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Background Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA‐HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). Methods and Results A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5–20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site‐interpreted Valsalva left ventricular outflow tract gradient

Abstract Left ventricular (LV) hypertrophy is a common finding in patients with severe aortic stenosis (AS). Cardiac magnetic resonance (CMR) is the gold-standard technique to evaluate LV remodeling. Our aim was to assess the prevalence and describe the patterns of LV adaptation in AS patients before and after surgical aortic valve replacement (AVR). Prospective study of 130 consecutive patients (71y [IQR 68–77y], 48% men) with severe AS, referred for surgical AVR. Patterns of LV remodeling were assessed by CMR. Besides normal LV ventricular structure, four other patterns were considered: concentric remodeling, concentric hypertrophy, eccentric hypertrophy, and adverse remodeling. At baseline CMR study: mean LV indexed mass: 81.8 ± 26.7 g/m2; mean end-diastolic LV indexed volume: 85.7 ± 23.1 mL/m2 and median geometric remodeling ratio: 0.96 g/mL [IQR 0.82–1.08 g/mL]. LV hypertrophy occurred in 49% of subjects (concentric 44%; eccentric 5%). Both normal LV structure and concentric remodeling had a prevalence of 25% among the cohort; one patient had an adverse remodeling pattern. Asymmetric LV wall thickening was present in 55% of the patients, with predominant septal involvement. AVR was performed in 119 patients. At 3–6 months after AVR, LV remodeling changed to: normal ventricular geometry in 60%, concentric remodeling in 27%, concentric hypertrophy in 10%, eccentric hypertrophy in 3% and adverse remodeling (one patient). Indexes of AS severity, LV systolic and diastolic function and NT-proBNP were significantly different among the distinct patterns of remodeling. Several distinct patterns of LV remodelling beyond concentric hypertrophy occur in patients with classical severe AS. Asymmetric hypertrophy is a common finding and LV response after AVR is diverse.

Abstract Aims Increased collagen content of the myocardium modifies tissue reflectivity and integrated backscatter (IBS) indexes are suggested as markers of myocardial fibrosis (MF). We sought to assess the correlation between calibrated (c) IBS and bidimensional (2D) strain derived IBS with left ventricular (LV) MF in patients with severe aortic stenosis (AS). Methods and results We made a prospective observational cohort study including 157 patients with severe AS referred for surgical aortic valve replacement (AVR), with complete preoperative transthoracic echocardiography, cardiac magnetic resonance (CMR) and endomyocardial biopsy (EMB) obtained from the anterior basal septum at the time of surgery. Two groups of 30 patients were specifically evaluated, with and without late gadolinium enhancement (LGE) at CMR. IBS was obtained at QRS peak from both parasternal long axis (PLAX) and apical-three-chamber (AP3C) views and measured in decibels (dB). Whole-cardiac cycle IBS at basal anterior septum was obtained from 2D longitudinal strain. Correlation analysis of reflectivity indexes was performed with global and segmental (anterior basal septum) values of native T1 and extracellular volume (ECV), and EMB collagen volume fraction (CVF) (Masson´s Trichrome). IBS values were compared in both group of patients (LGE + vs. LGE –). 60 patients (74 [36–74] years, 45% male) with high gradient (mean gradient: 63 ± 20mmHg), normal flow (45 ± 10mL/m2) AS and preserved left ventricular ejection fraction (60 ± 9%) were included. Basal septum cIBS was − 17.45 (–31.2–10.95) and − 9.17 ± 9.45dB from PLAX and A3C views, respectively. No significant correlations were found between IBS and both non-invasive CMR tissue characterization and CVF: median MF of 9.7(2.1–79.9)%. Acoustic indexes were not significantly different according to the presence of pre-operative LGE. Conclusion In this group of patients with classical severe AS, IBS reflectivity indexes are of no added value to discriminate the presence of MF. Graphical Abstract

