of exercise and not related to recreational or moderate exercise levels. These deleterious effects of heavy endurance exercise on the right heart can be studied by several methods, including standard and newer echocardiographic techniques, stress testing methods, standard ECG, cardiac magnetic resonance imaging, biomarkers, electroanatomical mapping and/or an electrophysiology study, and in specific cases by genetic testing. All these issues are reviewed in this chapter.

Conventional right heart pacing with leads placed at the right atrial appendage (RAA) and right ventricular (RV) apex produces iatrogenic dyssynchrony. Atrial dysssynchrony may favor the development of atrial tachyarrhythmias, but the data have been relatively limited and have not yet had any influence on clinical practice. However, the evidence of deleterious effects of the iatrogenic dyssynchrony in the form of left bundle branch block (LBBB) which is produced by RV apical pacing has been compelling and has led to some degree of a paradigm shift in our approach to conventional RV pacing by adopting selective site pacing and avoiding the RV apex, at least for patients with left ventricular (LV) dysfunction and/or heart failure, who are the ones who seem to be afflicted the most and are apparently better responders to non-RV apical pacing. The type of inter- and intra-ventricular dyssynchrony produced by classical RV apical pacing (iatrogenic LBBB) leads to pacing-induced cardiomyopathy similar to the dyssynchrony conferred by spontaneous LBBB, both manageable by biventricular pacing or cardiac resynchronization therapy (CRT). The evidence regarding the adverse effects of conventional right heart pacing is analyzed and reviewed in this chapter together with the data concerning selective or alternate site right heart pacing.

BackgroundAtrial fibrillation (AF) is a frequent comorbidity in patients with pacemaker and is a recognized cause of mortality, morbidity, and quality-of-life impairment. The international MINimizE Right Ventricular pacing to prevent Atrial fibrillation and heart failure trial established that atrial preventive pacing and atrial antitachycardia pacing (DDDRP) in combination with managed ventricular pacing (MVP) reduce permanent AF occurrence in comparison with standard dual-chamber pacing (DDDR).ObjectiveWe aimed to determine the role of new-generation atrial antitachycardia pacing (Reactive ATP) in preventing AF disease progression.MethodsPatients with dual-chamber pacemaker and with previous atrial tachyarrhythmias were randomly assigned to DDDR (n = 385 (33%)), MVP (n = 398 (34%)), or DDDRP+MVP (n = 383 (33%)) group. The incidence of permanent AF, as defined by the study investigator, or persistent AF, defined as ≥7 consecutive days with AF, was estimated using the Kaplan-Meier method, while its association with patients’ characteristics was evaluated via multivariable Cox regression.ResultsAt 2 years, the incidence of permanent or persistent AF was 26% (95% confidence interval [CI] 22%–31%) in the DDDR group, 25% (95% CI 21%–30%) in the MVP group, and 15% (95% CI 12%–20%) in the DDDRP+MVP group (P < .001 vs DDDR; P = .002 vs MVP). Generalized estimating equation–adjusted Reactive ATP efficacy was 44.4% (95% CI 41.3%–47.6%). Multivariate modeling identified high Reactive ATP efficacy (>44.4%) as a significant predictor of reduced permanent or persistent AF risk (hazard ratio 0.32; 95% CI 0.13–0.781; P = .012) and episodes’ characteristics, such as long atrial arrhythmia cycle length, regularity, and the number of rhythm transitions, as predictors of high ATP efficacy.ConclusionIn patients with bradycardia, DDDRP+MVP delays AF disease progression, with Reactive ATP efficacy being an independent predictor of permanent or persistent AF reduction.

Ranolazine, a newly introduced, FDA-approved antianginal agent, has more recently been shown to have additional beneficial antiarrhythmic actions attributed to its inhibitory effect on both peak and late sodium current. The first clinical evidence of ranolazine's antiarrhythmic efficacy has been provided by the MERLIN-TIMI 36 trial, which showed that ranolazine may suppress both supraventricular and ventricular arrhythmias in patients with non-ST-segment elevation acute coronary syndrome. An interesting observation of available studies is that ranolazine seems to be more effective in pathological conditions, such as heart failure, ischemia, tachyarrhythmias or long QT3 syndrome, and has little effect on normal myocytes. Importantly, the drug may have an antiarrhythmic effect without causing proarrhythmia. The mechanisms involved in the antiarrhythmic action of ranolazine, experimental and clinical data for its antiarrhythmic efficacy in suppressing atrial fibrillation and ventricular tachyarrhythmias, are herein reviewed. Current data from small randomized trials indicate that further larger randomized controlled trials are needed that will examine the antiarrhythmic effects of ranolazine and its potential use in patients with arrhythmias.

