Takotsubo syndrome (TTS), also known as Takotsubo cardiomyopathy, is a transient left ventricular wall dysfunction that is often triggered by physical or emotional stressors. Although TTS is a rare disease with a prevalence of only 0.5% to 0.9% in the general population, it is often misdiagnosed as acute coronary syndrome. A diagnosis of TTS can be made using Mayo diagnostic criteria. The initial management of TTS includes dual antiplatelet therapy, anticoagulants, beta-blockers, angiotensin-converting enzyme inhibitors or aldosterone receptor blockers, and statins. Treatment is usually provided for up to three months and has a good safety profile. For TTS with complications such as cardiogenic shock, management depends on left ventricular outflow tract obstruction (LVOTO). In patients without LVOTO, inotropic agents can be used to maintain pressure, while inotropic agents are contraindicated in patients with LVOTO. In TTS with thromboembolism, heparin should be started, and patients should be bridged to warfarin for up to three months to prevent systemic emboli. Our comprehensive review discussed the management in detail, derived from the most recent literature from observational studies, systematic review, and meta-analyses. Takotsubo syndrome (TTS), also commonly known as Takotsubo cardiomyopathy or apical ballooning syndrome, is characterized by transient left ventricular (LV) wall dysfunction triggered by physical or emotional factors with similar presentation features as acute coronary syndrome (ACS) . TTS accAs the clinical presentation of TTS is often indistinguishable from ACS, it is a diagnosis of exclusion once true ACS is ruled out with coronary angiography. According to Luscher and Templin et al., TTS and ACS commonly present with chest pain and dyspnea on exertion ,5. HowevLiterature search and data sourceA systematic search was performed on PubMed, MEDLINE, Cochrane Library, and Google Scholar databases. The search included MeSH terms for ‘Takotsubo Cardiomyopathy’, ‘Takotsubo Syndrome’, ‘Broken Heart Syndrome’, ‘Stress Cardiomyopathy’, ‘Transient Apical Ballooning Syndrome’, ‘Apical Ballooning Syndrome’, ‘'Left Ventricular Apical Ballooning Syndrome’, ‘Treatment’, and ‘Management’. The MeSH terms were combined using Boolean operators AND and OR. The studies included were from inception to July 31, 2019. Inclusion criteria were studies that are in English language or foreign languages that are translated into English, and articles that are focused on the management of TTS with measurable outcomes. Exclusion criteria were single case reports and management with no measurable outcomes or follow-up. Two physicians conducted a literature search and independently screened all titles and abstracts. A total of 4,313 articles were found of which 248 articles met the inclusion criteria. Based on predefined criteria, only 16 of these articles were included in this review  flow diagram Figure .Our review of TTS is divided into a short discussion about diagnosis and an extended discussion about management. The extended discussion is divided into TTS with and without complications.Diagnosis of TTSThe diagnosis of TTS should be based on differentials in patients with ACS symptoms such as chest pain or dyspnea on exertion with positive cardiac biomarkers, including troponin, particularly when echocardiographic and clinical manifestations do not fit the pattern of ACS . A carefA diagnosis of TTS should also be considered if wall motion defects do not correlate with an obstructed coronary artery. The exception is a percentage of patients that have concurrent obstructed coronary artery disease (CAD) and TTS; per the International Takotsubo Registry, this subset included 15.3% of TTS cases [Diagnostic ImagingCoronary angiogram is useful for diagnosing TTS. Serial LV systolic function assessment can be done with serial echocardiograms, a one-time assessment with coronary ventriculography, and then cardiac magnetic resonance imaging. It is imperative to suspect TTS during the evaluation of ACS. The approach detailed in Figure Detection of wall defects on echocardiography or LV ventriculography suggests a review of the following wall defect patterns Table  5,24-26-2624-26.Cardiac Magnetic ResonanceCardiac magnetic resonance can highlight the absence of late gadolinium enhancement in TTS as compared to the presence of late gadolinium enhancement seen in transmural or subendocardial regions in myocardial infarction .ManagementGeneral ManagementThe management of TTS is generally conservative and focused on emotional or physical stress relief. However, in some cases, acute complications such as heart failure and shock develop, and intensive management is required. The management of heart failure and shock is similar to that in the general guidelines of their management in non-TTS cases except in the presence of LVOTO. In cases of LVOTO, caution should be taken in preventing volume depletion or with vasodilatory medications. Generally, the duration of treatment of TTS ranges from three months to one year depending on expert opinion. In a study by Fazio et al., it was found that TTS treatment of more than three months did not add any significant change to survival and should be avoided .The management of TTS is divided into TTS without complications and TTS with complications. These complications include hypotension and cardiogenic shock with heart failure or LVOTO, cardiac arrhythmias, and thromboembolism.TTS without ComplicationsAfter a comprehensive assessment, if patients are hemodynamically stable with no other signs of complications such as acute heart failure, arrhythmia, or thromboembolism, they should be admitted to cardiology for further monitoring. In a study by Yeyehd et al., the acute and post-discharge management of TTS with dual antiplatelet therapy (DAPT) including aspirin and clopidogrel, anticoagulation such as low molecular weight heparin or fondaparinux, beta-blockers, statins, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), and psychological stress relief management helped to lower inpatient mortality and recurrence of TTS . FurtherTTS with Complications - Hypotension and Cardiogenic ShockFor TTS patients with hypotension or shock, continuous monitoring of clinical parameters such as vital signs, mental status, urine output, and renal function should be done along with telemonitoring. Up to 5%-10% of patients with TTS can develop cardiogenic shock . A varieThe management of hypotension or cardiogenic shock can be further divided into cases with and without LVOTO as follows.Cardiogenic shock without LVOTO: In patients with hypotension without pulmonary congestion, cautious fluid resuscitation can be performed, even in patients with or without LVOTO. In patients with LV systolic dysfunction but without LVOTO, a trial of inotropic agents such as dopamine or dobutamine can serve as a temporary measure; however, an inotropic agent can cause mild LVOTO in these patients . In modeCardiogenic shock with LVOTO: In patients with cardiogenic shock with moderate to severe LVOTO, inotropic agents should not be used because they can increase the degree of obstruction ,34. In aThe recommended treatment of TTS with moderate to severe LVOTO is similar to hypertrophic cardiomyopathy. The management of this subset of patients includes fluid resuscitation in the absence of pulmonary congestion ,31. The In TTS with severe LVOTO, alpha agonists such as phenylephrine can help in a closely monitored setting by increasing afterload. However, phenylephrine should be used with caution as it can cause coronary vasospasm. Patients with severe/persistent hypotension not responsive to fluid resuscitation or initial measure with an intra-aortic balloon pump should be closely monitored. As IABPs can decrease afterload, this effect should be monitored closely ,34. A fuTTS with Complications - Heart FailureAcute heart failure (HF) in TTS is managed the same way as HF from any other illness: by oxygen, respiratory support as needed, and preload and afterload reduction. The exception to the regular management is that preload and afterload reduction therapies should be avoided in cases with LVOTO. In TTS patients with HF without LVOTO, the standard cocktail of medications for HF can be prescribed. This includes diuretics, ACE inhibitors, or ARBs . Beta-blThe recommended duration of treatment is not well known, but in general, treatment with HF medication is four weeks until systolic function improves. A Mayo clinic study failed to show any survival benefits of ACE inhibitors and beta-blockers in TTS patients . An obseTTS with Complications - ThromboembolismVentricular thrombus is found in 1.3% of the 1,750 TTS patients in the International Takotsubo Registry -23. A syIn conclusion, we have reviewed the most recent observational studies and clinical trials to summarize the management of TTS. The initial management should include optimal medical therapy with antiplatelet medications, statins, beta-blockers, and ACE/ARBs. Pressor medications are contraindicated in TTS with LVOTO. In TTS with thromboembolism, heparin with warfarin should be continued for at least three months.


