Arrhythmic Sudden Cardiac Death Research Articles

Phenotypic expression is a prerequisite for malignant arrhythmic events and sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy.

Whether a desmosomal (DS)-gene defect may in itself induce life-threatening ventricular arrhythmias regardless of phenotypic expression of arrhythmogenic right ventricular cardiomyopathy (ARVC) is still debated. This prospective study evaluated the long-term outcome of DS-gene mutation carriers in relation to the ARVC phenotypic expression. The study population included 116 DS-gene mutation carriers [49% males; median age 33 years (16-48 years)] without prior sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). The incidence of the arrhythmic endpoint, including sudden cardiac death (SCD), aborted SCD, sustained VT, and appropriate implantable cardioverter-defibrillator (ICD) intervention was evaluated prospectively and stratified by the presence of ARVC phenotype and risk factors (syncope, ventricular dysfunction, and non-sustained VT). At enrolment, 40 of 116 (34%) subjects fulfilled the criteria for definite ARVC while the remaining were either borderline or phenotype negatives. During a median follow-up of 8.5 (5-12) years, 10 patients (9%) had arrhythmic events (0.9%/year). The event rate was 2.3%/year among patients with definite ARVC and 0.2%/year among borderline or phenotype negative patients (P = 0.002). In patients with definite ARVC, the incidence of arrhythmias was higher in those with ≥1 risk factors (4.1%/year) than in those with no risk factors (0.4%/year, P = 0.02). Mortality was 0.2%/year (1 heart failure death and 1 SCD). The ARVC phenotypic expression is a prerequisite for the occurrence of life-threatening arrhythmias in DS-gene mutation carriers. The vast majority of malignant arrhythmic events occurred in patients with an overt disease phenotype and major risk factors suggesting that this subgroup most benefits from ICD therapy.

SCD-HeFT: Use of R-R interval statistics for long-term risk stratification for arrhythmic sudden cardiac death

In the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), a significant fraction of the patients with congestive heart failure ultimately did not die suddenly of arrhythmic causes. Patients with CHF will benefit from better tools to identify if implantable cardioverter-defibrillator (ICD) therapy is needed. We aimed to identify predictor variables from baseline SCD-HeFT patients' R-R intervals that correlate to arrhythmic sudden cardiac death (SCD) and mortality and to design an ICD therapy screening test. Ten predictor variables were extracted from prerandomization Holter data from 475 patients enrolled in the ICD arm of the SCD-HeFT by using novel and traditional heart rate variability methods. All variables were correlated to SCD using the Mann-Whitney-Wilcoxon test and receiver operating characteristic analysis. ICD therapy screening tests were designed by minimizing the cost of false classifications. Survival analysis, including log-rank test and Cox models, was also performed. A short-term fractal exponent, α1, and a long-term fractal exponent, α2, from detrended fluctuation analysis, the ratio of low- to high-frequency power, the number of premature ventricular contractions per hour, and the heart rate turbulence slope are all statistically significant for predicting the occurrences of SCD (P < .001) and survival (log-rank, P < .01). The most powerful multivariate predictor tool using the Cox proportional hazards regression model was α2 with a hazard ratio of 0.0465 (95% confidence interval 0.00528-0.409; P < .01). Predictor variables extracted from R-R intervals correlate to the occurrences of SCD and distinguish survival functions among patients with ICDs in SCD-HeFT. We believe that SCD prediction models should incorporate Holter-based R-R interval analysis to refine ICD patient selection, especially to exclude patients who are unlikely to benefit from ICD therapy.

Sudden cardiac death risk stratification.

