The scar: the wind in the perfect storm-insights into the mysterious living tissue originating ventricular arrhythmias.

BACKGROUND: Arrhythmic death is very common among patients with structural heart disease, and it is estimated that in European countries, 1 per 1000 inhabitants yearly dies for sudden cardiac death (SCD), mainly as a result of ventricular arrhythmias (VA). The scar is the result of cardiac remodelling process that occurs in several cardiomyopathies, both ischemic and non-ischemic, and is considered the perfect substrate for re-entrant and non-re-entrant arrhythmias. METHODS: Our aim was to review published evidence on the histological and electrophysiological properties of myocardial scar and to review the central role of cardiac magnetic resonance (CMR) in assessing ventricular arrhythmias substrate and its potential implication in risk stratification of SCD. RESULTS: Scarring process affects both structural and electrical myocardial properties and paves the background for enhanced arrhythmogenicity. Non-uniform anisotropic conduction, gap junctions remodelling, source to sink mismatch and refractoriness dispersion are some of the underlining mechanisms contributing to arrhythmic potential of the scar. All these mechanisms lead to the initiation and maintenance of VA. CMR has a crucial role in the evaluation of patients suffering from VA, as it is considered the gold standard imaging test for scar characterization. Mounting evidences support the use of CMR not only for the definition of gross scar features, as size, localization and transmurality, but also for the identification of possible conducting channels suitable of discrete ablation. Moreover, several studies call out the CMR-based scar characterization as a stratification tool useful in selecting patients at risk of SCD and amenable to implantable cardioverter-defibrillator (ICD) implantation. CONCLUSIONS: Scar represents the substrate of ventricular arrhythmias. CMR, defining scar presence and its features, may be a useful tool for guiding ablation procedures and for identifying patients at risk of SCD amenable to ICD therapy.

Starting dose and dose adjustment of non-vitamin K antagonist oral anticoagulation agents in a nationwide cohort of patients with atrial fibrillation.

This study aims to provide real-world data about starting-dose of NOACs and dose-adjustment in patients with atrial fibrillation (AF). In fact, even if new oral anticoagulation agents (NOACs) have a predictable effect without need for regular monitoring, dose-adjustments should be performed according to the summary of product information and international guidelines. We employed the Italian Medicines Agency monitoring registries comprising data on a nationwide cohort of patients with AF treated with NOACs from 2013 to 2018. Logistic regression analysis was used to evaluate the determinants of dosage choice. During the reference period, treatment was commenced for 866,539 patients. Forty-five percent of the first prescriptions were dispensed at a reduced dose (dabigatran 60.3%, edoxaban 45.2%, apixaban 40.9%, rivaroxaban 37.4%). The prescription of reduced dose was associated with older age, renal disease, bleeding risk and the concomitant use of drugs predisposing to bleeding, but not with CHA2DS2-VASc and HAS-BLED. A relative reduction of the proportion of patients treated with low dosages was evident overtime for dabigatran and rivaroxaban; whereas prescription of low dose apixaban and edoxaban increased progressively among elderly patients. Evidence based on real-world data shows a high frequency of low dose prescriptions of NOACs in AF patients. Except for older age, renal disease, bleeding risk and the concomitant use of drugs predisposing to bleeding, other factors that may determine the choice of reduced dose could not be ascertained. There may be potential under-treatment of AF patients, but further evaluation is warranted.

