Specific Therapy for Transthyretin Cardiac Amyloidosis: A Systematic Literature Review and Evidence-Based Recommendations.

Background The emergence of specific therapies for transthyretin cardiac amyloidosis (CA) warrants the need for a systematic review of the literature. Methods and Results A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was performed on MEDLINE, PubMed, and Embase databases on November 29, 2019. Studies were selected based on the following predefined eligibility criteria: English-language randomized controlled trials (RCTs), non-RCTs, or observational studies, which included adult patients with variant/wild-type transthyretin-CA, assessed specific therapies for transthyretin-CA, and reported cardiovascular outcomes. Relevant data were extracted to a predefined template. Quality assessment was based on National Institute for Health and Care Excellence recommendations (RCTs) or a checklist by Downs and Black (non-RCTs). From 1203 records, 24 publications were selected, describing 4 RCTs (6 publications) and 16 non-RCTs (18 publications). Tafamidis was shown to significantly improve all-cause mortality and cardiovascular hospitalizations and reduce worsening in 6-minute walk test, Kansas City Cardiomyopathy Questionnaire-Overall Summary score, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in variant/wild-type transthyretin-CA. Patisiran showed promising results in a subgroup analysis of patients with variant transthyretin-CA, which have to be confirmed in RCTs. Inotersen showed conflicting results on cardiac imaging parameters. The one study on AG10 had only a 1-month duration and cardiovascular end points were exploratory and limited to cardiac biomarkers. Limited evidence from noncomparative single-arm small non-RCTs existed for diflunisal, epigallocatechin-3-gallate (green tea extract), and doxycycline+tauroursodeoxycholic acid/ursodeoxycholic acid. Conclusions This systematic review of the literature supports the use of tafamidis in wild-type and variant transthyretin-CA. Novel therapeutic targets including transthyretin gene silencers are currently under investigation.

Double coronary thrombosis in a patient with Behçet's disease.

Behçet's disease is a chronic relapsing multisystem autoinflammatory condition, in which cardiac involvement is rare, but among the most life-threatening complications. Treatment is largely empirical, and is aimed at suppressing vasculitis. In this role glucocorticoids and colchicine are frequently used. We present the case of a 42-year-old male with previously diagnosed Behçet's disease presenting to our emergency department with an anterior-inferior STEMI. He presented combined thrombosis of the distal anterior descending coronary artery and proximal right coronary artery, and was treated with sequential primary percutaneous coronary interventions and implantation of drug-eluting stents, but required two interventions due to high thrombotic load. His clinical course during hospitalization was good, with no systolic dysfunction at discharge. During follow-up, he has so far had no new cardiovascular events.

Arrhythmogenic right ventricular cardiomyopathy: contribution of different electrocardiographic techniques.

Arrhythmogenic right ventricular cardiomyopathy, also known as arrhythmogenic right ventricular dysplasia, is a condition in which myocardium is replaced by fibrous or fibrofatty tissue, predominantly in the right ventricle. It is clinically characterized by potentially lethal ventricular arrhythmias, and is a leading cause of sudden cardiac death. Its prevalence is not known exactly but is estimated at approximately 1:5000 in the adult population. Diagnosis can be on the basis of structural and functional alterations of the right ventricle, electrocardiographic abnormalities (including depolarization and repolarization alterations and ventricular arrhythmias) and family history. Diagnostic criteria facilitate the recognition and interpretation of non-specific clinical features of this disease. The authors present a case in which the diagnosis of arrhythmogenic right ventricular cardiomyopathy was prompted by the suspicion of right ventricular disease on transthoracic echocardiography. This was confirmed by detection of epsilon waves on analysis of the ECG, which generally go unnoticed but in this case were the key to the diagnosis. Their presence was also shown by non-conventional ECG techniques such as modified Fontaine ECG. The course of the disease culminated in the occurrence of ventricular tachycardia, which prompted placement of an implantable cardioverter-defibrillator.

Hypertrophic cardiomyopathy associated with left ventricular noncompaction cardiomyopathy and coronary fistulae: a case report. One genotype, three phenotypes?