Arrhythmic sudden cardiac death (SCD) may be caused by ventricular tachycardia/fibrillation or pulseless electric activity/asystole. Effective risk stratification to identify patients at risk of arrhythmic SCD is essential for targeting our healthcare and research resources to tackle this important public health issue. Although our understanding of SCD because of pulseless electric activity/asystole is growing, the overwhelming majority of research in risk stratification has focused on SCD-ventricular tachycardia/ventricular fibrillation. This review focuses on existing and novel risk stratification tools for SCD-ventricular tachycardia/ventricular fibrillation. For patients with left ventricular dysfunction or myocardial infarction, advances in imaging, measures of cardiac autonomic function, and measures of repolarization have shown considerable promise in refining risk. Yet the majority of SCD-ventricular tachycardia/ventricular fibrillation occurs in patients without known cardiac disease. Biomarkers and novel imaging techniques may provide further risk stratification in the general population beyond traditional risk stratification for coronary artery disease alone. Despite these advances, significant challenges in risk stratification remain that must be overcome before a meaningful impact on SCD can be realized.

Impact of the presence and amount of myocardial fibrosis by cardiac magnetic resonance on arrhythmic outcome and sudden cardiac death in nonischemic dilated cardiomyopathy

Current risk stratification for sudden cardiac death (SCD) in nonischemic dilated cardiomyopathy (NIDC) relies on left ventricular (LV) dysfunction, a poor marker of ventricular electrical instability. Contrast-enhanced cardiac magnetic resonance has the ability to accurately identify and quantify ventricular myocardial fibrosis (late gadolinium enhancement [LGE]). To evaluate the impact of the presence and amount of myocardial fibrosis on arrhythmogenic risk prediction in NIDC. One hundred thirty-seven consecutive patients with angiographically proven NIDC were enrolled for this study. All patients were followed up for a combined arrhythmic end point including sustained ventricular tachycardia (VT), appropriate implantable cardioverter-defibrillator (ICD) intervention, ventricular fibrillation (VF), and SCD. LV-LGE was identified in 76 (55.5%) patients. During a median follow-up of 3 years, the combined arrhythmic end point occurred in 22 (16.1%) patients: 8 (5.8%) sustained VT, 9 (6.6%) appropriate ICD intervention, either against VF (n = 5; 3.6%) or VT (n = 4; 2.9%), 3 (2.2%) aborted SCD, and 2 (1.5%) died suddenly. Kaplan-Meier analysis revealed a significant correlation between the LV-LGE presence (not the amount and distribution) and malignant arrhythmic events (P < .001). In univariate Cox regression analysis, LV-LGE (hazard ratio [HR] 4.17; 95% confidence interval [CI] 1.56-11.2; P = .005) and left bundle branch block (HR 2.43; 95% CI 1.01-5.41; P = .048) were found to be associated with arrhythmias. In multivariable analysis, the presence of LGE was the only independent predictor of arrhythmias (HR 3.8; 95% CI 1.3-10.4; P = .01). LV-LGE is a powerful and independent predictor of malignant arrhythmic prognosis, while its amount and distribution do not provide additional prognostic value. Contrast-enhanced cardiac magnetic resonance may contribute to identify candidates for ICD therapy not fulfilling the current criteria based on left ventricular ejection fraction.

The Future Role, Clinical and Economic Implications of Cardiac Magnetic Resonance (CMR) Imaging in Non-Ischemic Dilated Cardiomyopathy

The use of cardiovascular magnetic resonance (CMR) imaging for assessing and evaluating cardiovascular pathologies is growing rapidly. This non-invasive, non-ionizing technology has multiple advantages compared with the X-ray or gamma ray derived technologies. For instance, CMR is a non-invasive and sensitive tool for detecting islands of fibrosis. Cardiac fibrosis may occur in both ischemic and non-ischemic cardiac pathologies.This finding has a negative impact on sudden cardiac arrhythmic death. A correlation has been found between CMR data and histo-pathologic findings. The presence of this pathology among normal looking fibers indicates the presence of non-functional areas that may evoke malignant arrhythmia, and contribute to deterioration in cardiac mechanical function. By using this non-invasive modality, the role of cardiac fibrosis as a potential source for cardiac arrhythmia and or LV dysfunction can be better evaluated and managed. This finding may serve as a useful tool for risk stratification of patients with borderline indication for primary AICD implantation.