Non-vitamin K antagonist oral anticoagulation agents in patients with atrial fibrillation: Insights from Italian monitoring registries.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia associated with an increased risk of stroke and thromboembolism. Anticoagulation with Vitamin K antagonists (VKAs) or with novel oral anti-coagulants (NOACs) represents the cornerstone of the pharmacological treatment to reduce the risk of thromboembolism. This study aims to provide real-world data from a whole large European country about NOAC use in "non-valvular atrial fibrillation" (NVAF). METHODS: We analysed the Italian Medicines Agency (AIFA) monitoring registries collecting data of a nationwide cohort of patients with "NVAF" treated with NOACs. Using logistic regression analysis, baseline characteristics and treatment discontinuation information were compared among initiators of the 4 NOACs. RESULTS: In the reference period, the NOAC database collected data for 683,172 patients. The median age was 78 years with 19.5% aged 85 or older. Overall, the treatments were in accordance with guidelines. About 1/3 of patients switched from a prior VKA treatment; in the 72.3% of cases, these patients had a labile International Normalized Ratio (INR) at first prescription. The most prescribed NOAC was rivaroxaban, followed by apixaban, dabigatran and edoxaban. CONCLUSIONS: This study is the largest European real-world study ever published on NOACs. It includes all Italian patients treated with NOACs since 2013 accounting for about 1/3 of subjects with AF. The enrolled population consisted of very elderly patients, at high risk of ischemic adverse events. The AIFA registries are consolidated tools that guarantee the appropriateness of prescription and provide important information for the governance of National Health System by collecting real-world data.

Hypertriglyceridemia and omega-3 fatty acids: Their often overlooked role in cardiovascular disease prevention.

AIMS: This review aims to describe the pathogenic role of triglycerides in cardiometabolic risk, and the potential role of omega-3 fatty acids in the management of hypertriglyceridemia and cardiovascular disease. DATA SYNTHESIS: In epidemiological studies, hypertriglyceridemia correlates with an increased risk of cardiovascular disease, even after adjustment for low density lipoprotein cholesterol (LDL-C) levels. This has been further supported by Mendelian randomization studies where triglyceride-raising common single nucleotide polymorphisms confer an increased risk of developing cardiovascular disease. Although guidelines vary in their definition of hypertriglyceridemia, they consistently define a normal triglyceride level as <150 mg/dL (or <1.7 mmol/L). For patients with moderately elevated triglyceride levels, LDL-C remains the primary target for treatment in both European and US guidelines. However, since any triglyceride level in excess of normal increases the risk of cardiovascular disease, even in patients with optimally managed LDL-C levels, triglycerides are an important secondary target in both assessment and treatment. Dietary changes are a key element of first-line lifestyle intervention, but pharmacological treatment including omega-3 fatty acids may be indicated in people with persistently high triglyceride levels. Moreover, in patients with pre-existing cardiovascular disease, omega-3 supplements significantly reduce the risk of sudden death, cardiac death and myocardial infarction and are generally well tolerated. CONCLUSIONS: Targeting resistant hypertriglyceridemia should be considered as a part of clinical management of cardiovascular risk. Omega-3 fatty acids may represent a valuable resource to this aim.

Cardiac autonomic dysfunction and functional outcome after ischaemic stroke.

ischaemic stroke has been associated with an impairment of cardiac autonomic balance. The aim of this study was to assess the impact of cardiac autonomic derangement on functional outcome after a rehabilitation program in patients with recent ischaemic stroke. The study population included 85 consecutive first-ever stroke survivors (46 men and 39 women; mean age 60.0 +/- 12.4 years), who underwent 24-h Holter monitoring before the beginning of a 60-day rehabilitation program. Time-domain measures of heart-rate variability (HRV) were considered in all cases. By the end of the rehabilitation program an unfavorable functional outcome with dependency (Barthel Index score of <75) was found in 44.7% of patients. Multivariate analysis demonstrated that age [odds ratio (OR) 1.09, 95% CI 1.04-1.19, P = 0.002], stroke severity (OR 1.12, 95% CI 1.01-1.34, P = 0.004), Barthel Index score (OR 0.92, 95% CI 0.87-0.98, P = 0.01) and Rankin Scale score (OR 3.88, 95% CI 2.13-7.56, P = 0.02) on admission, as well as lower values of the standard deviation of normal-to-normal R wave to R wave (RR) intervals (OR 9.67, 95% CI 2.58-18.67, P = 0.006) were independent predictors of an unfavorable functional outcome. Assessment of HRV before a rehabilitation program may provide additional information on the probability of a functional recovery in stroke survivors.