BackgroundHuman umbilical cord matrix-mesenchymal stromal cells (hUCM-MSC) have demonstrated beneficial effects in experimental acute myocardial infarction (AMI). Reperfusion injury hampers myocardial recovery in a clinical setting and its management is an unmet need. We investigated the efficacy of intracoronary (IC) delivery of xenogeneic hUCM-MSC as reperfusion-adjuvant therapy in a translational model of AMI in swine.MethodsIn a placebo-controlled trial, pot-belied pigs were randomly assigned to a sham-control group (vehicle-injection; n = 8), AMI + vehicle (n = 12) or AMI + IC-injection (n = 11) of 5 × 105 hUCM-MSC/Kg, within 30 min of reperfusion. AMI was created percutaneously by balloon occlusion of the mid-LAD. Left-ventricular function was blindly evaluated at 8-weeks by invasive pressure-volume loop analysis (primary endpoint). Mechanistic readouts included histology, strength-length relationship in skinned cardiomyocytes and gene expression analysis by RNA-sequencing.ResultsAs compared to vehicle, hUCM-MSC enhanced systolic function as shown by higher ejection fraction (65 ± 6% vs. 43 ± 4%; p = 0.0048), cardiac index (4.1 ± 0.4 vs. 3.1 ± 0.2 L/min/m2; p = 0.0378), preload recruitable stroke work (75 ± 13 vs. 36 ± 4 mmHg; p = 0.0256) and end-systolic elastance (2.8 ± 0.7 vs. 2.1 ± 0.4 mmHg*m2/ml; p = 0.0663). Infarct size was non-significantly lower in cell-treated animals (13.7 ± 2.2% vs. 15.9 ± 2.7%; Δ = −2.2%; p = 0.23), as was interstitial fibrosis and cardiomyocyte hypertrophy in the remote myocardium. Sarcomere active tension improved, and genes related to extracellular matrix remodelling (including MMP9, TIMP1 and PAI1), collagen fibril organization and glycosaminoglycan biosynthesis were downregulated in animals treated with hUCM-MSC.ConclusionIntracoronary transfer of xenogeneic hUCM-MSC shortly after reperfusion improved left-ventricular systolic function, which could not be explained by the observed extent of infarct size reduction alone. Combined contributions of favourable modification of myocardial interstitial fibrosis, matrix remodelling and enhanced cardiomyocyte contractility in the remote myocardium may provide mechanistic insight for the biological effect.

Abstract Anomalous origin of the right coronary artery from the opposite sinus (right-ACAOS) with interarterial course (IAC) has been associated with increased risk of sudden cardiac death (SCD). Widespread use of coronary computed tomography angiography (CCTA) has led to increased recognition of this condition, even among healthy individuals. Our study sought to examine the prevalence, anatomical characteristics, and outcomes of right-ACAOS with IAC in patients undergoing CCTA for suspected coronary artery disease (CAD). We conducted a retrospective analysis of consecutive patients referred for CCTA at one tertiary hospital from January 2012 to December 2020. Patients exhibiting right-ACAOS with IAC were analyzed for cardiac symptoms and mid-term occurrence of first MACE (cardiac death, SCD, non-fatal myocardial infarction (MI) or revascularization of the anomalous vessel). CCTAs were reviewed for anatomical high-risk features and concomitant CAD. Among 10,928 patients referred for CCTA, 28 patients with right-ACAOS with IAC were identified. Mean age was 55 ± 17 years, 64% were male and 11 (39.3%) presented stable cardiac symptoms. Most patients had at least one high risk anatomical feature. During follow-up, there were no cardiac deaths or aborted SCD episodes and only 1 patient underwent surgical revascularization of the anomalous vessel. Right-ACAOS with IAC is an uncommon finding (prevalence of 0.26%). In a contemporary population of predominantly asymptomatic patients who survived this condition well into adulthood, most patients were managed conservatively with a low event rate. Additional studies are needed to support medical follow-up as the preferred option in this setting.