Pharmacotherapy to reduce arrhythmic mortality

Fatal ventricular arrhythmias and heart failure are the common modes of death in patients with cardiovascular diseases. Intracardiac defibrillator (ICD) implantation reduces arrhythmic mortality to a significant extent in the high risk patient. However, there continues to be a need for effective drug therapy to reduce the arrhythmic and overall mortality in patients with or without an ICD. Although anti-arrhythmic drugs (AAD) appear inferior to ICD, the role of beta-blockers and to an extent amiodarone along with non AAD like angiotensin converting enzyme inhibitors (ACE-I), mineralocorticoid blockers (MRB) and HMG-CoA reductase inhibitors (statins) need to be emphasized. There have been many drug trials and meta-analysis to this effect and we review the role of drugs especially in their ability to reduce arrhythmic mortality and sudden cardiac death (SCD). The focus is on post myocardial infarction (MI) and heart failure patients with a brief overview of role of drugs in channelopathies.

Compound and Digenic Heterozygosity Predicts Lifetime Arrhythmic Outcome and Sudden Cardiac Death in Desmosomal Gene–Related Arrhythmogenic Right Ventricular Cardiomyopathy

Mutations in genes encoding for desmosomal proteins are the most common cause of arrhythmogenic right ventricular cardiomyopathy (ARVC). We assessed the value of genotype for prediction of lifetime major arrhythmic events and sudden cardiac death (SCD) in desmosomal gene-related ARVC. The overall study population included 134 desmosomal gene mutation carriers (68 men; median age 36 years [22-52]) from 44 consecutive ARVC families undergoing comprehensive genetic screening. The probability of experiencing a first major arrhythmic event or SCD during a lifetime was determined by using date of birth as start point for the time-to-event analysis, and was stratified by sex, desmosomal genes, mutation types, and genotype complexity (single versus multiple mutations). One hundred thirteen patients (84%) carried a single desmosomal gene mutation in desmoplakin (n=44; 39%), plakophilin-2 (n=38; 34%), desmoglein-2 (n=30; 26%), and desmocollin-2 (n=1; 1%), whereas 21 patients (16%) had a complex genotype with compound heterozygosity in 7 and digenic heterozygosity in 14. Over a median observation period of 39 (22-52) years, 22 patients (16%) from 20 different families had arrhythmic events, such as SCD (n=1), aborted SCD because of ventricular fibrillation (n=6), sustained ventricular tachycardia (n=14), and appropriate defibrillator intervention (n=1). Multiple desmosomal gene mutations and male sex were independent predictors of lifetime arrhythmic events with a hazard ratio of 3.71 (95% confidence interval, 1.54-8.92; P=0.003) and 2.76 (95% confidence interval, 1.19-6.41; P=0.02), respectively. Compound/digenic heterozygosity was identified in 16% of ARVC-causing desmosomal gene mutation carriers and was a powerful risk factor for lifetime major arrhythmic events and SCD. These results support the use of comprehensive genetic screening of desmosomal genes for arrhythmic risk stratification in ARVC.

Searching for Sudden Death SNPs in Calcium Handling Genes

Cardiac arrhythmias are a major clinical problem and lead to more than 250 000 sudden cardiac deaths (SCDs) each year in the United States alone.[1][1] Our ability to predict those at risk for sudden death remains poor. The majority of patients who die suddenly are not identified as being at high

Hyperpolarization‐Activated Cyclic Nucleotide‐Gated Channels and Ventricular Arrhythmias in Heart Failure: A Novel Target for Therapy?

Arrhythmias are a common and often fatal complication of heart failure accounting for 50% to 70% of cardiac deaths due to tachyarrhythmic mechanisms.[1][1] In the failing heart, disturbances in cardiac rhythm are the likely result of cardiac remodeling consisting of structural and/or

Post-Mortem Cardiac 3-T Magnetic Resonance Imaging: Visualization of Sudden Cardiac Death?

