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Over 1.5 million deaths worldwide are caused by neurocardiogenic syndromes. Furthermore, the consequences of deleterious brain-heart interactions are not limited to fatal complications. Cardiac arrhythmias, heart failure, and nonfatal coronary syndromes are also common. The brain-heart axis is implicated in post-stroke cardiovascular complications known as the stroke-heart syndrome, sudden cardiac death, and Takotsubo syndrome, among other neurocardiogenic syndromes. Multiple pathophysiological mechanisms with the potential to be targeted with novel therapies have been identified in the last decade. In the present state-of-the-art review, we describe recent advances in the understanding of anatomical and functional aspects of the brain-heart axis, cardiovascular complications after stroke, and a comprehensive pathophysiological model of stroke-induced cardiac injury.

Over 1.5 million deaths worldwide are caused by neurocardiogenic syndromes. Furthermore, the consequences of deleterious brain-heart interactions are not limited to fatal complications. Cardiac arrhythmias, heart failure, and nonfatal coronary syndromes are also common. The brain-heart axis is implicated in post-stroke cardiovascular complications known as the stroke-heart syndrome, sudden cardiac death, and Takotsubo syndrome, among other neurocardiogenic syndromes. Multiple pathophysiological mechanisms with the potential to be targeted with novel therapies have been identified in the last decade. In the present state-of-the-art review, we describe recent advances in the understanding of anatomical and functional aspects of the brain-heart axis, cardiovascular complications after stroke, and a comprehensive pathophysiological model of stroke-induced cardiac injury.

Prognosis in light-chain (AL) and transthyretin (ATTR) amyloidosis is influenced by cardiac involvement. ATTR amyloidosis has better prognosis than AL amyloidosis despite more amyloid infiltration, suggesting additional mechanisms of damage in AL amyloidosis.The aim of the study was to assess the presence and prognostic significance of myocardial edema in patients with amyloidosis.The study recruited 286 patients: 100 with systemic AL amyloidosis, 163 with cardiac ATTR amyloidosis, 12 with suspected cardiac ATTR amyloidosis (grade 1 onMyocardial T2 was increased in amyloidosis with the degree of elevation being highest in untreated AL patients (untreated AL amyloidosis 56.6 ± 5.1 ms; treated AL amyloidosis 53.6 ± 3.9 ms; ATTR amyloidosis 54.2 ± 4.1 ms; each p 0.01 compared with control subjects: 48.9 ± 2.0 ms). Left ventricular (LV) mass and extracellular volume fraction were higher in ATTR amyloidosis compared with AL amyloidosis while LV ejection fraction was lower (p 0.001). Histological evidence of edema was present in 87.5% of biopsy samples ranging from 5% to 40% myocardial involvement. Using Cox regression models, myocardial T2 predicted death in AL amyloidosis (hazard ratio: 1.48; 95% confidence interval: 1.20 to 1.82) and remained significant after adjusting for extracellular volume fraction and N-terminal pro-B-type natriuretic peptide (hazard ratio: 1.32; 95% confidence interval: 1.05 to 1.67).Myocardial edema is present in cardiac amyloidosis by histology and cardiovascular magnetic resonance T2 mapping. T2 is higher in untreated AL amyloidosis compared with treated AL and ATTR amyloidosis, and is a predictor of prognosis in AL amyloidosis. This suggests mechanisms additional to amyloid infiltration contributing to mortality in amyloidosis.