Introduction: Although there is evidence that a significant proportion of veteran athletes have coronary atherosclerotic disease (CAD), its prevalence in recreational athletes with low to intermediate cardiovascular (CV) risk is not established. This study aimed to characterize the coronary atherosclerotic burden in veteran male recreational athletes with low to intermediate CV risk. Methods: Asymptomatic male athletes aged ≥40 years with low to intermediate risk, who exercised >4 hours/week for >5 years, underwent cardiac computed tomography (CT) for coronary artery calcium (CAC) scoring and CT angiography. High coronary atherosclerotic burden was defined as at least one of the following: CAC score >100; CAC score ≥75th percentile; obstructive CAD; disease involving the left main, three vessels or two vessels including the proximal left anterior descending artery; segment involvement score >5; or CT Leaman score ≥5. Athletes were categorized by tertiles of exercise volume, calculated by metabolic equivalent of task (MET) scores. Results: A total of 105 athletes were included, all with SCORE 100, 13 (12.4%) had CAC score ≥75th percentile and six (5.7%) had obstructive lesions. The extent and severity of coronary plaques did not differ according to exercise volume. Conclusions: The prevalence of subclinical CAD detected by cardiac CT in veteran male recreational athletes with low to intermediate CV risk was high. Up to a quarter of our cohort had a high coronary atherosclerotic burden. Resumo: Introdução: Apesar de estar descrita uma proporção significativa de atletas veteranos com doença arterial coronária aterosclerótica (DAC), a sua prevalência em atletas de nível recreativo com risco cardiovascular (CV) baixo-intermédio não está esclarecida. O objetivo deste estudo foi caracterizar a carga aterosclerótica coronária em atletas veteranos do género masculino de nível recreativo com risco CV baixo-intermédio. Métodos: Atletas assintomáticos do género masculino com ≥40 anos com risco baixo-intermédio, praticantes de >4horas/semana de exercício durante >5 anos, realizaram tomografia computorizada cardíaca com determinação do score de cálcio (ScCa) e angiografia coronária (Angio-TC). Definiu-se elevada carga aterosclerótica coronária a presença de pelo menos uma das seguintes características: ScCa >100; ScCa≥p75 (percentil); DAC obstrutiva; doença envolvendo tronco comum, 3-vasos ou 2-vasos incluindo a artéria descendente anterior proximal; segment involvement score >5; CT-adapted Leaman score ≥5. Os atletas foram categorizados em tercis de volume de exercício, calculado por Metabolic Equivalent Task (MET) scores. Resultados: Foram incluídos 105 atletas, todos com score 100, 13 (12,4%) ≥p75 e 6 (5,7%) lesões obstrutivas. A extensão e a gravidade das placas coronárias não diferiram de acordo com o volume de exercício. Conclusões: A prevalência de DAC subclínica detetada por Angio-TC cardíaca em atletas veteranos do género masculino de nível recreativo com risco CV baixo-intermédio foi elevada. Um quarto da nossa amostra apresentou uma elevada carga aterosclerótica coronária.

Introduction and objectives: Hypertrophic cardiomyopathy (HCM) is a genetically and phenotypically heterogeneous disease; there is still a large proportion of patients with no identified disease-causing mutation. Although the majority of mutations are found in the MYH7 and MYBPC3 genes, mutations in Z-disk-associated proteins have also been linked to HCM. Methods: We assessed a small family with HCM based on family history, physical examination, 12-lead ECG, echocardiogram and magnetic resonance imaging. After exclusion of mutations in eleven HCM disease genes, we performed direct sequencing of the TCAP gene encoding the Z-disk protein titin-cap (also known as telethonin). Results: We present a novel TCAP mutation in a small family affected by HCM. The identified p.C57W mutation showed a very low population frequency, as well as high conservation across species. All of the bioinformatic prediction tools used considered this mutation to be damaging/deleterious. Family members were screened for this new mutation and a co-segregation pattern was detected. Both affected members of this family presented with late-onset HCM, moderate asymmetric left ventricular hypertrophy, atrial fibrillation and heart failure with preserved ejection fraction and low risk of sudden cardiac death. Conclusions: We present evidence supporting the classification of the TCAP p.C57W mutation, encoding the Z-disk protein titin-cap/telethonin as a new likely pathogenic variant of hypertrophic cardiomyopathy, with a specific phenotype in the family under analysis. Resumo: Introdução e objetivos: A miocardiopatia hipertrófica (HCM) é uma doença genética e fenotipicamente heterogénea, existindo ainda uma grande proporção de doentes sem uma mutação patogénica identificada. Embora a maioria das mutações seja encontrada nos genes MYH7 e MYBPC3, mutações em proteínas associadas ao disco Z também foram associadas à HCM. Métodos: Avaliámos uma pequena família com HCM com base na história familiar e exame objetivo, eletrocardiograma de 12 derivações, ecocardiograma e ressonância magnética. Após exclusão de mutações em 11 genes causadores de HCM, realizámos a sequenciação direta do gene TCAP que codifica a proteína titin-cap do disco-Z (também conhecida como teletonina). Resultados: Relatamos aqui uma nova mutação do gene TCAP numa pequena família com HCM. A mutação identificada, p.C57W, mostrou uma frequência populacional muito baixa, bem como alta conservação entre as espécies. Todas as ferramentas de previsão de bioinformática usadas previram que essa mutação seria funcionalmente prejudicial. A presença desta nova mutação foi avaliada nos outros membros da família, tendo-se detetado um padrão de cossegregação. Ambos os membros da família afetados apresentaram HCM de início tardio, com hipertrofia ventricular esquerda assimétrica moderada, fibrilhação auricular e insuficiência cardíaca com fracão de ejeção preservada, com baixo risco de morte súbita cardíaca. Conclusão: Apresentamos evidência que suporta a classificação da mutação TCAP p.C57W, que codifica a proteína titin-cap do disco-Z (teletonina), como uma nova variante provavelmente patogénica da HCM, com um perfil fenotípico específico na família analisada.