This study aimed to investigate post-mortem magnetic resonance imaging (pmMRI) for the assessment of myocardial infarction and hypointensities on post-mortem T2-weighted images as a possible method for visualizing the myocardial origin of arrhythmic sudden cardiac death. Sudden cardiac death has challenged clinical and forensic pathologists for decades because verification on post-mortem autopsy is not possible. pmMRI as an autopsy-supporting examination technique has been shown tovisualize different stages of myocardial infarction. In 136 human forensic corpses, a post-mortem cardiac MR examination was carried out prior to forensic autopsy. Short-axis and horizontal long-axis images were acquired in situ on a 3-T system. In 76 cases, myocardial findings could be documented and correlated to the autopsy findings. Within these 76 study cases, a total of 124 myocardial lesions were detected on pmMRI (chronic: 25; subacute: 16; acute: 30; and peracute: 53). Chronic, subacute, and acute infarction cases correlated excellently to the myocardial findings on autopsy. Peracute infarctions (age range: minutes to approximately 1 h) were not visible on macroscopic autopsy or histological examination. Peracute infarction areas detected on pmMRI could be verified in targeted histological investigations in 62.3% of cases and could be related to a matching coronary finding in 84.9%. A total of 15.1% of peracute lesions on pmMRI lacked a matching coronary finding but presented with severe myocardial hypertrophy or cocaine intoxication facilitating a cardiac death without verifiable coronary stenosis. 3-T pmMRI visualizes chronic, subacute, and acute myocardial infarction in situ. In peracute infarction as a possible cause of sudden cardiac death, it demonstrates affected myocardial areas not visible on autopsy. pmMRI should be considered as a feasible post-mortem investigation technique for the deceased patient if no consent for a clinical autopsy is obtained.

Controversy surrounding the best time for ICD implantation after myocardial infarction

Controversy surrounding the best time for ICD implantation after myocardial infarction

Riata type implantable cardiac defibrillator leads: increasingly small, progressively troublesome

Already in 1970, Mirowski and colleagues worked on the development of the first implantable cardiac defibrillator (ICD). Since then, important progression has been made by increasingly complex pacing and defibrillation functions, higher battery durability, and reduction of both device and shock lead size. A large amount of evidence has shown that ICDs are life-saving and cost-effective, both for primary and secondary prevention of sudden arrhythmic cardiac death. In the last decade, a quest for smaller shock lead design was initiated, but unfortunately increasing dysfunction rates of ICD generators and leads were to be unmasked only a few years later.[1, 2] Medtronic’s 6.7 Fr Sprint Fidelis lead was recalled by the FDA in 2007 and St. Jude’s 7.6 Fr Riata and 6.3 Riata ST leads were recalled by the manufacturer, FDA and the Dutch authorities in 2011. By then, the vast amount of approximately 227,000 Riata leads, and 268,000 Sprint Fidelis leads had been distributed worldwide.

Abstract 18314: Fragmented QRS on a 12-lead ECG: A Predictor of Major Arrhythmic Events and Sudden Cardiac Death in Patients with Hypertrophic Cardiomyopathy; Long-term Follow-up Study