Atrial flutter (AFlu) is usually a fast (>240 bpm) and regular right atrial macroreentrant tachycardia, with a constrained critical region of the reentry circuit located at the cavotricuspid isthmus (CTI; typical CTI-dependent AFlu). However, a variety of right and left atrial tachycardias, resulting from different mechanisms, can also present as AFlu (atypical non-CTI-dependent AFlu). The electrocardiogram can provide clues to its origin and location; however, additional entrainment and more sophisticated electro-anatomical mapping techniques may be required to identify its mechanism, location, and target area for a successful ablation. Although atrial fibrillation and AFlu are 2 separate arrhythmias, they often coexist before and after drug and/or ablation therapies. Indeed, there appears to be a close interrelationship between these 2 arrhythmias, and one may “transform” into the other. These issues are discussed in this overview, and practical algorithms are proposed to guide AFlu localization and illustrate the AFlu and atrial fibrillation continuum.

Background Renal artery stenosis (RAS) has a high prevalence in older patients, especially in the context of general atherosclerosis. It is frequently associated with resistant hypertension and impaired renal function and their attendant consequences. The issue whether revascularization via percutaneous renal angioplasty and stenting (PRA/S) can benefit these patients remains unsettled. Objective To present a case series of patients with refractory hypertension and RAS undergoing PRA/S and also to provide an extensive review of the literature on the current status of PRA/S for resistant hypertension. Methods Data of all consecutive patients undergoing PRA/S by a single operator over 1 year were prospectively collected. These were 9 patients with hypertension refractory to drug therapy who also had other clinical cardiac problems that led to their hospitalization, including flash pulmonary edema and coronary artery disease. They were all receiving ≥3 antihypertensive drugs and renal angiography revealed critical RAS (unilateral in 3 and bilateral in 6). In addition, an extensive literature review of the topic was carried out in PubMed, Scopus and Google Scholar. Results PRS was successful in all 9 high-risk RAS patients with resistant hypertension (5 men, mean age 71 years) without complications and helped in bringing under control their elevated blood pressure (BP) and in maintaining their renal function over a mean of 21 months. Literature review of this controversial topic indicates that in carefully selected patients, PRA/S may play an important role in controlling BP, alleviating symptoms and perhaps preventing renal failure, albeit without concrete evidence of significantly affecting hard end-points of renal events, major cardiovascular events and death. Randomized controlled studies (RCTs), including a large one (CORAL trial), although heavily criticized, have not provided evidence in favor of revascularization. Although RCTs are rather neutral, a multitude of prospective, observational cohort studies, comparing the outcomes of patients after PRA/S have demonstrated significant improvement in systolic and diastolic BP in about two thirds and improvement and/or stabilization in renal function in 30-40% of patients undergoing PRA/S. Nevertheless, the issue remains unsolved and a subject of future studies for further more definitive settlement. Suggestions have been made to adopt physiological and functional renal lesion assessment that may enhance patient selection, at least for RAS cases of moderate lesion severity. Based on this small case series and on exhaustive literature review, an algorithm for approaching patients with significant RAS is herein proposed. Conclusion In high-risk RAS patients with truly resistant hypertension, flash pulmonary edema, and/or rapid deterioration of renal function, PRA/S, a procedure with currently high technical success, may constitute the only viable option. Importantly, despite the unfavorable results of RCTs, current guidelines have not yet changed and clinicians should continue to abide by them. They recommend PRA/S as a reasonable option for patients with hemodynamically significant (especially ostial) RAS and uncontrolled, resistant or malignant hypertension, recurrent, unexplained congestive heart failure or pulmonary edema or unstable angina.