Abstract Background Identifying the patients with hypertrophic cardiomyopathy (HCM) in whom the risk of sudden cardiac death (SCD) justifies the implantation of a cardioverter-defibrillator (ICD) in primary prevention remains challenging. Different risk stratification and criteria are used by the European and American guidelines in this setting. We sought to evaluate the role of cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) in improving these risk stratification strategies. Methods We conducted a multicentric retrospective analysis of HCM patients who underwent CMR for diagnostic confirmation and/or risk stratification. Eligibility for ICD was assessed according to the HCM Risk-SCD score and the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) algorithm. The amount of LGE was quantified (LGE%) and categorized as 0%, 0.1–10%, 10.1–19.9% and ≥ 20%. The primary endpoint was a composite of SCD, aborted SCD, sustained ventricular tachycardia (VT), or appropriate ICD discharge. Results A total of 493 patients were available for analysis (58% male, median age 46 years). LGE was present in 79% of patients, with a median LGE% of 2.9% (IQR 0.4–8.4%). The concordance between risk assessment by the HCM Risk-SCD, ACCF/AHA and LGE was relatively weak. During a median follow-up of 3.4 years (IQR 1.5–6.8 years), 23 patients experienced an event (12 SCDs, 6 appropriate ICD discharges and 5 sustained VTs). The amount of LGE was the only independent predictor of outcome (adjusted HR: 1.08; 95% CI: 1.04–1.12; p

Resumo: Introdução: O objetivo deste registo foi caracterizar a prática clínica em Portugal no que respeita à utilização de dispositivos eletrónicos na terapêutica dos doentes com insuficiência cardíaca (IC) e fração de ejeção ventricular esquerda (FEVE) diminuída. Métodos: O estudo Síncrone é um registo observacional, multicêntrico e prospetivo que foi conduzido em 16 centros portugueses de 2006 a 2014. Incluiu doentes adultos com diagnóstico de IC, FEVE

Introduction: In adults, unexplained left ventricular hypertrophy is usually due to sarcomeric hypertrophic cardiomyopathy (HCM). Fabry disease (FD) is rare but may mimic sarcomeric HCM, and has an adverse prognosis in the absence of specific treatment. We aimed to assess cardiologists’ awareness of FD based on data from the Portuguese Registry of Hypertrophic Cardiomyopathy. Methods: A total of 811 index patients, aged 55 ± 16 years, 486 (59.9%) male, were included. Three groups were characterized: A – 128 patients, 74 (57.8%) male, with pathogenic or likely pathogenic mutation(s) in sarcomeric genes; B – 234 patients, 146 (62.4%) male, with negative genetic testing; and C – 449 patients, 266 (59.2%) male, no genetic testing performed. The groups were compared in terms of whether FD was excluded in the registry. Potential red flags for FD were also analyzed and compared between groups. Results: Patients in group A were younger and more frequently had familial HCM (A – 53.9% vs. B – 20.1% vs. C – 18.3%; p

Restrictive cardiomyopathies (RCMs) are a diverse group of myocardial diseases with a wide range of aetiologies, including familial, genetic and acquired diseases and ranging from very rare to relatively frequent cardiac disorders. In all these diseases, imaging techniques play a central role. Advanced imaging techniques provide important novel data on the diagnostic and prognostic assessment of RCMs. This EACVI consensus document provides comprehensive information for the appropriateness of all non-invasive imaging techniques for the diagnosis, prognostic evaluation, and management of patients with RCM.