The authors present a rare case of hypertrophic cardiomyopathy associated with left ventricular noncompaction cardiomyopathy and coronary artery-left ventricular fistulae in a 42-year-old woman presenting with non-ST-elevation myocardial infarction. Coronary angiography, transthoracic echocardiography and cardiac magnetic resonance revealed the structural abnormalities of the left ventricle and the coronary tree.

[Purulent pericarditis: a rare diagnosis]. / Pericardite purulenta: um diagnóstico raro.

The authors present two cases of purulent pericarditis secondary to pneumococcus pneumonia, a rare entity in the antibiotic era, one of them in an apparently healthy person. A systematized diagnostic approach to moderate pericardial effusion is presented, together with a review of purulent pericarditis. The presence of pericardial effusion with persistent fever with or without known etiology, particularly in the immunocompromised but also in the apparently healthy patient, should always raise the possibility of purulent pericarditis.

Left bundle branch block, atrioventricular block, torsade de pointes and long QT syndrome: is this too much for a rare cardiomyopathy?

Left ventricular noncompaction (LVNC) is now recognized as a distinct form of cardiomyopathy with a clinical presentation and natural history of its own. Common manifestations of LVNC include heart failure, ventricular arrhythmias and embolic events, but serious atrioventricular conduction disturbances are rarely reported in the literature. The authors describe the case of a 40-year-old woman who went to the emergency department due to syncope. The ECG revealed left bundle branch block (LBBB) and 2:1 atrioventricular block (AVB) and the patient was admitted for pacemaker implantation. During hospitalization she developed torsade de pointes and complete AVB with increased QTc. The echocardiogram showed images compatible with LVNC. This case provides additional evidence that LVNC may be complicated by 2:1 (or complete) AVB, intraventricular conduction disturbances (LBBB) and repolarization abnormalities (long QT). This combination of electrocardiographic changes has rarely been reported in the literature. We describe a series of affected patients, focusing on electrocardiographic characteristics.

[Clot burden score in the evaluation of right ventricular dysfunction in acute pulmonary embolism: quantifying the cause and clarifying the consequences]. / O valor da carga embólica na avaliação de disfunção ventricular direita no tromboembolismo pulmonar agudo: quantificando a causa e clarificando as consequências.

INTRODUCTION: Pulmonary angiography by computed tomography (CT) is the method of choice for the detection of acute pulmonary embolism (PE). Studies have shown that the severity of PE can be estimated by clot burden scores. OBJECTIVE: To evaluate the correlation between an angiographic clot burden score (Qanadli score - QS) and parameters of right ventricular dysfunction (RVD) in patients admitted for PE. METHODS: We performed a retrospective study of 107 patients (60% female) admitted to an intensive care unit for PE (intermediate/high risk) between January 1, 2007 and September 30, 2011. Images from 16-slice multidetector CT angiography were reviewed in 102 patients and the QS calculated. Based on a cut-off of 18 points established by ROC curve analysis, two groups were formed (A<18 points vs. B ≥18 points) and the clinical, laboratory, ECG, echocardiographic and CT angiography parameters were compared. The statistical analysis was performed using SPSS. RESULTS: The overall mean age was 61.4 years. With regard to symptoms at admission, there was a greater prevalence in group B of fatigue, chest pain and syncope (p=0.017), with higher Geneva and Wells scores and shock index. In terms of ECG parameters, heart rate and percentage of right bundle branch block, T-wave inversion (V(1)-V(3)) and S(1)Q(3)T(3) pattern (p=0.034) were higher in group B, as was the ECG score (p=0.009). Laboratory tests revealed that group B had higher troponin and d-dimers, with lower creatinine clearance by the MDRD formula (p=0.020) and PO(2)/FiO(2) ratio. Echocardiography showed higher pulmonary artery systolic pressure in group B, and CT angiography revealed larger right ventricular (RV) diameters and higher RV/LV ratio (p=0.002), and greater superior vena cava, azygos vein and coronary sinus diameters in this group. Pulmonary artery (PA) diameter and the PA/aorta ratio were similar. Interventricular septal bowing and reflux of contrast into the inferior vena cava (p=0.001) were greater in group B, and QS>18 was an independent predictor of RVD (RV/LV ratio>1) (OR: 10.85; p<0.001) (area under the curve on ROC analysis: 0.79; p<0.001). The percentage of patients receiving fibrinolytic treatment was higher in group B (p=0.045), and in-hospital mortality was similar in both groups (overall 4.9%). CONCLUSIONS: QS >18 points proved to be an independent predictor of RVD in PE, and correlated linearly with variables associated with higher morbidity and mortality.