Exercise-related syncope in young competitive athletes without evidence of structural heart disease. Clinical presentation and long-term outcome.

AIMS: Exercise-related syncopal spells in athletes receive great attention and are a source of anxiety in the sporting world. The aim of the present study is to describe the clinical presentation, the yield of the initial diagnostic work-up and the long-term outcome of a series of consecutive competitive athletes with recurrent exercise-related syncopal spells. METHODS AND RESULTS: The study cohort included 33 athletes (20 females, mean age 21.4+/-3.2 years) referred for recurrent unexplained episodes of exercise-related syncope (mean number of spells before evaluation 4.66+/-1.97). All athletes underwent an extensive evaluation, including echocardiography, 24-h electrocardiographic monitoring, exercise testing, cardiac electrophysiological study and head-up tilt testing. The echocardiographic examination revealed the presence of a mitral valve prolapse in two cases (6.0%). During maximal exercise testing, four athletes (12.1%) developed hypotension associated with pre-syncope. Twenty-two subjects (66.6%) showed a positive response to head-up tilt testing. During follow-up (33.5+/-17.2 months) 11/33 athletes (33.3%) showed at least one recurrence of exercise-related syncope (mean time to first recurrence 20.4+/-14.5 months). No other adverse event of any kind was noted during follow-up. The Kaplan-Meier estimates of first recurrence of exercise-related syncope after 12, 36 and 60 months were 9.1%, 24.4% and 42.9%. The number and frequency of exercise-related syncopal spells before evaluation were found to be univariate predictors of syncope recurrence (P<0.001). However, in the multivariate analysis, the number of exercise-related syncopal spells before evaluation was found to be the only independent predictor of syncope recurrence (P<0.05). CONCLUSIONS: These findings support the idea that recurrent exercise related-syncope is not associated with an adverse outcome in athletes without cardiac disease.

Acute abdominal symptoms in malignant hypertension: clinical presentation in five cases.

Malignant hypertension causes anatomical and functional damage in several target organs, in particular brain, retina, heart and kidneys. Although vascular lesions in the gastroenteric tract are known to occur in several instances, their clinical relevance is unknown. In this study five cases of malignant hypertension, presenting with acute abdominal symptoms, are reported. A history of essential arterial hypertension was present in three patients; while one patient had a previous diagnosis of renovascular hypertension and one patient had renoparenchymal hypertension. However, in all cases the antihypertensive treatment was discontinued and inadequate before the accelerated malignant phase. The acute abdominal symptoms at presentation were due to intestinal infarction in 3 patients and acute pancreatitis in 2 patients. One patient with intestinal infarction died of postoperative cardiogenic shock. Our data are in agreement with previous reports describing the possible intra-abdominal complications of malignant hypertension. The therapeutic approach in such conditions should always consider an effective antihypertensive treatment in conjunction with surgical options.

Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope: a multicenter, randomized, controlled trial.

BACKGROUND: This clinical investigation was performed to compare the effects of permanent dual-chamber cardiac pacing with pharmacological therapy in patients with recurrent vasovagal syncope. METHODS AND RESULTS: Patients from 14 centers were randomized to receive either a DDD pacemaker provided with rate-drop response function or the beta-blocker atenolol at the dosage of 100 mg once a day. Inclusion criteria were age >35 years, >/=3 syncopal spells in the preceding 2 years, and positive response to tilt table testing with syncope occurring in association with relative bradycardia. The primary outcome was the first recurrence of syncope after randomization. Enrollment was started in December 1997, and the first formal interim analysis was performed on July 30, 2000. By that time, 93 patients (38 men and 55 women; mean age, 58.1+/-14.3 years) had been enrolled and randomized, although follow-up data were available for all patients (46 patients in the pacemaker arm, 47 patients in the pharmacological arm). The interim analysis showed a significant effect in favor of permanent cardiac pacing (recurrence of syncope in 2 patients [4.3%] after a median of 390 days) compared with medical treatment (recurrence of syncope in 12 patients [25.5%] after a median of 135 days; OR, 0.133; 95% CI, 0.028 to 0.632; P=0.004). Consequently, enrollment and follow-up were terminated. CONCLUSIONS: DDD pacing with rate-drop response function is more effective than beta-blockade for the prevention of syncopal recurrences in highly symptomatic vasovagal fainters with relative bradycardia during tilt-induced syncope.