Familial hypertrophic cardiomyopathy is an autosomal dominant genetic disease considered the most common cause of sudden cardiac death in individuals under 35 years old, especially the athletes. This study aimed to investigate the association between the presence of late potentials and a family history of sudden death, syncope, and complex ventricular arrhythmias on patients with hypertrophic cardiomyopathy. A case series study was carried out from March 2001 to December 2002, including 22 patients with hypertrophic cardiomyopathy according to transthoracic echocardiogram criteria. Patients on a cardiac pacemaker, right bundle branch block, cardiac transplant, and under no possibilities to realize the exams were excluded. The results showed that asymmetric septal hypertrophy was the most common type (73%), 63% had a positive familial history of hypertrophic cardiomyopathy, 55% sudden cardiac death, and 23% syncope. Also, complex ventricular arrhythmias were detected in 14% and late potentials in 23% of patients. According to this study, the presence of late potentials was not associated with familial sudden death, syncope, and complex ventricular arrhythmias. Hypertrophic cardiomyopathy (HCM) is an uncommon cardiac condition that has a 1:500 population prevalence and is the most common cause of sudden death in the young, especially in the athletes . The cliHCM presents an important familial characteristic. Even considering that ethnic and racial differences can affect the familial history and genetic profile of the affected subjects, around 1,500 mutations in at least 20 genes encoding the myofilaments of the sarcomere or Z-disc have been studied and associated to this condition -6.The histopathological features include myocytes disarray with disorganized sarcomeric alignment, abnormalities in the coronary arteriolar walls, diastolic dysfunction, elongation, or malformation of mitral valve leaflets and presence of myocardial fibrosis ,7-9. HCMThe primary method to evaluate and diagnose HCM is echocardiography, which provides the characterization of diastolic and systolic function, intraventricular obstruction, and valvular abnormalities . HCM diaAs a complementary exam, the cardiac magnetic resonance (CMR) provides a better analysis of the morphology, function, and tissue characterization, being mainly used to evaluate the presence of fibrosis as well as morphological abnormalities on the mitral valve (MV) apparatus, especially elongation of the MV leaflets ,9. The pA retrospective case series was performed from March 2001 to December 2002 at the Federal University of Pernambuco Clinics Hospital (HC/UFPE). The diagnosis was based on the identification of hypertrophic ventricle  in the absence of another cardiac or systemic disease capable of explaining the cardiac hypertrophy -8.The inclusion criteria were HCM diagnosis, according to a two-dimensional transthoracic echocardiogram. Those subjects with a cardiac pacemaker, right bundle branch block, and cardiac transplant were excluded. Initially, 32 patients were selected following the two-dimensional transthoracic echocardiogram criteria for hypertrophic cardiomyopathy (HCM).Data were collected from medical records, including a family history of HCM and sudden death, history of syncope, 24-h Holter, and high-resolution electrocardiography results. From the initial sample, 10 patients were excluded: three presented right bundle branch block; two had cardiac pacemaker implant; two did not follow-up the consults; one was submitted to cardiac transplant; one did not collect the necessary exams due to technical issues. A total of 22 patients were included in the final analysis.Definition of sudden deathSudden death was defined as witnessed acute collapse, which has taken place within one hour from the onset of symptoms and signs of disease in previously healthy subjects or unexpected non-witnessed death during sleep.Dynamic electrocardiography (24-h Holter)A continuum digital recorder  was used to record and analyze the Holter tests in 24 h. The electrodes were positioned in the electrocardiographic derivations CM1, CM5, and modified D2. The results were analyzed in the DMI Burdick analyzer®  software by an independent observer searching for complex cardiac arrhythmias.High-resolution electrocardiographyA multivariate digital cardiograph  was used to record the high-resolution electrocardiogram for continuous 16 minutes. The electrodes were positioned in the orthogonal bipolar derivations X, Y, and Z. A 40-Hz filter was applied. The results were analyzed in the DMI Burdick analyzer® . A positive result was defined as the presence of at least two of the following parameters: a) filtered QRS durations > 144ms; b) QRS terminal voltage <20 µV in the last 40 ms; and c) late potential total duration > 38 ms. In complete left branch bundle blockage, the reference values adopted for the QRS terminal voltage and the late potential duration were 17 µV and 55 ms, respectively.Statistical analysesX² test. A significance level of 0.05 was adopted to reject the null hypothesis.Data were analyzed descriptively using the Statistical Package for the Social Sciences version 20.0 . Continuous variables were presented with measures of central tendency and dispersion (mean and standard deviation), and categorical variables were described as absolute (n) and relative (%) frequencies. Fisher's test was used to identify any correlations between late potential, family sudden death, history syncope, and complex ventricular arrhythmias as the distributions did not meet the criteria for the Ethical standardsThe study was approved by the Institutional Ethics Committee and conformed to the Resolution 466/12 of the Brazilian National Health Council, which deals with the guidelines and standards for research involving humans. The investigation was also conducted in accordance with the Declaration of Helsinki. Informed consent was not necessary as the data were collected from medical records, and there was no direct contact between researchers and subjects.In this study, we analyzed 22 patients with HMC. Their ages ranged from 7 to 54 years (mean: 25.6 ± 14.7 years), and 55% (n = 12) were women. Clinical characteristics of the sample, including symptoms and imaging exam results, are available in Table Most patients were asymptomatic . Dyspnea and precordial pain were the most frequent symptoms. A familial history of HCM was reported in 64% (n = 17) of subjects. About 59% (n = 13) of the individuals were in use of medications: β-blockers ; calcium channel blocker ; and amiodarone . Only one patient was in use of more than one medication. The other nine either used no medication or used medications that do not interfere with the presence of late potentials.Regarding the ventricular hypertrophy predominance on echocardiography, 73% n = 16) of the individuals presented septal asymmetrical hypertrophy, 9% (n = 2) presented concentric hypertrophy, 14% (n = 3) presented medium-ventricular hypertrophy, and 5% (n = 1) presented septal asymmetrical hypertrophy associated to right ventricular hypertrophy. Regarding the hemodynamic status, the non-obstructive hypertrophy was the most prevalent type . Figure 6 of the p = 1.00). Syncope and late potentials were associated with two patients, with no significant statistical correlation between them (p = 0.54).Familial sudden death was found in 55% (n = 12) of patients, and 23% (n = 5) of them reported a history of syncope. A total of 23% (n = 5) of the sample had the presence of late potentials in the electrocardiogram. Only in three subjects, both familial sudden death and late potential were present. However, no significant correlation between these variables was found (p = 1.00).Complex ventricular arrhythmias were found in three patients (14%). The concordance between late potentials and complex ventricular arrhythmia was found in only one patient, with no statistical association . A recent study conducted by Tobita ividuals -14.Regarding the pattern of hypertrophy, asymmetric septal hypertrophy was the most common in our sample, corresponding to 73%, which is compatible with previous studies . HoweverIn our sample, late potentials in electrocardiograms were identified in 23% of subjects. Its role in the physiopathology of HCM is still controversial. Nevertheless, some evidence suggests it might be a useful marker for sudden death as it is correlated to an increased risk of fatal arrhythmias . CurrentThe implantable cardioverter-defibrillator (ICD) is the most effective therapy in preventing sudden cardiac death. However, in HCM patients, the indications for the implant remain unclear. Primary and secondary sudden death prevention in HCM patients is supported by the European Society of Cardiology Guidelines, especially in patients with a familial history of HCM, unexplained syncope, severe left ventricular hypertrophy, non-sustained tachycardia and history of aborted sudden death -19. MaroAdvances in biomolecular allow the genetic diagnostic of HCM; however, this laboratory approach is not globally available in clinical practice. New studies are needed to determine specific mutations for high-risk individuals. This way, early pharmacological and clinical intervention might reduce the disease progression and the mortality in this population. Nevertheless, in our reality, risk stratification for HCM is expected to be as practical, and low cost as possible, so pharmacological management or ICD implants might be attempted as preventive measures.The most obvious challenge to conducting rigorous research with rare diseases such as HCM is the small number of eligible participants for a given study, which possibly might be a limitation from our analysis.According to this study, the presence of late potentials was not associated with familial sudden death, syncope, and complex ventricular arrhythmias. Familial history of sudden death was present in most of the subjects, which is compatible with the literature description, but complex ventricular arrhythmias and syncope were only observed in a minority of them. On echocardiography, the asymmetric septal hypertrophy was the most common variable, and the non-obstructive form was the hemodynamic pattern most seen.