Isolated pulmonary valve endocarditis in a normal heart.

Isolated pulmonary valve endocarditis is a very rare entity, usually associated with intravenous drug abuse. We describe a case of isolated pulmonary valve endocarditis in a diabetic patient with no apparent precipitating factors besides a lesion on the right hallux. The clinical course was favorable and he was discharged home after a six-week course of antibiotic therapy.

[Diagnostic criteria for the Brugada syndrome: can they be improved?]. / Critérios de diagnóstico da síndrome de Brugada. Podemos melhorar?

INTRODUCTION: Diagnosis of Brugada syndrome (BS) currently requires documentation of a characteristic repolarization pattern (type 1 Brugada ECG). Mutations in the SCN5A gene, which codes for sodium channel Na(v) 1.5, are found in 38% of familial cases of BS. Sodium current dysfunction negatively affects the cardiac fast response action potential, particularly in atrial and ventricular myocytes and in the fast-conducting Purkinje system. OBJECTIVES: To detect carriers of SCN5A mutations without using the characteristic repolarization pattern (type 1 Brugada ECG). METHODS: Of a total of 141 members of three different families including 55 carriers of two nonsense SCN5A mutations causing BS, all those aged over 16 (113 individuals, 42 carriers) were studied. The PR interval (PR) and QT dispersion (QTd) between leads V1 and V3 were measured on conventional ECG. Using signal-averaged ECG the total duration of the filtered QRS complex (fQRS), the root-mean-square (RMS40) and the low-amplitude signal (LAS) were measured. The following procedures were developed to detect carriers/To detect carriers the following procedures were developed: (1) a screening test (ScreenTest) with PS (PR+fQRS) > or = 250 (250ms is 80% of the theoretical maximum in healthy individuals); and (2) a diagnostic test (DiagTest) for the simultaneous fulfillment of four conditions: PS > or = 250 and QTd > or = 10 and LAS > 26 and RMS40 < or = 29 (the latter two cut-offs are approximately 70% of the theoretical maximum in healthy carriers). RESULTS: Significant differences in PR, QTd, QRSf, RMS40 and LAS were found between carriers and non-carriers. The SCN5A gene was associated with all these variables, the strongest association being with PR. Both tests were applied to 63 family members (38 carriers). The ScreenTest was positive in 38 of 38 carriers, with eight false positives in 27 non-carriers (sensitivity [SE] = 100% and specificity [SP] = 66.67%). From ROC curve analysis a cut-off of PS = 252.5 shows SE = 100% and SP = 76% and a cut-off of PS = 260 shows SE=94.7% and SP = 84%. The DiagTest was positive in 36 of 38 carriers, with three false positives: SE = 94.74% and SP = 88.89%. From ROC curve analysis a multivariate logistic model identifies a cut-off with SE = 92% and SP = 92%. In the same group the SE and SP of the characteristic spontaneous repolarization pattern (type 1 Brugada ECG) to detect carriers were 52.4% and 97.2%, respectively, and the difference between the SE of the DiagTest and of the typical repolarization pattern is statistically significant. CONCLUSIONS: The ScreenTest and DiagTest are more effective tools than the characteristic repolarization pattern to discriminate between carriers and non-carriers of these two nonsense SCN5A mutations. We suggest their use in first-degree relatives of Brugada patients when the results of genetic testing are not available, in a score of disease probability in individuals with idiopathic Brugada ECG, and in patients with arrhythmias or other Brugada-related symptoms presenting type 2 or type 3 Brugada ECG.

Criteria to predict carriers of a novel SCN5A mutation in a large Portuguese family affected by the Brugada syndrome.