Prevalence and correlates of syncope-related traumatic injuries in tilt-induced vasovagal syncope.

BACKGROUND: Vasovagal syncope represents the most common form of syncope in the general population and is usually considered as a benign affection. However, syncope-related traumatic injuries may represent a major complication of such a condition in a relevant percentage of cases. The aim of this study was to assess the prevalence and clinical correlates of syncope-related trauma in a cohort of consecutive patients with recurrent vasovagal syncope. METHODS: Three hundred and forty-six consecutive patients were studied in whom a diagnosis of vasovagal syncope was established. All subjects were interviewed with a standard questionnaire in order to collect all possible information about their clinical history and the occurrence of trauma during syncopal spells. RESULTS: Ninety-four of the 346 patients (27.2%) reported at least one syncope-related traumatic injury. In 31/346 cases (8.9%) the severity of trauma had determined hospital admission and surgical treatment. When compared to the rest of the study population, patients with syncope-related trauma showed a higher prevalence of male gender (p < 0.01), a higher absolute number (p < 0.01) and frequency (p < 0.01) of syncopal episodes in their history. Patients with trauma also reported a shorter duration of warning symptoms preceding syncope (p < 0.01), while showing a higher prevalence of positive cardioinhibitory response to tilt table testing (p < 0.01). Moreover, the number of syncope-related injuries was found to correlate significantly with the number of syncopal spells (r = 0.64, p < 0.01). CONCLUSIONS: Most practicing physicians consider vasovagal syncope as simply a benign affection in young people. However, such a clinical view should be partially revised, as recurrent vasovagal syncope is associated with significant trauma-related morbidity.

Diagnosing syncope in clinical practice. Implementation of a simplified diagnostic algorithm in a multicentre prospective trial - the OESIL 2 study (Osservatorio Epidemiologico della Sincope nel Lazio)

BACKGROUND: In some patients with syncope health care is inappropriate and ineffective. In a recent observational investigation in community hospitals of the Lazio region of Italy (the OESIL study) 54.4% of patients admitted with syncope from the emergency room were discharged without a conclusive diagnosis. AIM OF THE STUDY: A simplified two-step diagnostic algorithm was developed and prospectively implemented in nine community hospitals of the Lazio region of Italy in order to improve the diagnostic performance of clinicians, thereby reducing the number of undiagnosed patients. STUDY POPULATION: The study population included 195 consecutive patients (85 males and 110 females, mean age 62.5 years, range 13-95 years) presenting with a syncopal spell at the emergency room of one of the nine participating hospitals in a 2-month period. RESULTS: The systematic implementation of the proposed diagnostic algorithm resulted in a striking reduction of undiagnosed cases. The percentage of patients discharged without a conclusive diagnosis decreased from 54.4% to 17.5%. Neurally mediated syncope was diagnosed in 35.2% of cases, cardiac syncope in 20.9% and neurological syncope in 13.8%. CONCLUSIONS: The use of specific, simplified diagnostic guidelines and algorithms results in an improvement of overall clinical performance. However, the development of such decision-making aids should carefully consider the local circumstances of daily clinical practice.

Transoesophageal low-energy cardioversion of atrial fibrillation. Results with the oesophageal-right atrial lead configuration.