Some patients with congestive heart failure have greater improvement of cardiac remodelling after cardiac resynchronisation therapy (CRT) and they are identified as super-responders (SRs). It remains unclear if echocardiographic markers of dyssynchrony could accuratelly predict super-response to CRT. The aim of this study is to evaluate potential echocardiographic predictors associated with super-response to CRT.n = 20) and non-SRs  and baseline data were analyzed to identify the predictors.Fifthy nine CRT patients  with congestive heart failure (54% ischaemic and 46% non-ischaemic aetiology) II-IV NYHA functional class were enrolled. To assess mechanical dyssynchrony we evaluated interventricular mechanical delay, the maximum delay between peak systolic velocities of the septal and posterior walls of left ventricle, duration of left ventricular pre-ejection period (LVPEP), left ventricular and interventricular dyssynchrony by tissue Doppler imaging and systolic dyssynchrony index by 3D echocardiography. After six months the patients were assessed for response and classified as SRs (reduction in left ventricular end-systolic volume (LVESV) ≥30%, p = 0.011) was an independent predictor for CRT super-response. In ROC curve analysis LVPEP with a cut-off value of 147 ms demonstrated 73.7% sensitivity and 75% specificity  for the prediction of super-response to CRT.Both groups demonstrated significant improvement in NYHA functional class, increase in left ventricular ejection fraction and reduction in LVESV. All parameters of mechanical dyssynchrony at baseline were significantly higher in SR group. Multiple logistic regression analysis showed that LVPEP (HR 1.031; 95% CI 1.007–1.055; Greater mechanical dyssynchrony is associated with super-response to CRT in patients with congestive heart failure. It is probable that an LVPEP > 147 ms can be used as independent predictor of super-response. Cardiac resynchronisation therapy (CRT) is an effective treatment for patients with congestive heart failure with reduced ejection fraction (HF-rEF) and prolonged QRS duration. Several large multicentre clinical trials have confirmed that CRT can improve heart function, exercise capacity and quality of life. CRT reduces mortality and hospitalization and can also improve the prognosis in patients with HF-rEF . This beA decrease in the left ventricular end-systolic volume (LVESV) ≥15% is used as a standardized criterion of CRT response. However, some patients show greater improvement in cardiac function after CRT and are identified as super-responders (SRs) .The aim of the study was to evaluate potential echocardiographic predictors associated with super-response to CRT.This study enrolled 59 patients from a local database of implanted CRT devices  with HF-rEF (32 patients with ischaemic and 27 with non-ischaemic aetiology) [The main criteria for CRT implantation were: New York heart association (NYHA) functional class II-IV, reduced left ventricular ejection fraction (LVEF) < 35%, interventricular and/or intraventricular dyssynchrony assessed by echocardiography, with QRS width taken into account , 4. All n = 20); II) non–SR  [According to the change in LVESV assessed after six months, the patients were divided into two groups: I) SR  . ClinicaStandard echocardiography was performed using a commercially available system, i.e., Philips IE 33. Patients underwent baseline and six-month post-implantation echocardiography. The examination included 2D grayscale, colour and spectral blood pool Doppler and tissue Doppler imaging (TDI). Three cardiac cycles were obtained for each acquisition. 3D echocardiograpms were recorded as multibeat electrocardiography-gated data sets, which were obtained over one cardiac cycle. Using 3D echocardiography, we evaluated the left ventricular end-diastolic volume (LVEDV), LVESV, LVEF, stroke volume and systolic dyssynchrony index (SDI) , 7. All As for dyssynchrony parameters, three mechanical dyssynchrony indexes were quantified by 2D echocardiography: septal-to-posterior wall motion delay (SPWMD) (> 130 ms), interventricular mechanical delay (IVMD) as the delay in the onset of outflow between the left and right ventricle , and left ventricular preejection period (LVPEP) . Interventricular  and intraventricular  dyssynchrony were assessed by TDI based on the difference between time to onset of the systolic velocity spectrum, recorded from the lateral tricuspid and lateral mitral annulus, using four-chamber apical view (interventricular) and lateral and septal left ventricular annulus, using four-chamber apical view (intraventricular) asynchrony. Additionally, SDI ≥5.6% assessed by 3D echocardiography, was applied as a criterion of interventricular dyssynchrony .t test. The χ2 or Fisher’s exact test was used to compare categorical variables. Differences in continuous variables between the baseline and follow-up visits were compared using paired t-tests. Multiple logistic regression analysis was used to evaluate potential predictors related to super-response. ROC-analysis was used to assess the sensitivity and specificity of evaluated parameters in predicting CRT super-response. p < 0.05 was considered to be statistically significant.Statistical analyses were performed using SPSS for Windows version 21.0 . All values had normal distribution, with results expressed as mean value±standard deviation (mean ± SD), while mean changes in echocardiographic parameters were expressed as median and the interquartile range . Continuous variables were compared using Student’s At baseline, there were no differences in the demographic, clinical and functional characteristics between the groups Table . After sSix months after implantation, both groups demonstrated a significant decrease in NYHA functional class, increase in 6-min walking distance and improvement in echocardiographic parameters according to 3D echocardiography. The improvement in these parameters was significantly higher in SRs, as defined by reverse remodeling Table , includiAt baseline, the parameters of mechanical dyssynchrony were significantly more pronounced in SRs: the values of SDI, LVPEP, IVMD, and interventricular delay, as assessed by TDI, were significantly higher in this group Table . After sp = 0.011) was an independent predictor for CRT super-response. In ROC curve analysis, LVPEP with a cut-off value of 147 ms demonstrated 73.7% sensitivity and 75% specificity  for the prediction of super-response to CRT , some exhibited a normalization of LVEF fter CRT . Bulava fter CRT . In recefter CRT , 15.To date, there is no universally accepted criterion of super-response. Some authors defined SRs in terms of an improvement in LVESV although different cut-offs were selected , 17. In Prior clinical studies have reported the incidence of super-response to be in the range of 10–29% . In the n = 32) had ischaemic aetiology of HF, while 71.9% of them (n = 23) were SRs. In univariate and multivariate analysis non-ischaemic aetiology of HF was not associated with super-response to CRT.Different factors associated with super-response to CRT have been reported. Jin reported that biventricular pacing percentage greater than 98% was a good predictor of a super-response . Some dan = 39) was not homogeneous: 41% of patients (n = 16) were non-responders (a decrease in LVESV < 15%) and 59% of patients (n = 23) were responders (a decrease in LVESV 15–29%). Furthermore, the effect of CRT could be quite different between these subgroups, but this issue needs further investigation.In our study, SRs demonstrated more pronounced improvement in echocardiographic parameters and an increase in LVEF. At the same time, it is obvious that the group of non-SRs , a QRS width > 120 ms was one of the main criteria for CRT implantation. We enrolled patients with a QRS width > 120 ms or <120 ms + two parameters of mechanical dyssynchrony. It should be noted that, from 2005 until the latest update to the clinical recommendations in 2013, in our clinic, we used the St. Mary’s Hospital and Imperial College (London) protocol for CRT implantation, which included parameters of mechanical dyssynchrony assessed by TDI .New echocardiographic techniques, such as speckle tracking, visual criteria of dyssynchrony as apical rocking, septal flash and visual late lateral activation, were not evaluated.Due to our retrospective design, no intra- or interobserver reproducibility analysis of this study was performed regarding electrocardiographic and echocardiographic variables.Greater mechanical dyssynchrony is associated with super-response to CRT. It is probable that an LVPEP > 147 ms can be used as an independent predictor of super-response.