Introduction: We report the results of the Portuguese Registry of Hypertrophic Cardiomyopathy, an initiative that reflects the current spectrum of cardiology centers throughout the territory of Portugal. Methods: A direct invitation to participate was sent to cardiology departments. Baseline and outcome data were collected. Results: A total of 29 centers participated and 1042 patients were recruited. Four centers recruited 49% of the patients, of whom 59% were male, and mean age at diagnosis was 53±16 years. Hypertrophic cardiomyopathy (HCM) was identified as familial in 33%. The major reason for diagnosis was symptoms (53%). HCM was obstructive in 35% of cases and genetic testing was performed in 51%. Invasive septal reduction therapy was offered to 8% (23% of obstructive patients). Most patients (84%) had an estimated five-year risk of sudden death of

Regular physical exercise is responsible for various health benefits, and is recommended for primary and secondary cardiovascular (CV) prevention. Despite these recognized benefits, various clinical events can occur in athletes, including acute myocardial infarction and sudden cardiac death (SCD); the main cause of SCD in veteran athletes is coronary artery disease (CAD). The relationship between intense exercise training and CAD is controversial, and a U-shaped association has been hypothesized. If this is the case, screening for subclinical CAD in older athletes may be justified, and various different methodologies have been proposed. However, the methodology for screening veteran athletes is not consensual, and several markers of CAD, in addition to clinical CV risk factors, could improve risk stratification in this population. In the present paper we review the published data on CAD in athletes, focusing on the relationship between the dose of exercise and CAD, as well as the implications for pre-participation screening of veteran athletes. Resumo: O exercício físico associa-se a múltiplos benefícios para a saúde, estando recomendado na prevenção cardiovascular (CV) primária e secundária. Apesar dos benefícios comprovados, diversos eventos clínicos podem ocorrer em atletas, incluindo enfarte agudo do miocárdio e morte súbita, nos atletas veteranos maioritariamente devido a doença das artérias coronárias (DAC). A relação entre exercício físico intenso e DAC permanece controversa, colocando-se a hipótese de associação tipo «curva em U». Neste contexto, a deteção subclínica de DAC em atletas veteranos pode ser justificada, estando propostas algumas metodologias. No entanto, a metodologia para a avaliação pré-competitiva dos atletas veteranos não é consensual e diversos marcadores de risco, adicionais aos fatores de risco CV clínicos tradicionais, poderão melhorar a estratificação de risco nesta população. Neste artigo revêm-se os dados publicados sobre DAC em atletas, com relevância para a relação entre a dose de exercício e DAC, bem como as implicações para a avaliação pré-competitiva de atletas veteranos. Keywords: Veteran athletes, Dose of exercise, Coronary artery disease, Coronary computed tomography angiography, Palavras-chave: Atletas veteranos, Dose de exercício, Doença das artérias coronárias, Angiografia coronária por tomografia computorizada

Resumo: Introdução: A interpretação do eletrocardiograma (ECG) do atleta permanece controversa, com ausência de estandardização e dificuldade na aplicação de critérios específicos na sua interpretação. O objetivo deste trabalho é avaliar a variabilidade na interpretação do ECG de atletas. Metodologia: Vinte ECG de atletas foram avaliados por cardiologistas e internos de cardiologia, 11 normais ou apenas com alterações fisiológicas e nove patológicos. Cada ECG foi classificado pelos inquiridos em normal/com alterações fisiológicas ou patológico, usando ou não critérios específicos na sua interpretação. Resultados: Foram incluídas as respostas de 58 médicos, 42 (72,4%) cardiologistas. Dezasseis (27,6%) afirmaram avaliar frequentemente atletas e 32 (55,2%) não usar critérios específicos na interpretação do ECG, sendo os mais usados os critérios de Seattle (n = 13). Em média, cada médico interpretou corretamente 15 ± 2 ECG, correspondendo a 74% dos traçados (variação: 45‐100%). A interpretação dos ECG foi correta em 68% (variação: 22‐100%) dos patológicos e em 79% (variação: 55‐100%) dos normais/com alterações fisiológicas. Não houve diferença significativa na interpretação entre cardiologistas e internos (74 ± 10% versus 75 ± 10%; p = 0,724), nem entre os que avaliam frequentemente ou não atletas (77 ± 12% versus 73 ± 9%; p = 0,286), verificando‐se uma tendência para interpretação mais correta com critérios específicos (77 ± 10% versus 72 ± 10%; p = 0,092). A reprodutibilidade do estudo foi excelente (intraclass correlation coefficient = 0,972; p