BACKGROUND: Low energy internal cardioversion is a safe and effective procedure to restore sinus rhythm in patients with atrial fibrillation refractory to external cardioversion. However the procedure is invasive and fluoroscopy is mandatory. Aim of the study To assess the efficacy, safety and tolerability of a new simplified procedure of low energy internal cardioversion. METHODS: Twenty-five consecutive patients (19 males and 6 females) with persistent atrial fibrillation were submitted to low energy internal cardioversion using a step-up protocol (in steps of 50 V, starting from 300 V). A large surface area lead (cathode) was positioned in the oesophagus, 45 cm from the nasal orifice. A second large surface area lead (anode) was positioned in the right atrium. A quadripolar lead was positioned at the right ventricular apex to achieve ventricular synchronization and back-up pacing. Oesophageal endoscopy was performed within 24 h of the end of the procedure and repeated after 48 h, if injury to the oesophageal mucosa had occurred. RESULTS: Sinus rhythm was restored in 23 patients (92%) with a mean delivered energy of 15.74 J (range 5-27) and a mean impedance of 48 Omega. In two patients, endoscopy revealed that small burns had occurred in the oesophageal mucosa. Such lesions spontaneously healed after 48 h. CONCLUSIONS: This new technique of performing low energy internal cardioversion is effective and safe and avoids the positioning of a lead in the coronary sinus or in the left pulmonary artery, thereby simplifying the procedure.

The effect of atropine in vasovagal syncope induced by head-up tilt testing.

AIMS: This single-blinded, randomized, placebo-controlled study was designed and undertaken to assess the efficacy of intravenous atropine administration on haemodynamic impairment induced by head-up tilt testing in patients with vasovagal syncope. METHODS AND RESULTS: One hundred and thirteen consecutive patients (62 male and 51 female, mean age 46.3 years) with recurrent syncope, no evidence of cardiac, neurological or metabolic disease and a positive head-up tilt test were included in the study. Within 2 weeks of the first head-up tilt test all patients underwent a second tilt test. During this second test, all patients were randomized to receive a bolus of either atropine (0.02 mg. kg(-1)) or placebo (isotonic saline solution). The administration of atropine or placebo was performed at the onset of the haemodynamic modifications (heart rate and/or blood pressure fall) in conjunction with typical vasovagal prodromal symptoms. Treatment was taken as effective when symptoms aborted and the test was completed. In 29 of 113 patients the second tilt test was negative and these patients were excluded from final data analysis. Forty-one patients received placebo, which was effective in nine cases (21.9%). Atropine was administered to 43 patients and was effective in 30 cases (69.7%, P<0.01 vs placebo). The effects of treatment were analysed further to consider the haemodynamic patterns of tilt-induced vasovagal reflex. In the cardio-inhibitory form, placebo was never effective (15 cases), while atropine was effective in 15 of 18 cases (83.3%, P<0.001 vs placebo). In the vasodepressor form, placebo was effective in nine of 26 patients (34.6%), while atropine was effective in 15 of 25 cases (60.0%, no significant difference vs placebo). CONCLUSIONS: Atropine is fully effective in the cardio-inhibitory form of tilt-induced vasovagal reflex, but is limited in the vasodepressor form.

[The management of syncope in the hospital: the OESIL Study (Osservatorio Epidemiologico della Sincope nel Lazio)]. / Gestione della sincope in ospedale: lo Studio OESIL (Osservatorio Epidemiologico della Sincope nel Lazio).

BACKGROUND: While syncope is generally considered a frequent finding in clinical practice, no clear epidemiological evidence is available about the relevance of such an event in the general population of Italy. METHODS: The OESIL Study was designed and undertaken in 15 hospitals of the Italian region of Latium in order to assess the percentage of emergency-room visits and admissions due to syncope, as well as to analyze the in-hospital diagnostic work-up performed for this condition. RESULTS: During a two-month observation period, 781 (372 males and 409 females, mean age 55.2 (22.8 years) consecutive patients came to the emergency rooms of the 15 hospitals included in the investigation due to a syncope spell (0.9% of emergency room visits); 450/781 patients (57.6%) were subsequently hospitalized (1.3% of all admissions): 48.0% of the admissions were admitted to a general medical ward, 29.3% to an observation ward, 13.3% to a cardiology section, 1.6% to a neurology section and 7.8% to other clinical sections (neurosurgery, general surgery). The mean duration of in-hospital stay was 6.9 (5.8 days; range 1-40 days). During the hospitalization period, 93.1% of patients underwent an ECG, 51.0% an EEG, 44.3% a CT scan of the central nervous system, 40.2% an echocardiogram and 19.5% a tilt-test. The syncope spell was considered to have a cardiovascular origin in 33.8% of the cases and a non-cardiovascular in 11.6% of the cases, while the origin was unknown in 54.4% of the cases. CONCLUSIONS: Collected data support the idea that syncope represents a frequent event in the general population and is responsible for a significant percentage of emergency-room visits and hospital admissions. However, the performance of conventional diagnostic work-ups is far from being satisfactory.