Ventricular hypertrophy is a common pathological finding at autopsy that can act as a substrate for arrhythmogenesis. Pathologists grapple with the significance of ventricular hypertrophy when assessing the sudden and unexpected deaths of young people and what it could mean for surviving family members. The pathological spectrum of left ventricular hypertrophy (LVH) is reviewed herein. This article is oriented to the practicing autopsy pathologist to help make sense of various patterns of increased heart muscle, particularly those that are not clearly cardiomyopathic, yet present in the setting of sudden cardiac death. The article also reviews factors influencing arrhythmogenesis as well as genetic mutations most commonly associated with ventricular hypertrophy, especially those associated with hypertrophic cardiomyopathy (HCM). Myocardial hypertrophy is a common finding at autopsy. It represents a pathological substrate that is associated with arrhythmogenesis and for the forensic pathologist may help explain why on individual may die suddenly and unexpectedly. Myocardial hypertrophy may not only underlay some sudden, natural deaths, but also deaths that occur by accidental means, such as following sudden loss of consciousness while operating a motorized vehicle or a large piece of machinery in the workplace or under circumstances where there is struggle and restraint by police at the time of apprehension. Forensic pathologists frequently face the circumstance where an individual is witnessed to die suddenly and unexpectedly or is found deceased, despite appearing entirely well a short time earlier. In the absence of a clear alternative cause for death following evaluation of all information available, including a complete autopsy with additional ancillary studies where appropriate, such as toxicology, biochemistry and microbiology, it is reasonable to consider that death (or the circumstances leading to death) may be best explained as the result of an acute arrhythmic event caused by some underlying cardiac substrate. This is where the careful consideration of any myocardial hypertrophy identified is warranted.Significant left ventricular hypertrophy (LVH) increases the risk of sudden cardiac death 6- to 8-fold in men and 3-fold in women. In patients with definite electrocardiographic (ECG) evidence of LVH there is a 59% overall mortality at 12 years. LVH is an independent risk factor for coronary artery disease and increases the risk of congestive heart failure 10-fold by 16 years [Inferring the cause of death from a chronic, stable pathological substrate such as myocardial hypertrophy may be causally challenging at the level of the individual case. It is recognized that sudden death from conditions associated with significant LVH is not rare. In addition, in many autopsies where myocardial hypertrophy is identified, the severity of the myocardial disease is more than sufficient to increase the risk of arrhythmogenesis, the history often coheres with a sudden cardiac death and the remaining postmortem examination (including ancillary studies) fails to identify an alternative cause for death. Arguably the severity of the myocardial disease identified was the same as it was the week or month prior to a given person’s death. Thus, functionally there was likely a new circumstance, such as physical exertion, physiological stress, emotional distress or a drug effect, as well as the establishment of a pro-arrhythmic pathway within the myocardium that may help explain why a given person died when they did. The challenge arises for the pathologist when one is dealing with an apparent sudden cardiac death and the only significant finding is a borderline degree of myocardial hypertrophy; in other words, was there sufficient pathological substrate to support arrhythmogenesis?Depending on the circumstances of the death and the age of the decedent, other causes of sudden cardiac death, such as a primary arrhythmia syndrome, may need to be considered, even though the heart is not “structurally normal” as is often the dogma that is taught when considering channelopathies as a potential cause for death. When trying to establish the most reasonable cause for death, much is dependent on the age of the individual, the medical history available and an understanding the scene and circumstances of the death. Furthermore, the pathologist must be cautious when inferring the functional severity of any myocardial disease that is identified at autopsy in the period prior to death. For example, while the macroscopic and microscopic features of the myocardium may speak to the severity of the pathological process that was present at the time of death, there is an imperfect overlap between the quality of cardiac performance (or degree of dysfunction) and the severity of the myocardial disease identified at autopsy. We certainly recognize instances where an individual presents with very severe myocardial disease pathologically and the decedent was clinically asymptomatic prior to death and may not have even known they had severe heart disease. The same may be said in some instances for the opposite circumstance, where there was a history of severe congestive heart failure and the myocardial pathology identified at autopsy was very modest. Furthermore, the nature of heart failure that may have been present, whether with preserved ejection fraction (HFpEF) from a typically hypertrophied and/or stiff myocardium or reduced ejection fraction (HFrEF)  cannot amildly increase in late middle aged and elderly individuals  as part of normal aging. It is interesting to note that the type of endurance exercise may impact the nature of the cardiac hypertrophy that is identified [not associated with increased interstitial fibrous tissue deposition, chronic degenerative changes or cell loss [The pathologist must also recognize common physiological causes of hypertrophy. These are generally mild in nature and can occur following chronic endurance exercise , within entified . In adulell loss . In adulell loss . All hypell loss . For theunexplained hypertrophy or hypertrophy that is more severe than expected for the circumstances (i.e. hypertrophy out of context) should raise suspicion of a possible primary cardiomyopathic process, which entails the pathologist bank a source of DNA and recommend that first-degree family members consider referral to a heritable heart disease clinic. The guideline produced by the National Association of Medical Examiners, amongst others are useful references when considering collection of tissue or blood for DNA banking and genetic testing when necessary [This is not necessarily an elementary exercise. For instance, the sudden and unexpected death of a woman 2 weeks after delivering a child should not be caused by physiological hypertrophy. Misinterpreting physiological hypertrophy as hypertensive heart disease for instance (particularly where there was no history of hypertension either before or during pregnancy) misses the likely cause of death, which may yet be cardiac (e.g. such as a primary arrhythmia syndrome) or non-cardiac in nature. Nevertheless, following the death of a young person, ecessary . In someIn regard to myocardial hypertrophy, unfortunately confusion sometimes arises with nomenclature. For instance, cardiomegaly and cardiac hypertrophy are not interchangeable concepts. Cardiomegaly is simply an enlarged heart. One could have a dilated cardiomyopathy with markedly enlarged chambers and a thin myocardial wall; the heart would exhibit cardiomegaly, but not myocardial hypertrophy. It is acknowledged that most hearts that exhibit cardiomegaly also exhibit myocardial hypertrophy and often some degree of ventricular remodeling, but it should be recognized that cardiomegaly is not an aetiologically specific diagnosis and it is simply a global descriptor of the heart. The more serious challenge with nomenclature arises between “hypertrophy” and “hypertrophic cardiomyopathy”. For some clinicians and pathologists who do not understand the difference, these concepts become interchanged, which leads to the impression that a heart with mere myocardial hypertrophy from whatever cause gets labelled as being due to HCM. HCM is an aetiologically specific diagnosis characterized by marked cardiomyocyte hypertrophy, geographic regions of myofibre disarray, myocardial scar and in most cases is likely associated with an underlying genetic anomaly. When a death is attributed to HCM, it entails a recommendation by the pathologist or coroner that first-degree family members be assessed in a heritable heart disease clinic because of the potential for heritability. This would not be appropriate if the decedent died of hypertensive heart disease, valvular disease or some other acquired cause for the cardiac hypertrophy and would lead to undue anxiety for the family and cost to the family or health care system to investigate surviving family members.There are three primary patterns of myocardial hypertrophy that are observed at autopsy: concentric, eccentric and asymmetric. Other non-specific patterns of hypertrophy are also observed by the pathologist that are often characterized by regional wall changes associated with conditions such as atherosclerotic heart disease where significant segments of myocardium undergo a “compensatory” hypertrophy in response to separate regions of myocardium that are poorly or no longer contractile due to scar tissue. The patchy myocardial hypertrophy and accompanying global change in chamber dimensions that inevitably follows represent myocardial remodeling following regional myocardial injury. Nevertheless, most cases of myocardial hypertrophy observed at autopsy that globally involve the left ventricular myocardium conform to the concentric, eccentric and asymmetric phenotypes.Concentric LVH, represented by an increase in the ratio of the wall thickness to the chamber dimension , may be Eccentric hypertrophy is a pattern of myocardial change where there is actually a decrease in the ratio of the wall thickness relative to the chamber size. This pattern of ventricular hypertrophy is not rare . The lefAsymmetric septal hypertrophy is commonly associated with the classical variant of HCM. Here the interventricular septum is markedly thickened relative to the free wall; although often the free wall can also exhibit significant hypertrophy. There may be significant variability in the regional wall thickness with HCM. Less common variants of HCM may be seen