BACKGROUND: Familial evaluation after a sudden death with negative autopsy (sudden arrhythmic death syndrome; SADS) may identify relatives at risk of fatal arrhythmias.OBJECTIVES: This study aimed to assess the impact of systematic ajmaline provocation testing using high right precordial leads (RPLs) on the diagnostic yield of Brugada syndrome (BrS) in a large cohort of SADS families.METHODS: Three hundred three SADS families (911 relatives) underwent evaluation with resting electrocardiogram using conventional and high RPLs, echocardiography, exercise, and 24-h electrocardiogram monitor. An ajmaline test with conventional and high RPLs was undertaken in 670 (74%) relatives without a familial diagnosis after initial evaluation. Further investigations were guided by clinical suspicion.RESULTS: An inherited cardiac disease was diagnosed in 128 (42%) families and 201 (22%) relatives. BrS was the most prevalent diagnosis (n = 85, 28% of families; n = 140, 15% of relatives). Ajmaline testing was required to unmask the BrS in 97% of diagnosed individuals. The use of high RPLs showed a 16% incremental diagnostic yield of ajmaline testing by diagnosing BrS in an additional 49 families. There were no differences of the characteristics between individuals and families with a diagnostic pattern in the conventional and the high RPLs. On follow-up, a spontaneous type 1 Brugada pattern and/or clinically significant arrhythmic events developed in 17% (n = 25) of the concealed BrS cohort.CONCLUSIONS: Systematic use of ajmaline testing with high RPLs increases substantially the yield of BrS in SADS families. Assessment should be performed in expert centers where patients are counseled appropriately for the potential implications of provocation testing.

Background Accurate knowledge of causes of sudden cardiac death (SCD) in athletes and its precipitating factors is necessary to establish preventative strategies. Objectives This study investigated causes of SCD and their association with intensive physical activity in a large cohort of athletes. Methods Between 1994 and 2014, 357 consecutive cases of athletes who died suddenly (mean 29 ± 11 years of age, 92% males, 76% Caucasian, 69% competitive) were referred to our cardiac pathology center. All subjects underwent detailed post-mortem evaluation, including histological analysis by an expert cardiac pathologist. Clinical information was obtained from referring coroners. Results Sudden arrhythmic death syndrome (SADS) was the most prevalent cause of death (n = 149 [42%]). Myocardial disease was detected in 40% of cases, including idiopathic left ventricular hypertrophy (LVH) and/or fibrosis (n = 59, 16%); arrhythmogenic right ventricular cardiomyopathy (ARVC) (13%); and hypertrophic cardiomyopathy (HCM) (6%). Coronary artery anomalies occurred in 5% of cases. SADS and coronary artery anomalies affected predominantly young athletes (≤ 35 years of age), whereas myocardial disease was more common in older individuals. SCD during intense exertion occurred in 61% of cases; ARVC and left ventricular fibrosis most strongly predicted SCD during exertion. Conclusions Conditions predisposing to SCD in sports demonstrate a significant age predilection. The strong association of ARVC and left ventricular fibrosis with exercise-induced SCD reinforces the need for early detection and abstinence from intense exercise. However, almost 40% of athletes die at rest, highlighting the need for complementary preventive strategies.

We read with interest the provocative work by Pieroni et al. [(1)][1] describing the relationship between electroanatomic abnormalities and pathological substrate in Brugada syndrome (BrS). In particular, we noted that right ventricular (RV) biopsy guided by 3-dimensional RV electroanatomic mapping

Accurate knowledge of causes of sudden cardiac death (SCD) in athletes and its precipitating factors is necessary to establish preventative strategies.This study investigated causes of SCD and their association with intensive physical activity in a large cohort of athletes.Between 1994 and 2014, 357 consecutive cases of athletes who died suddenly (mean 29 ± 11 years of age, 92% males, 76% Caucasian, 69% competitive) were referred to our cardiac pathology center. All subjects underwent detailed post-mortem evaluation, including histological analysis by an expert cardiac pathologist. Clinical information was obtained from referring coroners.Sudden arrhythmic death syndrome (SADS) was the most prevalent cause of death (n = 149 [42%]). Myocardial disease was detected in 40% of cases, including idiopathic left ventricular hypertrophy (LVH) and/or fibrosis (n = 59, 16%); arrhythmogenic right ventricular cardiomyopathy (ARVC) (13%); and hypertrophic cardiomyopathy (HCM) (6%). Coronary artery anomalies occurred in 5% of cases. SADS and coronary artery anomalies affected predominantly young athletes (≤ 35 years of age), whereas myocardial disease was more common in older individuals. SCD during intense exertion occurred in 61% of cases; ARVC and left ventricular fibrosis most strongly predicted SCD during exertion.Conditions predisposing to SCD in sports demonstrate a significant age predilection. The strong association of ARVC and left ventricular fibrosis with exercise-induced SCD reinforces the need for early detection and abstinence from intense exercise. However, almost 40% of athletes die at rest, highlighting the need for complementary preventive strategies.