Objective: To evaluate the performance of traditional cardiovascular (CV) risk factors in identifying a higher than expected coronary atherosclerotic burden. Methods: We assessed 2069 patients undergoing coronary CT angiography, with assessment of calcium score (CS), for suspected coronary artery disease. A higher than expected atherosclerotic burden was defined as CS >75th percentile (CS >P75) according to age and gender-adjusted monograms. The ability of traditional CV risk factors to predict a CS >P75 was assessed in a customized logistic regression model (“Clinical Score”) and by the calculation of SCORE (Systemic Coronary Risk Evaluation). The population attributable risk (PAR) of risk factors for CS >P75 was calculated. Results: The median CS was 3.0 (IQR 0.0–98.0); 362 patients had CS >P75. The median SCORE was 3.0 (IQR 1.0–4.0). With the exception of hypertension, all traditional CV risk factors were independent predictors of CS >P75: diabetes, dyslipidemia, smoking and family history (OR 1.3–2.2, p≤0.026). The areas under the ROC curves for CS >P75 were 0.64 for the Clinical Score (95% CI 0.61–0.67, pP75 were in the two lower quartiles of the Clinical Score. Altogether, the traditional risk factors explain 56% of the prevalence of CS >P75 (adjusted PAR 0.56). Conclusion: Despite the association of CV risk factors with a higher than expected atherosclerotic burden, they appear to explain only half of its prevalence. Even when integrated in scores, the predictive power of these risk factors was modest, exposing the limitations of risk stratification based solely on demographic and clinical risk factors. Resumo: Objetivo: O objetivo deste trabalho foi avaliar o desempenho dos fatores de risco cardiovascular (CV) clássicos na identificação de carga aterosclerótica superior ao esperado. Métodos: Avaliámos 2069 doentes (dts) que realizaram AngioTC cardíaca e ScCa para exclusão de doença coronária. Definiu-se carga aterosclerótica superior ao esperado um ScCa acima do percentil 75 (ScCa>p75) de acordo com nomogramas ajustados para o sexo e idade. A capacidade dos fatores de risco clássicos preverem ScCa>p75 avaliou-se num modelo de regressão logística customizado (score clínico) e pelo SCORE. Avaliou-se o Population Attributable Risk (PAR) dos fatores de risco para ScCa>p75. Resultados: A mediana de ScCa foi 3,0 [IIQ 0,0-98,0]; 362 dts com ScCa>p75. A mediana do HeartScore foi 3,0 [IIQ 1,0-4,0]. Exceto a hipertensão arterial, todos os fatores de risco foram preditores independentes de CaSc>p75: diabetes mellitus, dislipidemia, tabagismo e história familiar (OR 1,3-2,2, p≤0,026). As áreas abaixo da curva ROC para SaCa>p75 foram 0,64 para score clínico (IC95% 0,61-0,67; pp75 encontravam-se nos dois quartis de score clínico mais baixos. No seu conjunto, os fatores de risco clássicos explicam 56% da prevalência de ScCa>p75 (PAR ajustado 0,56). Conclusão: Apesar de os fatores de risco CV se associarem a uma carga aterosclerótica superior ao esperado, justificam pouco mais de metade da sua prevalência. O poder preditor destes fatores de risco é modesto, mesmo integrados em scores, revelando as limitações da estratificação de risco baseada apenas em dados demográficos e fatores de risco clínicos. Keywords: Atherosclerotic burden, Risk factor, Attributable risk, Calcium score, CT angiography, Palavras-chave: Carga Aterosclerótica, Fator de risco, Score de cálcio, AngioTC