INTRODUCTION Fragmented QRS (fQRS) on a 12-lead electrocardiogram (ECG) is associated with major arrhythmic events (MAEs) included sudden cardiac death (SCD). However, Limited data was still shown in patients with hypertrophic cardiomyopathy (HCM). METHODS fQRS included various RSRpatterns (QRS duration &lt; 120ms), such as ≥1 R prime or notching of the R wave or S wave present on at least two contiguous leads of those representing anterior (V1-V5), lateral (I, aVL, V6), or inferior (II, III, aVF) myocardial segments on a 12-lead electrocardiogram (ECG). In the 454 (71% male, age 62±11 years, mean follow-up duration 10±1 years) patients with diagnosed HCM using echocardiography. We divided into two groups; fQRS and non-fQRS group at the time of diagnosis. MAEs (sustained VT or non-sustained VT on ambulatory 24-hr holter monitoring) including SCD were retrospectively reviewed. RESULTS fQRS was found (87/203, 42.8%) and predominantly located in inferior lead, the patients were divided into two groups: Heart rate, PR interval, QRS duration and QTc interval were similar in both groups. MAEs including SCD [14 (31.1%) vs. 2 (2.2%)] were higher in the fQRS group compared with the non-fQRS group (mean follow-up duration, 7.1±2.2 years). Multivariate Cox regression analysis revealed that fQRS was an independent significant predictor for MAE including SCD [hazard ratio 11.09 (confidence interval 2.40-51.09), p=0.002]. A Kaplan-Meier survival analysis revealed that fQRS group was significantly associated with lower MAE-free survival rate compared to non-fQRS group (P=0.004). CONCLUSION The fQRS complex is an independent predictor of MAEs including SCD in patients with HCM on long-term follow-up.

Abstract 19255: A Role for Mitochondria in Triggered Activity from Cardiomyocytes with Reduced Sarcoplasmic Reticulum Calcium Release

Introduction: A prominent feature of systolic heart failure is the reduction of Ca2+ induced Ca2+ release from sacroplasimic reticulum (SR). Moreover, patients with heart failure are at high risk of arrhythmic sudden cardiac death. Hypothesis: The basis for increased arrhythmic risk with reduced SR Ca2+ release was investigated using embryonic stem cell derived ventricular-like cardiomyocytes (CMs) deficient for the expression of the ryanodine receptor (RYR-/-). Methods: Action potentials (APs) and L-type Ca2+ currents were recorded in the perforated current-clamp and whole cell voltage-clamp respectively. Changes in [Ca2+]i were determined by confocal imaging of Fluo-4/AM ESCs. APs were recorded from CMs differentiated for 19 days. Results: Compared with wild type CMs, L-type Ca2+ channels showed less current density and slightly slower activation/inactivation kinetics in RyR-/- CMs. AP and Ca2+ transient frequency were decreased. Ca2+ transient amplitudes were smaller in RyR-/- CMs and had prolonged transient duration at 50% amplitude. Ca2+ transients are comparable to those of WT cells after SR depletion by caffeine, indicating that the SR in RyR-/- CMs did not contribute significantly to Ca2+ release or removal. Despite a shorter AP duration at 90% repolarization (APD90: 187.7 ± 13.8 ms vs. 274.3 ± 36.3 ms), RyR-/- ventricular-like CMs displayed more delayed after-depolarizations (DADs, 75% vs. 0%, p&lt;0.05) than WT CMs. Arrhythmia-inducing Ca2+ leak in RyR-/- CMs can come from IP3R mediated Ca2+ release or from mitochondrial Ca2+. In the presence of the IP3R blocker 2-APB, AP frequency decreased (from 1.3±0.1 to 0.3±0.1 Hz) supporting its role in pacemaker activity, but DADs remained. In the absence of [Ca2+]o, an increase in SR load after a caffeine-induced depletion of the SR indicated Ca2+ transfer from the mitochondria to the SR. Application of the mitochondrial NCX blocker (CGP) suppressed this transfer in WT CMs. Block of the mitochondrial Ca2+ uptake (Ru360) prevented DADs in RyR-/- CMs. Conversely application of PPT, an activator of the mitochondrial Ca2+ uniporter, enhanced DADs in RyR-/- ESCs. Conclusions: DADs may occur in the presence of reduced SR Ca2+ release. DADs in RyR-/- CMs depends on mitochondrial Ca2+ flux.