The prevalence of the Wolff-Parkinson-White (WPW) electrocardiogram (ECG) pattern is estimated between 0.1% and 0.3% [(1)][1]. The risk of malignant arrhythmias in asymptomatic individuals is low and ablation of the accessory pathway can abolish the risk of sudden cardiac death (SCD) [(2)][2].

We thank Drs. Patane and Martini for their letters in relation to our paper [(1)][1]. Dr. Patane points out the complexities underlying Connexin-43 expression including regulation by T-box (TBX)–linked transcription factors. Indeed, work from our group and colleagues has associated common

ObjectivesThis study characterizes the histology of myocardium predicted to be hibernating using three different imaging techniques to explain the discordance among them.BackgroundBoth radionuclide and functional imaging techniques were used to assess myocardial hibernation. The former have high sensitivity and the latter high specificity for predicting functional recovery.MethodsNineteen patients underwent thallium-201 and 99m-technetium tetrofosmin myocardial perfusion imaging, and dobutamine magnetic resonance imaging (MRI), prior to coronary bypass grafting. Criteria for predicted hibernation for each technique were defined before operation. Postoperative criteria for scar and true hibernation were also defined. Biopsies were analyzed for myocyte volume fraction (MVF), glycogen deposition and pathologic cell features.ResultsThallium was most sensitive in predicting hibernation (88%) and MRI most specific (84%); and, although there was good agreement between thallium and tetrofosmin (85%), agreement between MRI and thallium (59%) or tetrofosmin (59%) was poor. For each technique, MVF was higher in segments predicted to be hibernating rather than scar (p < 0.05). The MVF was higher where both thallium and MRI predicted hibernation (0.77 ± 0.07) than in segments predicted by thallium alone (0.69 ± 0.13, p < 0.05). Proven hibernating segments had a higher MVF than scar (0.72 ± 0.11 vs. 0.6 ± 0.26, p < 0.05).ConclusionsPreservation of myocyte fraction is an important determinant of functional recovery after revascularization. A higher myocyte fraction is required to maintain contractile reserve than to achieve significant tracer uptake. This explains the higher sensitivity of radionuclide imaging compared with dobutamine MRI in the identification of myocardial hibernation.

We are grateful to Dr. Karam and colleagues for their interest in our paper. Their letter focuses on the circumstances of sudden cardiac death (SCD) in our athletes. Previous reports suggest over 80% of SCDs in athletes occur during or immediately after exercise. In contrast, we observed that a

Objectives We studied the prognostic implications of midwall fibrosis in dilated cardiomyopathy (DCM) in a prospective longitudinal study. Background Risk stratification of patients with nonischemic DCM in the era of device implantation is problematic. Approximately 30% of patients with DCM have midwall fibrosis as detected by late gadolinium-enhancement (LGE) cardiovascular magnetic resonance (CMR), which may increase susceptibility to arrhythmia and progression of heart failure. Methods Consecutive DCM patients (n = 101) with the presence or absence of midwall fibrosis were followed up prospectively for 658 ± 355 days for events. Results Midwall fibrosis was present in 35% of patients and was associated with a higher rate of the predefined primary combined end point of all-cause death and hospitalization for a cardiovascular event (hazard ratio 3.4, p = 0.01). Multivariate analysis showed midwall fibrosis as the sole significant predictor of death or hospitalization. However, there was no significant difference in all-cause mortality between the 2 groups. Midwall fibrosis also predicted secondary outcome measures of sudden cardiac death (SCD) or ventricular tachycardia (VT) (hazard ratio 5.2, p = 0.03). Midwall fibrosis remained predictive of SCD/VT after correction for baseline differences in left ventricular ejection fraction between the 2 groups. Conclusions In DCM, midwall fibrosis determined by CMR is a predictor of the combined end point of all-cause mortality and cardiovascular hospitalization, which is independent of ventricular remodeling. In addition, midwall fibrosis by CMR predicts SCD/VT. This suggests a potential role for CMR in the risk stratification of patients with DCM, which may have value in determining the need for device therapy.