with regional wall thickenings involving the mid-septal wall, the apex, the anterior-lateral free wall and posterior-basal septum/free wall. Portions of the left ventricular wall may be of normal thickness and only show subtle histological changes. Thus, regions of myocardium exhibiting myofibre disarray are quite variable with a distribution that may be patchy or that may diffusely involve the myocardium, including the right ventricular myocardium. There is also a variable degree of myocardial scar, both interstitial and replacement-type scar, observed within the myocardium of both ventricular chambers, although there does seem to be a predilection for the basal muscular interventricular septum or regions of greatest hypertrophy. Anecdotally, we see a number of cases of HCM at autopsy, either incidentally or in association with a sudden cardiac death, with a concentric (symmetric) pattern of hypertrophy. In children, LVH resembling HCM may be observed as part of other systemic conditions, such as Noonan Syndrome, mitochondrial myopathies and metabolic disorders, which are unrelated to sarcomeric protein mutations . FinallyA few words of caution for the pathologist are warranted. It should be recognized that virtually all forms of myocardial disease undergo structural changes as part of their natural history. This includes hypertrophy and remodeling  of the respective chamber involved and often secondarily involves other cardiac chambers due to the volume and pressure changes that may result . Moreover, a given disease process may be associated with a concentric pattern of hypertrophy in the earlier course of its natural history, whereas more advanced forms of disease may evolve to a more eccentric pattern. Ultimately, the end stage of most if not all forms of chronic myocardial disease is a dilated cardiomyopathic phenotype. Thus, the stage in the natural history you happen to examine the heart may dictate what pattern of hypertrophy you observe. For pathologists, having access to echocardiography reports as part of the clinical history provides additional points in time when the heart can be evaluated structurally and may assist in understanding how the heart has changed over time. As such, it is important to not be dogmatic about what differential diagnostic considerations are possible for any particular pattern of hypertrophy observed, but rather recognize that the concentric and eccentric patterns are simple guides to help elucidate potential aetiologies of disease. Both patterns may be present at different times for a given disease process. As always, when interpreting the cause for a particular form of hypertrophy, it is important to contextualize this with other autopsy findings and clinical record.A second issue that occasionally arises at the time of autopsy is that a heart may have been examined by echocardiography in the recent past  and interpreted as “normal”, only to find that it exhibits significant enlargement and increased mass (often with an eccentric pattern of hypertrophy) at autopsy. Echocardiographic measurement of LVH and myocardial mass has a specificity and sensitivity of 80% . AlthougA more general issue that needs comment is that the closer we look at the myocardium in the era of increased diagnostic sensitivity to genetic cardiovascular disease, the more natural variability in the gross and histological appearance of the heart muscle that is appreciated by pathologists, and the more frequently we must evaluate pathological findings of unknown significance. Thus, when macroscopic or microscopic changes are identified outside of the range of expected normal variability, the significance of such changes can be a challenge to interpret at the time of autopsy. One may evaluate a heart displaying none or only modest macroscopic evidence of hypertrophy, yet microscopically there may be significant cardiomyocyte hypertrophy with atypical, sometimes bizarre cardiomyocyte nuclei exhibiting an excess of pleomorphism and hyperchromasia for what would be expected for the age of the decedent, the size of the heart and the clinical history available. There may also be idiopathic fibrous tissue deposition out of context for the history available. In some instances this may be associated with multiple foci of myofibre disarray or markedly atypical myocyte architectural arrangements. In the setting of a sudden cardiac death where no other historical, anatomical or toxicological findings explain the death, these changes indicate the presence of diseased myocardium and would very reasonably be concluded to increase the risk of ventricular arrhythmia and sudden cardiac death. However, what pathophysiological process precisely represents is less clear.In the Papadakis study looking at a series of apparent sudden cardiac deaths for which no clear pathological substrate was identified to explain the death, there was a significant number of cases that showed some degree of myocardial hypertrophy/idiopathic fibrous tissue deposition that was not easily explained and did not fit into the classical diagnostic entities we recognize pathologically . In addiWhile there are different macroscopic patterns of myocardial hypertrophy that are observed at autopsy, microscopically, with the exception of a few diagnostic entities the changes observed are generally non-specific with respect to aetiology. For instance, the histological appearance of the left ventricular myocardium from an 800 g heart in a 26-year-old with idiopathic dilated cardiomyopathy may be identical to an 800 g heart in a 60-year-old with chronic aortic insufficiency. Establishing the most likely underlying cause for the hypertrophy comes from integrating all pathological findings, circumstances and clinical history. The severity and distribution of disease may differ from one case to another, but it is often not possible to infer the underlying aetiology from the histology of the left ventricular myocardium alone. Integration of the information gained from the structure of the heart at the time of autopsy, the clinical history, the age of the decedent and any cardiological investigations performed in the past may be necessary to establish a reasonable diagnosis. Nevertheless, there are exceptions to this premise, for instance: infiltrative disease such as sarcoid, amyloid and hemochromatosis or storage disease processes such as Pompe disease or Fabry disease will be diagnostically characteristic (or strongly suggestive) at autopsy, which can be further investigated with supplementary ancillary studies. In addition, marked cardiomyocyte hypertrophy associated with geographic regions myofibre disarray, sometimes along with architectural disarray of muscle bundles, as well as potentially aberrant microvascular changes are supportive of an HCM.As indicated above, when the ventricular myocardium undergoes hypertrophy, histologically the cardiomyocytes become enlarged and acquire changes to their nuclei. When assessing nuclear changes it is useful to remember that an internal size control exists with myofibroblast or endothelial nuclei located within the interstitium. Normal cardiomyocyte nuclei are typically round to ovoid, non-hyperchromatic with smooth edges and perhaps 3–5 times the size of an endothelial cell nucleus. With cardiac hypertrophy nuclei enlarge significantly, become hyperchromatic and pleomorphic in their appearance and size, they take on variable shapes that include angulations . With conditions such as HCM the nuclei can become markedly enlarged, typically much larger than what is seen in most forms of LVH and sometimes quite atypical in their morphology.Associated with cardiomyocyte hypertrophy are a number of changes to the interstitium. When the myocardium remodels, it is not only the cardiomyocytes that changes, but the interstitium remodels as does the microvasculature that supplies the heart muscle. As disease progresses there is an increase in interstitial and perivascular fibrous tissue deposition. Often this fibrous tissue is diffuse and non-specific in its appearance. Alternatively, the fibrous tissue may have a predilection for a specific region of the myocardium, such as within a specific vascular territory or within the subepicardium, mid-myocardium or subendocardium. These patterns of fibrous tissue deposition can be very diagnostically useful when assessing hypertrophied myocardium and formulating a view to the differential diagnosis. Epicardial predominant fibrous tissue deposition within the left ventricular myocardium, particularly when associated with fibrofatty tissue infiltration, may be indicative of arrhythmogenic cardiomyopathy. Subendocardial predominant fibrous tissue can be seen under circumstances where there has been a prior ischaemic insult to the myocardium. This could be due to concomitant coronary artery disease, but marked ventricular wall thickening alone can also be associated with cardiomyocyte loss and replacement with fibrous tissue within the subendocardium. It is recognized that as the ventricular myocardium undergoes hypertrophy there is a relative rarefaction of the microvasculature, indicating that the density of the microvasculature does not keep up with the increase in muscle mass. Specifically, coronary microvasculature rarefaction associated with a reduced microvascular density and the resultant reduction in coronary flow reserve renders the myocardium susceptible to ischaemia, particularly under conditions of physiological stress , 19. ThuWith myocardial hypertrophy, not only is there remodeling of cardiomyocyte architecture, but cardiomyocyte metabolism, induction of gene programs to increase expression of foetal gene expression, increased mitochondrial dysfunction, altered sarcomeric structure, altered ion channel expression and impaired calcium handling are also identified . The remWhen assessing the myocardium histologically following the autopsy, the presence of increased interstitial or even replacement-type fibrous tissue deposition should be seen as a cumulative change that progresses as disease severity increases. Thus, the presence of significant fibrous tissue deposition with cardiomyocyte dropout and occasional cardiomyocytes exhibiting chronic degenerative changes should be seen as advanced disease. The presence of advanced fibrous tissue deposition (moderate to marked in severity) and myocardial degenerative changes may be useful pathological markers of advanced disease when assessing whether someone may be at increased risk of sudden