AIMS: Brugada syndrome (BrS) is a life-threatening arrhythmia disorder associated with autosomal-dominant mutations in the SCN5A gene. We aimed to characterize the diagnostic challenges and clinical manifestations of a novel SCN5A mutation associated with BrS. METHODS AND RESULTS: From a novel SCN5A mutation (c.664C>T; p.Arg222X) identified in a proband with the characteristic electrocardiographic pattern and the history of sudden collapse, 122 family members were studied including 40 carriers of the mutation. The electrocardiographic diagnosis of BrS requires type 1 Brugada electrocardiogram (ECG) pattern in >1 right precordial lead (V1-V3), but recently an isolated lead with coved-type ECG was proposed to be enough for the diagnosis. In this family, these proposed criteria (PC) were more sensitive in detecting mutation carriers than the conventional criteria without repercussion on the specificity. Carriers had, on average, longer P-wave duration, PR, and QRS intervals and higher transmural dispersion of repolarization. The prevalence of late potentials was higher in carriers, and individual signal average ECG (SAECG) parameters (QRSf, LAS, and RMS40) also were related to SCN5A gene mutation. Three non-carriers were found to be affected by BrS, two with a spontaneous type 1 ECG with alternative placement of the precordial electrodes, and one only after the pharmacological provocative test, suggesting that other genes may play a role in the pathophysiology of this disease. CONCLUSION: The PC for BrS diagnosis should be implemented. Some parameters from the spontaneous ECG and the SAECG are more effective tools than the characteristic repolarization pattern to discriminate between carriers of SCN5A mutations.

[Mycotic aneurysm of the left ventricular free wall complicating aortic valve endocarditis]. / Aneurisma micótico da parede livre do ventrículo esquerdo como complicação de endocardite da válvula aórtica.

We report the case of a 34-year-old man with aortic valve infective endocarditis caused by methicillin-resistant Staphylococcus aureus, complicated by an aortic annular abscess. A 23-mm St. Jude HP aortic mechanical prosthesis was implanted. The pre-discharge echocardiogram revealed a mycotic aneurysm of the basal posteroinferior wall, confirmed by cardiac magnetic resonance imaging, and it was decided to reintervene. The aneurysm was closed with a patch and the mitral valve had to be replaced. Although a small leak from the aneurysm patch persisted on the pre-discharge transthoracic echocardiogram, there was no trace of the aneurysm at nine-month re-evaluation. This case illustrates a rare complication of aortic valve endocarditis and shows the evolution of the mycotic aneurysm after closure via a transmitral approach.

[Description of a new mutation in a female patient with Fabry disease]. / Mutação de novo causadora de doença de Fabry em paciente do sexo feminino.

Fabry disease is caused by intracellular accumulation of glycosphingolipids in various tissues, secondary to mutations in the GLA gene (Xq22). Classically described as affecting hemizygous males with no residual alpha-galactosidase A activity, it is now known to affect both sexes, with later and less severe manifestations in females. The manifestations of this disease are systemic: neurological, cutaneous (angiokeratomas), renal, cardiovascular (left ventricular hypertrophy, valve thickening or rhythm disturbances), cochlear-vestibular, and cerebrovascular. In the absence of treatment there is progressive damage to vital organs with renal failure, stroke, heart failure or rhythm perturbations, leading to severe impairment of quality of life as well as reduced life expectancy. We describe the case of a female patient with a history of cryptogenic ischemic stroke at the age of 38 years and chronic renal failure with proteinuria, who presented to the emergency room with atrial fibrillation. The echocardiogram revealed concentric left ventricular hypertrophy, diastolic dysfunction and decreased longitudinal strain in the basal septum. In the context of a screening protocol, she was diagnosed with Fabry disease and a previously undescribed mutation was identified.

[Severe left ventricular outflow tract obstruction as a complication of mitral valve repair: case report]. / Obstrução grave do tracto de saída do ventrículo esquerdo como complicação de valvuloplastia mitral: a propósito de um caso clínico.

Systolic anterior motion (SAM) is a postoperative complication of mitral valve repair, with an incidence of 5 to 10%. Early recognition of the signs and symptoms of SAM is essential for the management of these patients. This article focuses on the pathophysiology and dynamics of SAM and the treatment strategies described in the literature. The authors present a case study and echocardiographic images illustrating the clinical relevance of the mechanism involved, in order to clarify whether surgical reintervention is necessary.

Delayed lead perforation: a rare cause of pacemaker dysfunction.