Background Manufacturers of implantable cardioverter-defibrillators (ICDs) promise a 5- to 9-year projected longevity; however, real-life data indicate otherwise. The aim of the present study was to assess ICD longevity among 685 consecutive patients over the last 20 years. Hypothesis Real-life longevity of ICDs may differ from that stated by the manufacturers. Methods The study included 601 men and 84 women (mean age, 63.1 ± 13.3 years). The underlying disease was coronary (n = 396) or valvular (n = 15) disease, cardiomyopathy (n = 220), or electrical disease (n = 54). The mean ejection fraction was 35%. Devices were implanted for secondary (n = 562) or primary (n = 123) prevention. Single- (n = 292) or dual-chamber (n = 269) or cardiac resynchronization therapy (CRT) devices (n = 124) were implanted in the abdomen (n = 17) or chest (n = 668). Results Over 20 years, ICD pulse generator replacements were performed in 238 patients (209 men; age 63.7 ± 13.9 years; ejection fraction, 37.7% ± 14.0%) who had an ICD for secondary (n = 210) or primary (n = 28) prevention. The mean ICD longevity was 58.3 ± 18.7 months. In 20 (8.4%) patients, devices exhibited premature battery depletion within 36 months. Most (94%) patients had none, minor, or modest use of ICD therapy. Longevity was longest for single-chamber devices and shortest for CRT devices. Latest-generation devices replaced over the second decade lasted longer compared with devices replaced during the first decade. When analyzed by manufacturer, Medtronic devices appeared to have longer longevity by 13 to 18 months. Conclusions ICDs continue to have limited longevity of 4.9 ± 1.6 years, and 8% demonstrate premature battery depletion by 3 years. CRT devices have the shortest longevity (mean, 3.8 years) by 13 to 17 months, compared with other ICD devices. These findings have important implications, particularly in view of the high expense involved with this type of electrical therapy.

Background The association of migraine with intracardiac communications and a resultant improvement with their closure has been a matter of controversy. Mostly observational and retrospective studies indicate a significant improvement in migraine attacks in patients undergoing percutaneous closure procedures. However, there is a paucity of randomized trials on this topic and prospective data provide little evidence that the device closure approach has any significant effect on migrainous attacks. Objective The aim of this study is to further examine this important controversial topic by presenting our own prospective findings from a single-operator series of 110 patients with patent foramen ovale (PFO) or atrial septal defect (ASD) undergoing percutaneous device closure and also by conducting an in-depth literature review, amply discussing the data on this topic and finally proposing a practical strategy for migraineurs. Methods A prospective analysis of our own data was conducted among 110 patients undergoing percutaneous closure of either a patent foramen ovale (PFO) (n=75) or an atrial septal defect (ASD) (n=35), investigating the impact of PFO/ASD closure on migraine symptoms. Closure was effected with use of an Amplatzer occluder in a simplified procedure, performed under local anesthesia with use of plain fluoroscopy alone without intra-procedural echocardiographic guidance. Complete sealing was obtained in 98.7% of PFO patients and 94.3% of ASD patients. All patients were questioned about migraine symptomatology and were followed-up long-term for their clinical outcome. They all received dual antiplatelet therapy for 6 months. Results Great improvement in migraine symptomatology was observed after the closure procedures. Specifically, 54 (49%) patients suffered from migraine before the procedures, 45 PFO and 9 ASD patients. Improvement (50%) or abolition (33.3%) of migraine symptoms occurred in 45 patients, 37 (82.2%) PFO and 8 (88.9%) ASD patients, yielding an overall favorable effect of 83.3%. An atrial septal aneurysm was present in 44 (58.7%) PFO patients, which has recently been considered an important predictor of the occurrence of migraine in PFO patients. Importantly, the favorable effect extended beyond the 6-month period when dual antiplatelet therapy was discontinued. A recent comprehensive meta-analysis of 20 studies, comprising patients with unexplained stroke and migraine undergoing transcatheter PFO closure, showed that resolution of migraine occurred in a majority of patients with aura and for a smaller proportion of patients without aura. On the other hand, another recent review maintains that closure of PFO for migraine prevention does not significantly reduce the intensity and severity of migraine. Conclusion A high percentage (49%) of PFO/ASD patients in this series were also migraine sufferers. Percutaneous closure offered migraine relief in 83% of patients, 82% in PFO patients and 89% in ASD patients. Thus, based on this experience and on literature review, a strategic approach for device closure is proposed for migraineurs with a PFO or ASD.