and unexpected death. With advanced disease it may be difficult to pathologically separate advanced ventricular hypertrophy with remodeling from frank cardiomyopathy, particularly if the functionality of the heart (e.g. ejection fraction of the left ventricle) is unknown. Both may be associated with a reduction in the ejection fraction, although it is likely better to think of the myocardial phenotype as cardiomyopathic when there is significant reduction with cardiac performance. With respect to sudden cardiac death, although there is some evidence to suggest that the lower the ejection fraction (particularly if <35%), the greater the risk of sudden and unexpected death, this is an imperfect measure as a significant proportion of sudden cardiac deaths occur in patients with ejection fractions >40%, with significant differences noted between ischaemic and non-ischaemic pathologies .When does one actually have sufficient myocardial hypertrophy at autopsy to potentially cause death? There is not a straightforward answer to this question and opinions vary somewhat amongst pathologists depending on the circumstances. If we start from the position that we have what appears to be a sudden and unexpected death with no alternative cause for death identified and the only significant finding is the presence of myocardial hypertrophy, then there are a few factors that may assist in this deciding if there is sufficient hypertrophy to cause death. First, significantly increased cardiac mass is likely the best measure of severity of the degree of LVH present. One has to factor in any increase in mass contributed by a hypertrophied right ventricle as well (if present), but significant increases in mass will predominantly be left ventricular in origin. It is important to consistently remove any excess soft tissue and vascular tissues from the heart when establishing the mass, such as trimming off the superior and inferior caval veins, trimming the excess aorta and pulmonary trunk distal to the valves as well as removing any pericardium and attached mediastinal soft tissues. Although there will clearly be variability in the amount of epicardial adipose tissue present from person to person, it is not recommended that this tissue be removed systematically as each pathologist will differ in their completeness and this procedure is not generally performed when assembling data for reference tables (see below). Moreover, although there are recognized, older techniques requiring dissection of each of the left and right ventricular myocardium from the remainder of the heart and weighing these individually, this is time consuming, subject to the same variability in individual practice and is seldom of great utility. It is well recognized that the heart mass exhibits plasticity and adjusts in size to the individual in question, the sex of the individual and in response to any physiological or pathophysiological influence present. Thus, when evaluating the mass of the heart, these factors must be considered. The role of racial ancestry and what is considered normal in hearts is not entirely clear either. Classically it is thought that individuals of African or Afro-Caribbean ancestry may have larger hearts with modestly thicker ventricular walls compared to other groups. However, when considered across populations, some studies fail to identify statistically different values for heart mass at the time of autopsy . It is lThere are no perfect reference tables when considering heart masses in men and women . Each stMost forensic pathologists would consider heart weights >500 g  as being both significantly abnormal and likely to place the decedent at increased risk of sudden death. Another measure to consider when assessing if a heart is abnormal is total heart weight greater than 30% over the predicted norm . DifficuFinally, the presence of significant end-organ damage  detected histologically in the myocardium of borderline cases may assist in the determination of if the hypertrophy identified was potentially significant as these are histological markers for more advanced disease. Paediatric heart weights for infants and younger children appear to show somewhat greater predictability when compared against body weight, although the same problems likely arise with older children and adolescents with increased body mass index and other comorbidities that are seen with adults. Certainly for infants and younger children within normal body weight ranges and appropriate growth for age, the tables available in Scholz et al.  are helpdie of a cardiac disease process or die with a cardiac disease process? This too is not always an easy determination. It is dependent on the quality and completeness of the history available to the pathologist and what other competing causes for death are under consideration.When the myocardial hypertrophy was clearly sufficient to increase the risk of ventricular arrhythmia and sudden death, then determining if it did in fact cause death depends on an evaluation of all circumstantial factors, clinical history and autopsy findings. The question distils down to: did the person Sometimes the circumstances of the death are quite helpful in determining if a death was likely arrhythmic or not, for instance, if the death was witnessed to be sudden and unexpected in an individual who just appeared well prior to death, versus someone who is clearly sick and unwell in the hours or days prior to death. In other instances a potentially new intervening factor, such as a potentially lethal quantity of an intoxicant or an infection or a metabolic abnormality best explains death over a stable, chronic pathological substrate that does not exhibit evidence of a recent pathological change. Such evaluations are not always perfect and each individual pathologist must balance the evidence as best fits the death investigation.It is normal for there to be some variability in the thickness of the left and right ventricular myocardium at autopsy. The muscular interventricular septum is typically a little bit thicker than the left ventricular free wall, with a ratio of septum to free wall of 1.1. With left ventricular thickening caused by hypertensive heart disease, Fabry disease or amyloidosis, occasionally we see this ratio increases modestly. Caution is warranted not to over interpret the asymmetry of left ventricular thickening that can be observed under such conditions as representing HCM, as this has been noted to occur anecdotally by echocardiography, which was ultimately not confirmed at the time of autopsy. The right ventricular myocardium also exhibits some variability in the wall thickness between the anterior-lateral wall along the acute margin, the ventral wall, the posterior-basal wall and the right ventricular outflow tract. The latter two are typically somewhat thicker than the former. At autopsy, the right ventricular myocardial thickness is measured at the basal to mid ventricular level and should not exceed 0.3–0.5 cm and normally tapers as it approaches the apex. Measurements should always be of the compact myocardial layer and should not include the trabeculae carnae and care should be taken to avoid epicardial fat. The left ventricular myocardium is also measured at the basal to mid ventricular level  and is normally 1.2–1.5 cm in thickness . MeasureA few comments should be made about sampling the heart for histology. First, it is wise to avoid the junctions of the free wall with the muscular interventricular septum if possible  as in these regions there is normally a degree of myofibre disarray and sometimes fibrous tissue, particularly in the posterior septum. There can also be very focal myofibre disarray present in normal hearts where papillary muscles insert into the free wall as well as for large trabeculae carnae within the right ventricular myocardium. For those who are not aware of these naturally occurring sites of disarray, one may over interpret the histological appearance of the myocardium as evidence of HCM. Features to keep in mind that are helpful when encountering this issue are: (i) Cardiomyocytes in HCM are markedly enlarged, far more than what is typical for hypertensive heart disease or aortic stenosis; (ii) One wants to see geographic regions of myofibre disarray, typically across multiple sections of the heart to call it HCM. While the myofibre disarray associated with HCM need not involve all regions of the myocardium, it does not present as highly localized, minute disease of the myocardium. Finally, occasional small foci of chronic inflammation can be seen in the setting of HCM and should not be over interpreted as evidence of a lymphocytic myocarditis.Occasionally the severity of the LVH may suggest one type of cardiac pathology over another. For instance, a 40-year-old man with a 5-year history of hypertension dies suddenly and unexpectedly. At autopsy the heart has a mass of 850 g. While this man may certainly develop hypertensive heart disease given this clinical history, caution should be warranted given the relatively young age of the decedent, the limited time that he had clinical hypertension and the marked degree of hypertrophy present in an 850 g heart. Although there are certainly exceptions that are recognized, most hearts with masses >800–850 g are due to conditions such as longstanding atherosclerotic heart disease, valvular disease with elements of volume overload, obesity associated heart disease with longstanding morbid obesity, adult congenital heart disease or cardiomyopathies. In a 40-year-old man with only a 5-year history of hypertension, in the absence of other findings it may be reasonable to consider that this pathological process may better represent evidence of a primary cardiomyopathy instead of hypertensive heart disease.In some instances, pathologists may not recognize that the cardiac hypertrophy present (±remodeling) may help to explain death in the setting other cardiac pathologies. Examples include: (i) congenitally bicuspid aortic valve with severe stenosis and LVH, the risk of sudden death is tied to the degree of LVH and not merely the presence of a bicuspid valvular architecture; (ii) sudden death in the setting of mitral valve prolapse where often there is significant hypertrophy of the anterior-lateral and posterior-medial papillary muscles as well as hypertrophy and increased fibrous tissue deposition within the free wall  of the left ventricular myocardium; (iii) congenital heart disease with significant