Objectives We sought to identify the histologic basis of myocardial late gadolinium enhancement cardiovascular magnetic resonance (CMR) in hypertrophic cardiomyopathy (HCM). Background The histologic basis of late gadolinium CMR in patients with HCM is unknown. Methods A 28-year-old male patient with HCM and heart failure underwent late gadolinium enhancement CMR and, 49 days later, heart transplantation. The explanted heart was examined histologically for the extent of collagen and disarray, and the results were compared with a previous in vivo CMR scan. Results Overall, 19% of the myocardium was collagen, but the amount per segment varied widely (SD ± 19, range 0% to 71%). Both disarray and collagen were more likely to be found in the mesocardium than in the endo- or epicardium. There was a significant relationship between the extent of late gadolinium enhancement and collagen (r = 0.7, p 15% collagen were more likely to have late gadolinium enhancement. Regional wall motion was inversely related to the extent of myocardial collagen and late gadolinium enhancement but not disarray (p = 0.0003, 0.04, and NS, respectively). Conclusions In this patient with HCM and heart failure, regions of myocardial late gadolinium enhancement by CMR represented regions of increased myocardial collagen but not disarray.

Objectives We investigated the significance of fibrosis detected by late gadolinium enhancement cardiovascular magnetic resonance for the prediction of major clinical events in hypertrophic cardiomyopathy (HCM). Background The role of myocardial fibrosis in the prediction of sudden death and heart failure in HCM is unclear with a lack of prospective data. Methods We assessed the presence and amount of myocardial fibrosis in HCM patients and prospectively followed them for the development of morbidity and mortality in patients over 3.1 ± 1.7 years. Results Of 217 consecutive HCM patients, 136 (63%) showed fibrosis. Thirty-four of the 136 patients (25%) in the fibrosis group but only 6 of 81 (7.4%) patients without fibrosis reached the combined primary end point of cardiovascular death, unplanned cardiovascular admission, sustained ventricular tachycardia or ventricular fibrillation, or appropriate implantable cardioverter-defibrillator discharge (hazard ratio [HR]: 3.4, p = 0.006). In the fibrosis group, overall risk increased with the extent of fibrosis (HR: 1.18/5% increase, p = 0.008). The risk of unplanned heart failure admissions, deterioration to New York Heart Association functional class III or IV, or heart failure-related death was greater in the fibrosis group (HR: 2.5, p = 0.021), and this risk increased as the extent of fibrosis increased (HR: 1.16/5% increase, p = 0.017). All relationships remained significant after multivariate analysis. The extent of fibrosis and nonsustained ventricular tachycardia were univariate predictors for arrhythmic end points (sustained ventricular tachycardia or ventricular fibrillation, appropriate implantable cardioverter-defibrillator discharge, sudden cardiac death) (HR: 1.30, p = 0.014). Nonsustained ventricular tachycardia remained an independent predictor of arrhythmic end points after multivariate analysis, but the extent of fibrosis did not. Conclusions In patients with HCM, myocardial fibrosis as measured by late gadolinium enhancement cardiovascular magnetic resonance is an independent predictor of adverse outcome. (The Prognostic Significance of Fibrosis Detection in Cardiomyopathy; NCT00930735)