LONG QT SYNDROME AND TORSADES DE POINTS IN A PATIENT WITH ACUTE HEPATITIS E VIRUS INFECTION: AN UNUSUAL CASE

LONG QT SYNDROME AND TORSADES DE POINTS IN A PATIENT WITH ACUTE HEPATITIS E VIRUS INFECTION: AN UNUSUAL CASE

Predictors of sustained ventricular arrhythmia episodes in patients with primary ICD indication

Implantable cardioverter-defibrillators (ICD) reduce mortality in patients with severely impaired left ventricular function. In randomized studies, female patients are underrepresented and data on ICD therapy is limited. Atrial fibrillation (AF) is a determinant of poor prognosis but has not been consistently evaluated. We evaluated the risk factors for the occurrence of ventricular arrhythmia episodes in patients with primary ICD prophylaxis. Consecutive patients after ICD implantation for primary prophylaxis were followed. During follow-up, detected sustained episodes of ventricular arrhythmia were documented. Multivariate analysis controlled for propensity score was used to evaluate the correlation between gender, history of AF, and the occurrence of ventricular arrhythmia episodes. A total of 400 patients (19.8% female; n = 79) were included. During follow-up, 64 patients (16%) had appropriate ICD therapy episodes. Men (18%) had significantly more often episodes than women (8%; p = 0.025). Patients with a history of AF (102, 25.5%) had significantly more often episodes (30%) compared to patients without a history of AF (11%; p < 0.001). In a multivariate model, only gender (p = 0.02) and history of AF (p < 0.001) were significantly associated predictors of the occurrence of appropriate ICD therapies during follow-up. Based on the propensity score model, the adjusted hazard ratio for male gender was 2.7 (p = 0.02) and 2.6 (p = 0.0004) for history of AF. Male gender and history of AF are independent predictors for the occurrence of sustained ventricular arrhythmia in primary ICD prophylaxis. Further studies need to evaluate whether history of AF in female patients might be an indicator for higher risk of sudden cardiac arrhythmic death.

Role of Antiarrhythmic Drugs: Frequent Implantable Cardioverter-Defibrillator Shocks, Risk of Proarrhythmia, and New Drug Therapy

The implantable cardioverter-defibrillator (ICD) is the standard of care in patients with ischemic and nonischemic cardiomyopathy who are at high risk for arrhythmic events and sudden cardiac death. Although an ICD saves life, ICD shocks are emotionally and physically debilitating. Most patients receive adjuvant antiarrhythmic drug therapy to circumvent episodes of recurrent ventricular and supraventricular arrhythmias. Antiarrhythmic drugs including b-blockers, sotalol, amiodarone, and azimilide are effective at reducing the shock burden. This article describes data supporting the need for and potential risks and benefits of adjuvant antiarrhythmic drug therapy and examines the benefits and pitfalls of the same in ICD-implanted patients.

Horses and Zebras: complex cardiac anatomy in a patient with out-of-hospital cardiac arrest

This case report describes a woman presenting after out-of-hospital cardiac arrest with several cardiac anomalies, including a form fruste of Ebstein's anomaly complicated by a large tricuspid valve vegetation. On autopsy, she proved to have unstable plaques in epicardial vessels that likely caused arrhythmic sudden cardiac death, a reminder that even in the presence of rare anomalies, common things are common.

Regional Mitochondrial Depolarization Causes Spontaneous Ventricular Arrhythmia in Cardiac Tissue

Sudden cardiac death (SCD) resulting from ventricular arrhythmia remains a leading cause of death in the USA. The underlying molecular and structural mechanisms of arrhythmic SCD, however, are still unclear. We have recently reported that oxidative stress can trigger the abrupt collapse of mitochondrial inner membrane potential (ΔΨm), reverse of ATP synthase and decrease of ATP concentration. This could activate the sarcolemmal ATP sensitive potassium channel (KATP), affecting cellular electrical excitability and electrical wave propagation in the cardiac tissue. To test this hypothesis, we investigated the effect of regional mitochondrial depolarization on electrical wave propagation using combined optical mapping and computer simulations. The regional mitochondrial depolarization was induced in the center of cardiac cell monolayer by oxidative stress or mitochondrial uncoupler. The results show a coupling between ΔΨm depolarization, activation of KATP current and shortening of action potentials. When this effect is amplified, regional mitochondrial depolarization could form a metabolic current sink, preventing electrical wave propagation on the cardiac tissue. The overall influence involves a combination of a decrease in the action potential amplitude and shortening of the action potential duration. This mechanism introduces both temporal and spatial dispersion of electrical excitability and heterogeneous conduction, leading to wave breaks and spontaneous arrhythmia when the mitochondrial energetics within the metabolic current sink zone is recovering. In summary, this study illustrates the mechanism by which “metabolic” sinks can contribute the formation of fatal reentrant arrhythmias and reveal a novel way that reentry may be triggered in tissues recovering from metabolic inhibition (e.g., ischemia-reperfusion). The findings underscore the importance of considering mitochondrial targets for developing new therapies for SCD in the context of cardiovascular disease.