hypertrophy and remodeling due to chronic pressure and volume overload physiology. While most children do quite well following surgery for congenital heart disease and survive to adulthood, the presence of significant hypertrophy and remodeling that develops as a result of the congenital heart disease or its treatment can increase the risk of sudden arrhythmic death, particularly in the adult population , 35; andThe following scenario illustrates a pitfall that pathologists can fall to at the time of autopsy: a 38-year-old healthy man died suddenly and unexpectedly from what appeared to be a sudden cardiac death. The postmortem examination revealed a heart with a mass of 850 g with an eccentric pattern of hypertrophy. A fusiform ascending aortic aneurysm was also noted within the ascending aorta, although this did not appear to be ruptured, nor was there evidence of an acute aortic dissection. Because of the markedly enlarged heart with severe hypertrophy, the cause of death was provided as hypertensive heart disease.Unfortunately such cases are not rare in a busy autopsy service. While the pathological substrate likely responsible for triggering the sudden death was interpreted correctly, namely the marked myocardial hypertrophy, the underlying cause for this hypertrophy was not. In this particular instance, identifying the correct underlying cause for the myocardial hypertrophy is very important as it may impact surviving family members. Ascending aortic aneurysms often involve the aortic root. If the aortic root was significantly ectatic as a result, then there may have been chronic aortic insufficiency. In this instance, given the ascending aortic aneurysm (most often fusiform in structure), the size of the heart, the age of the decedent and eccentric pattern of hypertrophy present, chronic aortic insufficiency was the most likely principal cause for the LVH identified (particularly in someone with no reported history of hypertension). It must be stressed that mild aortic insufficiency or mild pathological changes to the aortic root are unlikely to lead to enough volume overload to cause marked LVH; thus, the degree of hypertrophy must correlate with the severity of the ascending aortic and aortic root disease. The reason recognizing this pattern of disease is so important is because this man was an otherwise healthy person who had an unexplained ascending aortic aneurysm. When examined histologically, the wall of these aneurysms often exhibit moderate to marked medial degenerative changes, which in a younger individual can indicate the presence of an underlying aortopathy. Such connective tissue disorders often have an underlying genetic anomaly, which can be heritable . Thus, wIdiopathic (left) ventricular hypertrophy is a pathological category of heart disease in need of better characterization. It is unclear if these enlarged and hypertrophied hearts, typically found in young people, represent a single clinical entity, a phenotypic variant of HCM  or a common phenotype for a number of pathophysiological processes not yet characterized. This pathological entity is identified in a number of studies in association with the sudden and unexpected deaths of young people, and has been studied in athletes , 39, 40,In some instances, the sudden death of an individual may be associated with a myocardium that exhibits evidence of significant cardiomyocyte hypertrophy histologically, along with degenerative changes, interstitial fibrous tissue deposition and even occasionally small foci of myofibre disarray/architectural disarray of muscle bundles, yet the heart may be in the normal size range or only modestly enlarged. With only occasional, small foci of myofibre disarray it would not be appropriate to diagnose this entity as an HCM. Importantly, the heart does not exhibit the typical phenotypic patterns of hypertrophic, dilated, restrictive or arrhythmogenic cardiomyopathy, yet based on the histological appearance is clearly cardiomyopathic in nature. This reinforces the need for cardiac histology on all cases of unexpected death and that one cannot use the structural phenotype of the heart to screen out the presence of a cardiomyopathic process.An interesting study by Tseng et al.  examinedFinally, when one encounters a heart that exhibits cardiomyopathic findings that are atypical or unexplained at the time of autopsy, a systemic myopathy also needs to be considered. Skeletal muscle should be sampled for histology.Obesity associated heart disease is a common finding at autopsy; however, it may be under recognized by pathologists as a potential explanation for sudden cardiac death. In obese individuals, particularly those who are morbidly obese, the heart can undergo a number of structural changes due to a state of chronically high cardiac output, which includes LVH  and ventricular remodeling. There is a positive correlation between the severity of obesity and measures of left ventricular mass. Hypertension, which is present in 50%–60% of obese individuals, is also a likely contributing comorbid factor for some , 45. Neuin vitro observations, which have stimulated active investigation of in vivo arrhythmogenesis. Myofibroblast-cardiomyocyte coupling seen in cell culture results in myocyte depolarization, after-depolarization, and ectopic arrhythmia generation [In HCM, patchy, multifocal replacement fibrosis can be detected in regions of hypertrophy . Myocardneration , 61 a phneration , 63, TGFneration .+ loss, extracellular acidosis and membrane depolarization [There are several mechanisms underlying myocardial ischaemia in HCM, including reduced coronary flow reserve, blunted myocardial blood flow and microvascular ischaemia . Coronarrization , and by rization , 71. Therization , but micrization . In thisrization .2+) hypersensitivity at the molecular level is well documented in HCM, and pathogenic variants in the genes encoding myofilament proteins have been shown to increase their Ca2+ sensitivity, but the specific mechanisms associated with these protein alterations are not yet clear [2+/calmodulin-dependent protein kinase II (CaMKII)-dependent phosphorylation of phospholamban (PLN) [2+/Mg2+ protein binding sites [2+ myofilament binding results in increased end-diastolic free Ca2+, potentiating the release of calcium from the sarcoplasmic reticulum after brief pauses, resulting in after-depolarizations and triggered activity [2+ hypersensitivity and ventricular arrhythmias [2+ sensitization caused by the troponin T mutation, and this could be reversed by myofilament desensitization. Ca2+ sensitization in this model resulted in variability of action potential duration, shorted ERPs, and increased heterogeneity in conduction velocity at elevated heart rates [2+ from the sarcoplasmic reticulum, resulting in triggered arrhythmia events [Calcium  , and altng sites . Enhanceactivity . The rolactivity . Animal hythmias . In one rt rates . Anothera events . Vulneraa events  as demona events .MYBPC3), β-myosin heavy chain (MYH7) and troponin T (TNNT2), all of which are associated with classic, autosomal dominant inheritance [GLA) and Danon disease (LAMP2) among others, can be associated with multi-systemic medical issues resulting in risks for additional, extra-cardiac conditions and different management recommendations for at-risk relatives [HCM is recognized to be the most common hereditary heart disease and is the most common cause of sudden death in the young . Numeroueritance , 95. Howelatives . Some ofelatives , 94, 96.elatives , 97. Clielatives , 98, 99.elatives  recently


Over the last decades, thyroid hormone metabolites (THMs) received marked attention as it has been demonstrated that they are bioactive compounds. Their concentrations were determined by immunoassay or mass-spectrometry methods. Among those metabolites, 3,5-diiodothyronine , occurs at low nanomolar concentrations in human serum, but might reach tissue concentrations similar to those of T4 and T3, at least based on data from rodent models. However, the immunoassay-based measurements in human sera revealed remarkable variations depending on antibodies used in the assays and thus need to be interpreted with caution. In clinical experimental approaches in euthyroid volunteers and hypothyroid patients using the immunoassay as the analytical tool no evidence of formation of 3,5-T2 from its putative precursors T4 or T3 was found, nor was any support found for the assumption that 3,5-T2 might represent a direct precursor for serum 3-T1-AM generated by combined deiodination and decarboxylation from 3,5-T2, as previously documented for mouse intestinal mucosa. We hypothesized that lowered endogenous production of 3,5-T2 in patients requiring T4 replacement therapy after thyroidectomy or for treatment of autoimmune thyroid disease, compared to production of 3,5-T2 in individuals with intact thyroid glands might contribute to the discontent seen in a subset of patients with this therapeutic regimen. So far, our observations do not support this assumption. However, the unexpected association between high serum 3,5-T2 and elevated urinary concentrations of metabolites related to coffee consumption requires further studies for an explanation. Elevated 3,5-T2 serum concentrations were found in several situations including impaired renal function, chronic dialysis, sepsis, non-survival in the ICU as well as post-operative atrial fibrillation (POAF) in studies using a monoclonal antibody-based chemoluminescence immunoassay. Pilot analysis of human sera using LC-linear-ion-trap-mass-spectrometry yielded 3,5-T2 concentrations below the limit of quantification in the majority of cases, thus the divergent results of both methods need to be reconciliated by further studies. Although positive anti-steatotic effects have been observed in rodent models, use of 3,5-T2 as a muscle anabolic, slimming or fitness drug, easily obtained without medical prescription, must be advised against, considering its potency in suppressing the HPT axis and causing adverse cardiac side effects. 