DDD pacing with rate drop response function versus DDI with rate hysteresis pacing for cardioinhibitory vasovagal syncope.

BACKGROUND: The effectiveness of cardiac pacing in preventing vasovagal syncope remains controversial. However, DDI pacing with rate hysteresis has been reported to prevent the recurrence of cardioinhibitory vasovagal syncope in up to 35% of affected subjects and to reduce the overall incidence of syncopal episodes in the others. Recently, DDD pacing with a new promising rate drop response function (Medtronic Thera-I model 7960) has become available in clinical practice. AIM OF THE STUDY: The aim of the present open trial was to test the effectiveness of this new pacing modality in patients with cardioinhibitory vasovagal syncope. STUDY POPULATION AND METHODS: The study population included 20 patients (12 males and 8 females; mean age 61.1 +/- 14 yrs) with recurrent syncope (mean number of prior episode = 6.8, range 5-11) and cardioinhibitory responses during two head-up tilt tests: the first diagnostic and the second during drug therapy with either beta-blockade or etilephrine. The study patients were randomized to receive either DDI pacing with rate hysteresis (8 patients) or DDD pacing with rate drop response function (11 patients). The head-up tilt test performed 1 month after pacemaker implantation was positive in 3 of 12 patients (25%) with DDD pacing with rate drop response function and in 5 of 8 patients (62.5%) with DDI pacing with rate hysteresis. The mean duration of follow-up was 17.7 +/- 7.4 months. During follow-up no patients with a DDD pacemaker with rate drop response function had syncope, while 3 of 8 patients with a DDI pacemaker with rate hysteresis had recurrence of syncope (P < 0.05). CONCLUSIONS: These data suggest that DDD pacing with rate drop response function is effective in cardioinhibitory vasovagal syncope and may be preferable to DDI pacing with rate hysteresis.

Variable cerebral dysfunction during tilt induced vasovagal syncope.

Electroencephalographic (EEG) monitoring was performed during head-up tilt testing (HUT) in a group of 63 consecutive patients (27 males, 36 females, mean age 41.5 years) with a history of recurrent syncope of unknown origin despite extensive clinical and laboratory evaluation. Syncope occurred in 27/63 patients (42.8%) during HUT and was cardioinhibitory in 11/27 (40.7%) and vasodepressor in 16/27 (59.3%). All patients with a negative response to HUT had no significant EEG modifications. In patients with vasodepressor syncope a generalized high amplitude 4-5 Hz (theta range) slowing of EEG activity appeared at the onset of syncope, followed by an increase in brain wave amplitude with a reduction of frequency at 1.5-3 Hz (delta range). The return to the supine position was associated with brain wave amplitude reduction and frequency increase to 4-5 Hz, followed by restoration of a normal EEG pattern and arousal (mean total duration of syncope 23.2 s). In patients with cardioinhibitory syncope, a generalized high amplitude EEG slowing in the theta range was noted at the onset of syncope, followed by a brain wave amplitude increase and slowing in the delta range. A sudden reduction of brain wave amplitude ensued leading to the disappearance of electroencephalographic activity ("flat" EEG). The return to the supine position was not followed by immediate resolution of EEG abnormalities or consciousness recovery, both occurring after a longer time interval (mean total duration of syncope 41.4 s). EEG monitoring during HUT allowed the recording and systematic description of electroencephalographic abnormalities developing in the course of tilt induced vasovagal syncope.