Neuropeptide Y-induced coronary microvascular dysfunction: A significant contributor to the adverse outcomes in stress cardiomyopathy?

⁎ Corresponding author. E-mail address: kyalta@gmail.com (K. Yalta). In their recently published article, Szardien et al. reported a 78year-old female patient who had suffered stress cardiomyopathy (SCM) accompanied by increased serum levels of neuropeptide Y (NPY) [1]. We agree with the authors that increased serum NPY levels may contribute to myocardial contractile dysfunction and hence may also be regarded as a prognostic marker in patients with SCM [1]. However, in the setting of SCM with substantial NPY levels, NPYinduced coronary microvascular dysfunction, as described below, may also contribute significantly to the adverse clinical outcomes including ischemic malign arrhythmias, etc. Transient wall motion abnormalities including left ventricular apical ballooning have been regarded as one of the main characteristics of SCM [2]. Catecholamine-induced myocardial dysfunction, coronary microvascular dysfunction and coronary spasm etc have been suggested as potential etiologies of this entity. Recently, NPY has also been suggested to contribute to myocardial dysfunction in SCM indicating its potential prognostic value [1]. Notwithstanding the generally accepted benign nature of SCM, relatively high rates of malign ventricular arrhythmias and mortality were reported in some patient series [3]. Even though the exact mechanisms leading to adverse events (malign ventricular arrhythmia, etc.) in SCM is still largely unknown, severe coronary microvascular dysfunction may be considered as a potential trigger in some patients. Endothelial dysfunction [4] and increased serum NPY (a vasoconstrictor hormone) [5] levels are well known to play the central role in the pathogenesis of coronary microvascular syndromes. Among these syndromes, coronary syndrome Y (characterized by coronary slow flow (CSF)) is associated with enhanced coronary resistance, and may present with the clinical picture of acute coronary syndrome (ACS) along with an increased proclivity to cardiac arrhythmias [4]. Similarly, in the setting of SCM, severe and transient coronary microvascular dysfunction induced by excessive levels of NPY may be associated with adverse clinical outcomes including ischemic malign arrhythmic events and sudden cardiac death (SCD), etc. (regardless of the presence of severe left ventricular systolic dysfunction). Therefore, besides clinical presentation, SCM with excessive NPY levels may resemble ACSs in terms of prognostic features. Even though, the case reported by Szardien et al. [1] did not suffer any SCM-related adverse event, substantial levels of NPY might indicate the possibility of severe coronary microvascular dysfunction (with or without CSF) in this case. It may be suggested that NPY-induced severe coronary microvascular dysfunction may account for life-threatening ischemic adverse events including malign ventricular arrhythmias in SCM patients with substantial levels of NPY during the disease course. Therefore, these patients may be regarded as a subgroup with potentially worse prognosis due to severe coronary microvascular dysfunction indicating the need for close monitoring and aggressive management as in the event of ACSs. Besides conventional therapeutic strategies including management of heart failure, arrhythmias and anticoagulation, etc., targeting enhancement of coronary blood flow along with the use of intensive anti-ischemic regimens may be of clinical value during the disease course and may help improve prognosis in SCM patients with substantial serum levels of NPY. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [6].