A 65-year-old woman with a dual-chamber pacemaker implanted in 2006 for symptomatic carotid sinus hypersensitivity was incidentally found to have loss of ventricular capture on routine pacemaker interrogation. A chest X-ray raised the suspicion of perforation and migration of the right ventricular lead, confirmed by three-dimensional echocardiogram and CT scan. On the basis of this case, we review myocardial lead perforation, including predisposing factors, pathophysiological mechanisms, diagnostic approach and therapeutic options.

Noncompaction of the ventricular myocardium: characterization and follow-up of an affected population.

Noncompaction of the ventricular myocardium (NVM) is a rare congenital disease caused by an arrest in normal myocardial embryogenesis, leading to persistence of numerous prominent trabeculations which communicate with the left ventricle. It was first described as a congenital condition affecting children, but several cases have been reported of late presentation, and recent studies suggest it may be underdiagnosed. The main clinical manifestations are congestive heart failure, arrhythmias (supraventricular or ventricular) and systemic embolism. We describe a series of twenty patients, focusing on clinical history, echocardiography and follow-up.

Longitudinal left ventricular strain in hypertrophic cardiomyopathy: correlation with nonsustained ventricular tachycardia.

AIMS: Stratifying risk of sudden death is a major issue in the management of hypertrophic cardiomyopathy (HCM). Existing risk factors have low positive predictive value and new parameters are needed. Determination of myocardial deformation (strain) by 2D Speckle tracking is a new methodology for determining LV regional function and could correlate with myocite disarray and fibrosis. The aim of this study was to assess the relationship between strain analysis and nonsustained ventricular tachycardia (NSVT) in patients with HCM. METHODS: Thirty-two consecutive patients with HCM (mean age 55, 17-78) were studied. All underwent standard echocardiographic and two-dimensional strain examination. Twenty-four-hour Holter monitoring was performed and echocardiographic parameters were correlated with NSVT. RESULTS: Nine patients (28%) had one or more episodes of NSVT. Patients with NSVT had a higher value of maximal LV thickness (23.6 mm vs. 19.4 mm, P = 0.027). There were no significant associations between NSVT on Holter monitoring and LV outflow gradient left atrial diameter, E/Em or left ventricle ejection fraction. Patients with HCM and NSVT had significant reductions in mid septal, apical-septal, apical-lateral strain, and in mean longitudinal strain. Midseptal strain >-10.5% had a sensitivity of 89% and a specificity of 74% (area under the curve, 0.787; P < 0.0013) for predicting NSVT independently of age or maximum wall thickness. CONCLUSION: Lower end-systolic peak longitudinal strain obtained by 2D speckle tracking was a predictor of NSVT in HCM patients. This parameter could become a useful tool in stratifying SCD risk in this population.

Spontaneous fluctuations between diagnostic and nondiagnostic ECGs in Brugada syndrome screening: Portuguese family with Brugada syndrome.

BACKGROUND: All family members of patients with Brugada syndrome (BS) should be screened. Fluctuations between diagnostic and nondiagnostic electrocardiogram (ECG) patterns in patients with BS are recognized, but systematic studies are lacking. The objective of this work was to prospectively evaluate the spontaneous changes between diagnostic and nondiagnostic ECG patterns in a family screened for BS. METHODS: One hundred twenty-nine family members were possibly affected plus the index case were screened with two ECGs with an interval of 6 months. Only coved-type ECG pattern was defined as diagnostic; type 2 and 3 ECGs were considered suggestive. RESULTS: The first ECG series made six diagnostics and the second 11, but only three patients maintained the diagnostic ECG. Patients with basal diagnostic ECG were older and more frequently symptomatic. Body mass index (BMI) was significantly lower in adults with diagnostic plus suggestive ECG when compared with the others. No significant gender difference was found among relatives with or without diagnostic ECG. CONCLUSION: Spontaneous phenotypic manifestation of BS was more frequent in older symptomatic patients, absent in children, and related with low BMI. ECG manifestations were intermittent in more than 3/4 of the affected patients. Fluctuations between diagnostic and nondiagnostic ECGs may have an implication on the correct phenotyping in family screening so several ECGs with drug challenging are mandatory.