Introduction: Risk stratification for sudden cardiac death in non-ischemic dilated cardiomyopathy (NIDCM) remains a clinical challenge. Areas covered: Currently, left ventricular ejection fraction (LVEF), severity of heart failure symptoms according to NYHA classification, and morphology and duration of the QRS complex guide device management in these patients with implantation of a cardioverter defibrillator (ICD) and/or cardiac resynchronization therapy (CRT) devices. Recently, the results of a randomized trial stirred some controversy regarding the utility of ICD in NIDCM patients, however, a subsequent meta-analysis confirmed prior findings of the survival-prolonging benefit of device therapy. Newer risk markers, like late gadolinium enhancement in cardiac magnetic resonance imaging (CMR) detecting myocardial fibrosis, are encouraging in improving risk stratification in these patients. Furthermore, resurgence of an old tool, the electrophysiology study (EPS), and technical advances in genetics in identifying highrisk familial NIDCM, appear promising in this direction. Expert commentary: Based on old and new tools, a more individualized approach may be applied in NIDCM patients, whereby CMR, EPS and genetics may provide further guidance, particularly in patients with LVEF>35%. These issues are herein reviewed and a practical algorithm is proposed for risk stratification and device implantation in NIDCM patients with LVEF below and above 35%.

Atrial tachycardia (AT) and atrial fibrillation (AF) are common in pacemaker patients and are associated with bad prognoses.The purpose of this study was to evaluate atrial antitachycardia pacing impact on AT/AF-induced atrial remodeling, measured by early recurrence of AT/AF (ERAF) and by change in left atrial diameter (LAD), and to evaluate the impact of AT/AF duration on ERAF incidence.Pacemaker patients were randomized to dual-chamber pacing (Control DDDR: 385 patients), managed ventricular pacing (MVP: 398 patients), or atrial antitachycardia pacing plus MVP (DDDRP+MVP: 383 patients). LAD change, estimated by echocardiography, was considered significant if the relative difference between baseline and 24-month measurements was10%.At median follow-up of 34 months, ERAF incidence was significantly lower in the DDDRP+MVP arm for all AT/AF durations, in particular, ERAF followed AT/AF longer than 3 hours in 53% cases in Control DDDR, in 51% cases in MVP, and in 39% cases in DDDRP+MVP (P.001 vs other groups). ERAF incidence showed a U-shaped pattern when evaluated as a function of previous AT/AF duration, decreasing for durations from 5 minutes to 12 hours and increasing for longer durations. Among patients with significant LAD change, the proportion of patients with a reduction in LAD was 35% in Control DDDR, 37% in MVP, and 70% in DDDRP+MVP (P.05 vs other groups).Our data suggest that atrial electrical remodeling becomes important after about 12 hours of continuous arrhythmia. Compared to DDDR or MVP, DDDRP+MVP reduces ERAF and favors LAD reduction, suggesting that atrial antitachycardia pacing may reverse electrical and mechanical remodeling.

Background Atrial electrical conduction properties have been implicated in atrial fibrillation (AF) pathogenesis. Objective The purpose of this study was to prospectively assess the potential association of interatrial conduction time (IACT) with incident AF. Methods The study included persons referred for invasive electrophysiologic study (EPS), aged ≥50 years, without AF history or valvular disease. IACT was defined as the interval between the high right atrium electrogram and the distal coronary sinus atrial electrogram. Results Six hundred twelve subjects were included (median follow-up 43 months, interquartile range 40–47). AF incidence was 21.7 cases per 1000 person-years. IACT was a significant predictor of AF with a c -statistic of 0.770 (95% confidence interval 0.702–0.838). In time-dependent analysis, IACT was a significant stratifier of AF risk (log-rank 28.0, P Conclusion IACT is independently associated with incident AF. The invasive nature of the measurement is a limitation for its use as a clinical risk stratifier (although it could be used in patients referred for EPS), but these results are of interest in themselves because they suggest a strong pathophysiologic connection between atrial conduction times and substrate alterations ultimately leading to AF.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide production. The purpose of this study was to assess the correlation between ADMA and treadmill stress test outcome parameters with known prognostic value, in patients with intermediate risk for coronary artery disease (CAD).Study participants were referred for treadmill exercise stress test (EST) due to symptoms of suspected CAD. Participants with prior history of CAD, cerebrovascular events, peripheral artery disease, systemic inflammatory disease or use of anti-inflammatory agents were excluded. ADMA levels were measured before EST.The study prospectively enrolled 209 individuals (165 males, aged 58.1±10.9). A significant negative correlation was detected between ADMA and maximal exercise time (r=-0.556, p0.001), metabolic equivalents (METs) (r=-0.555, p0.001) and Duke treadmill score (DTS) (r=-0.347, p0.001). Subjects who exercised to ≥10 METs (n=114) had lower ADMA levels than those who achieved7 METs (n=30) (0.58±0.06 vs 0.87±0.08μmol/L, p0.001), and those with DTS5 (n=63) had higher ADMA (0.75±0.19 vs 0.64±0.15μmol/L, p0.001) compared to those with DTS ≥5 (n=146). In multivariable analysis, ADMA remained an independent predictor of DTS (R(2)=0.210; beta=-10.5; 95% confidence interval -14.9 to -6.2; adjusted p0.001) and METs (R(2)=0.500; beta -8.5; 95% confidence interval -9.7 to -6.0; adjusted p0.001) after adjustment for age, BMI, gender, diabetes, smoking status, dyslipidemia, hypertension and family history of premature CAD.ADMA is correlated to EST parameters with proven prognostic value. This implies that ADMA itself might be a useful prognosticator in patients with suspected CAD.