3,5-T2 escapes regular detection by commercially available clinical routine assays used for thyroid function tests, which may be seriously disrupted in individuals self-administering 3,5-T2 obtained over-the counter or from other sources. Over them cells , 8. The em cells  antagoniem cells  as well em cells . As rT3 em cells . The iniem cells , 13 coultrations . These oThe TH metabolite 3,5-T2, possibly formed from its precursor T3 , has recTherefore, we intended to test several hypotheses using clinical experimental data, animal experiments, and cell culture approaches as well as recently developed novel analytical tools such as the sensitive chemoluminescence immunoassay (CLIA), highly specific for 3,5-T2 detection in human serum . We aime3,5-T2 is formed from T4 and T3 as its precursors via deiodinase reaction,3,5-T2 circulates in human serum, and that various pathophysiological as well as experimental conditions lead to alterations in 3,5-T2 serum concentrations.Furthermore, that effects of administration of physiological and pharmacological doses of 3,5-T2 in mouse models will provide information on its potential thyromimetic activity as well as for its potentially beneficial antisteatotic action.in vitro cellular models might convey an insight into postulated mechanism(s) of action of 3,5-T2 at the level of gene expression and/or mitochondrial energy metabolism.Moreover, analyses using various 3,5-T2 causes adverse effects if abused and/or overdosed.Janus-type endogenous thyroid hormone metabolite (THM) with beneficial and adverse biological effects. Analytical tools available, cannot yet dispel previously reported controversies regarding its baseline concentrations in human serum and the variations in concentration caused by pathophysiological states.This series of clinical, translational and basic science studies testing these options resulted in a complex picture of various actions of 3,5-T2. The outcome was variable depending on concentrations applied, experimental models used, and analytical tools applied so far. 3,5-T2 turned out to be an ambiguous, Currently, the thyroid community and patients discuss why a fraction of patients on established L-T4 replacement therapy, due to thyroidectomy or autoimmune thyroid disease, are subjectively discontent with this therapeutic regimen compared to individuals with intact thyroid, albeit their thyroid function test are in the reference range. We hypothesize that endogenous production of 3,5-T2 in some patients dependent on oral L-T4 might be less than that in individuals whose intact thyroid is the source of T4, and thus an inadequate 3,5-T2 concentration might contribute to this discontent based on its distinct thyromimetic activity compared to T3.in vitro systems . In addview see , these aview see , 89, 90.view see , who obso et al.  who showo et al. . Severalo et al. , 93 whilControversial with respect to this set of observations, several other teams reported that administration of 3,5-T2 in rodent models  dose-dependently resulted in significant suppression of the HPT axis as reflected by decreased TSH serum concentrations and/or pituitary beta-TSH transcript levels , 94, 95.The adverse effects observed in rodent hearts have not been studied in more detail, and 3,5-T2 concentrations in cardiac rodent tissue were found to be below detection limits  in a stuAll datasets generated for this study are included in the article/The Medical Ethics Committee of the relevant institutions approved each of the study protocols. The methods were performed in accordance with the approved guidelines. All included participants provided written informed consent in accordance with the Declaration of Helsinki. For the studies conducted at Georgetown University, the institutional review board approved the studies. The dialysis study was approved by the Institutional Review Boards of Hospital Divino Espírito Santo, Ponta Delgada, Açores-Portugal. The SHIP-TREND study was approved by the local ethics committee of the University of Greifswald and conformed to the principles of the declaration of Helsinki.The manuscript has been drafted and written by JK. IL has performed the 3,5-T2 serum concentration measurements. KRe, ER, and KRi implemented the immune extraction studies with the 3,5-T2 monoclonal antibody. MP contributed the data and evaluation of the metabolome analysis. JA performed the dialysis study. MD and JJ planned, conducted, and evaluated the two clinical Jonklaas studies , 54. AllThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Moreover,cardiovascular mortality is already considered the second most common cause of death,second only to cancer.3-5The first description of chemotherapy-induced heart failure (Stage C) was published in1967.6 The major concern isthat systolic dysfunction can lead to a therapeutic dose adjustment, less effectivealternative therapy regimens, or, in the worst-case scenario, to chemotherapydiscontinuation.The classically accepted definition for cardiotoxicity during treatment was proposed in2014, which described it as an absolute decrease in left ventricular (LV) ejectionfraction of 10 percentage points to values below 53%, with its re-evaluation beingrecommended after 2 to 3 weeks. Additionally, the subclinical lesion is based on therelative decrease in global LV longitudinal strain by 15% in relation to thebaseline.7That requires a conceptual amplification of the rationale in the cardiac monitoring ofthe oncological patient, which was previously restricted to an arbitrary ejectionfraction value, without respecting the individualization of the patient’s hemodynamicparameters, gender and age, which all influence ejection fraction calculation.In 2016, the European Society of Cardiology reviewed the definition ofchemotherapy-induced cardiotoxicity and extended it to include any structural orfunctional alteration in the heart and circulation, whether during cancer treatment,post-treatment or late post-treatment.8 the mid-basalportion of the inferolateral wall (two segments) and the mid-basal portion of theanteroseptal wall (two segments) are not analyzed, and this technical limitation isovercome by the three-dimensional echocardiogram.9 Considering this problem and a pragmatic observation of thosewho follow this patient population, the relevance of the isolated LV segmentalalterations as chemotherapy-induced toxicity and its prognostic impact has beenconsidered.It is important to note that the ejection fraction calculated by Simpson'stwo-dimensional method does not evaluate alterations in LV segmental contractilitycorresponding to 25% of its segments, considering the segmentation of 16segments:10A case-control study published in 2017 showed that the segmental motility alteration inthe interventricular septum was associated with a reduction in left ventricularperformance, despite the presence of a preserved ejection fraction.11 It is noteworthy that a high cardiotoxicity rate(16.1%) was observed in a population of which 35% were hypertensive; 22% were smokers;19% were dyslipidemic and 7% were diabetics. There is no description in the presentstudy of the doxorubicin and trastuzumab doses used in the treatment, the intervalbetween examinations was variable between the groups, and whether the appearance ofsegmental motility alterations could be related to obstructive coronary disease, sinceseveral patients had risk factors.The study published in this issue evaluated a prospective cohort of breast cancerpatients and showed the incremental value of altered LV segmental motility in predictingcardiotoxicity induced by anthracyclines and/or trastuzumab.12 described acohort of 347,476 breast cancer patients exposed to chemotherapy or radiotherapy duringa follow-up of more than 10 years and who showed no increase in cardiac mortality whencompared to the general population.12Weberpals et al. in 201813 and, in some institutions, it is indicated to initiatecardioprotection drugs even in the presence of a preserved ejection fraction. It isinteresting to note that the segmental motility alterations described in 14% of thepatients in the aforementioned article  are the same regions that physiologically show coronary flowreduction.14Another relevant piece of information not described in the text was whether there was adecrease of more than 15% of the LV global longitudinal strain (GLS) in patients whoshowed segmental contractility alterations. It is already well established that LV GLSis capable of predicting the reduction in LV ejection fractionTrypanosoma cruzi, for instance) would show a slower clearing inthese regions, increasing the time of cardiomyocyte deleterious exposure.The proposed concept as one of the pathophysiological possibilities for the preferentialsegmental involvement described in Chagas' disease is that the terminal circulation -between the anterior descending coronary artery and the posterior descending artery (LVapex) and the terminal circulation between the right coronary artery and the leftcircumflex artery  - contributes to the Chagasic lesionin these regions. Thus, it is likely that the aggressive agent . Of the 14 patients with altered segmental contractility,50% of cases consisted of atypical septal movement. Nevertheless, changes in septalmovement constitute a nonspecific finding, as there is an extensive range of etiologiesthat alter septal motility, such as conditions that cause LV volume or pressureincrease; primary involvement of the cardiomyocyte (cardiomyopathies); electricconduction changes; post-surgical status; pericardial disease; congenitalcardiomyopathies; post-systolic shortening and interventricular mass16,17An alternative that would help to understand the findings would be to expose theevolution of the LV GLS fall between the different groups and to analyze if there wasany similarity between the findings of segmental alterations and the parametricarrangement of LV GLS. Although the importance of myocardial deformation segmentalalterations is still debatable, there are studies that have shown the incremental roleof this type of analysis.The present cohort described in the article mentioned in this editorial does not clarifyhow the groups were divided, making it difficult to understand how the statisticalcalculation was carried out. It would be interesting to have a univariate and amultivariate analysis of the factors that contributed to the ejection fraction decrease. Moreover, a more detailedanalysis of ventricular volumes and diastolic function would allow a betterunderstanding of ventricular remodeling. Similarly, another limitation would be theinclusion of post-systolic shortening at the maximum strain peak, without consideringthe cardiac cycle phase.Regardless of the exposed limitations, the article shows the relevance of a limiteddiscussed finding, the alterations in LV segmental motility during chemotherapytreatment, which may be secondary to the disease, the treatment, or the decompensationof an underlying disease.