Objectives The aim of the present study was to assess the efficacy of remote ischemic post-conditioning (RIPC) by repeated intermittent balloon inflations in preventing acute kidney injury (AKI) in patients with a non–ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). Background AKI complicating PCI is associated with increased morbidity and mortality. Remote ischemic preconditioning, using cycles of upper limb ischemia-reperfusion as a conditioning stimulus, has been recently shown to prevent AKI in patients undergoing elective coronary angiography. Methods Eligible patients were randomized to receive RIPC by cycles of inflation and deflation of the stent balloon during PCI or a sham procedure (control patients). The primary endpoint was AKI, defined as an increase of ≥0.5 mg/dl or ≥25% in serum creatinine within 96 h from PCI. The 30-day rate of death or re-hospitalization for any cause was one of the secondary endpoints. Results A total of 225 patients were included (median age, 68 years; 36% female). The AKI rate in the RIPC group was 12.4% versus 29.5% in the control group (p = 0.002; odds ratio: 0.34; 95% confidence interval: 0.16 to 0.71). The number needed to treat to avoid 1 case of AKI was 6 (95% confidence interval: 3.6 to 15.2). The 30-day rate of death or re-hospitalization for any cause was 22.3% in the control group versus 12.4% in RIPC patients (p = 0.05). Conclusions RIPC by serial balloon inflations and deflations during PCI was found to confer protection against AKI in patients with a non–ST-segment elevation myocardial infarction undergoing PCI. The reduction in the rate of AKI translated into a clear trend (of borderline significance) toward better 30-day clinical outcome.

Platelets play a key role in the pathogenesis of atherothrombosis, involved in both the development and progression of atherosclerotic heart disease, and the attendant acute thrombotic complications. Antiplatelet therapy constitutes a mainstay therapy for patients with acute coronary syndromes and generally high-risk patients with atherothrombosis. Until recently, dual antiplatelet therapy (DAPT) for the treatment and prevention of the complications of atherothrombotic disease was traditionally limited to aspirin plus clopidogrel. However, a most important pertaining issue emerged, that of the occurrence of drug-resistance or tolerance observed in some patients for both these antithrombotic agents, which limited the efficacy and applicability of this combined therapy.The availability of the newer thienopyridine, prasugrel, and the cyclopentyl-triazolopyrimidine, ticagrelor, represents an important addition to the physician's armamentarium. Dual antiplatelet therapy with aspirin and clopidogrel or one of the newer agents interferes with platelet activation in complementary, but separate pathways. Aspirin irreversibly inhibits cyclooxygenase, thus preventing the production of thromboxane A2, which is a prothrombotic and vasoconstrictive substance. Thienopyridines (clopidogrel/prasugrel) irreversibly and ticagrelor reversibly prevent and inhibit platelet activation by blocking one of the three known adenosine 5'-diphosphate (ADP) receptors (the P2Y12 receptor) on the platelet surface, thus interfering with platelet activation, degranulation and aggregation. Each of these antiplatelet agents has a protective effect against adverse vascular events; classical DAPT with aspirin and clopidogrel has an even stronger antiplatelet effect compared with either agent alone, however DAPT combining aspirin with one of the newer more potent agents translates into superior antithrombotic protection in atherothrobotic vascular disease, albeit at an increased, though not inordinately, risk for bleeding complications. A number of randomized clinical trials have demonstrated and confirmed the incremental benefit and efficacy of DAPT with use of either classical or newer agents, above and beyond that of each antiplatelet agent alone. Data have also been obtained from studies where indications for the use of DAPT continue to expand into other patient groups, rendering and maintaining DAPT a sweeping combination in Cardiology. This article is a comprehensive review of all these data and the landmark trials on the two classical and also the newer antiplatelet agents, the issues involved and the current recommendations for their use in patients with atherosclerotic heart disease and other cardiovascular disorders and procedures.