Fundamento: O custo-efetividade é um fator de crescente importância na escolha de um exame ou terapêutica. Objetivo: Avaliar o custo-efetividade de vários métodos habitualmente empregados no diagnóstico de doença coronária estável em Portugal. Métodos: Foram avaliadas sete estratégias diagnósticas. O custo-efetividade de cada estratégia foi definido como o custo por cada diagnóstico correto (inclusão ou exclusão de doença arterial coronária obstrutiva) num doente sintomático. Os custos e a eficácia de cada método foram avaliados por meio de inferência bayesiana e análise de árvores de decisão, fazendo variar a probabilidade pré-teste entre 10 e 90%. Resultados: O custo-efetividade das várias estratégias diagnósticas é fortemente dependente da probabilidade pré-teste. Em doentes com probabilidade pré-teste ≤ 50%, os algoritmos diagnósticos, que incluem a angiotomografia computadorizada cardíaca são os mais custo-efetivos. Nesses doentes, dependendo da probabilidade pré-teste e da disponibilidade para pagar por diagnóstico correto adicional, a angiotomografia computadorizada pode ser usada como teste de primeira linha ou ser reservada a doentes com teste ergométrico positivo/inconclusivo ou escore de cálcio > 0. Em doentes com probabilidade pré-teste ≥ 60%, o envio direto para angiografia coronária invasiva parece ser a estratégia mais custo-efetiva. Conclusão: Os algoritmos diagnósticos, que incluem a angiotomografia computadorizada cardíaca, são os mais custo-efetivos em doentes sintomáticos com suspeita de doença arterial coronária estável e probabilidade pré-teste ≤ 50%. Em doentes de risco mais elevado (probabilidade pré-teste ≥ 60%), o envio direto para coronariografia invasiva parece ser a estratégia mais custo-efetiva. Em todas as probabilidades pré-teste, as estratégias baseadas em testes de isquemia parecem ser mais onerosas e menos eficazes que aquelas baseadas em testes anatômicos.

Resumo: O índice de resistência da microcirculação (IRM) permite o estudo quantitativo, invasivo e em tempo real do estado da microcirculação coronária. O objetivo principal foi a validação da técnica de determinação do IRM num modelo animal de grande porte. O objetivo secundário foi a comparação de duas doses de papaverina, 5 e 10 mg, para indução de hiperémia máxima e quanto à sua evolução temporal. Foram estudados oito porcos. Avaliou‐se a Pd e o Tmn em condições basais e com hiperémia máxima induzida pela injeção intracoronária de 5 ou 10 mg de papaverina e sucessivamente aos dois, cinco, oito e dez minutos. Para o compromisso da microcirculação foram injetadas microesferas de 40 μm de diâmetro. Em cada animal foram realizadas 14 determinações de IRM. Não se observaram diferenças significativas entre as duas doses de papaverina quanto às repostas da Pd e ao valor de IRM obtido, 11 ± 4,5 U com 5 mg de papaverina e de 10,6 ± 3 U com a dose de 10 mg (p = 0,612). A evolução temporal dos valores de IRM foi semelhante, deixando de haver diferenças relativamente ao valor basal após cinco minutos. Com a injeção das microesferas houve uma elevação significativa do IRM (41 ± 16 U, p = 0,001). O IRM avalia em tempo real a resistência da microcirculação coronária. A administração intracoronária de 5 mg de papaverina é tão eficaz como a de 10 mg para a indução de hiperémia máxima, com o retorno às condições basais a ocorrer cinco minutos após a sua administração. Abstract: Introduction: The index of microcirculatory resistance (IMR) enables/provides quantitative, invasive, and real‐time assessment of coronary microcirculation status. Aims: The primary aim of this study was to validate the assessment of IMR in a large animal model, and the secondary aim was to compare two doses of intracoronary papaverine, 5 and 10 mg, for induction of maximal hyperemia and its evolution over time. Methods: Measurements of IMR were performed in eight pigs. Mean distal pressure (Pd) and mean transit time (Tmn) were measured at rest and at maximal hyperemia induced with intracoronary papaverine, 5 and 10 mg, and after 2, 5, 8 and 10 minutes. Disruption of the microcirculation was achieved by selective injection of 40‐μm microspheres via a microcatheter in the left anterior descending artery. Results: In each animal 14 IMR measurements were made. There were no differences between the two doses of papaverine regarding Pd response and IMR values – 11±4.5 U with 5 mg and 10.6±3 U with 10 mg (p=0.612). The evolution of IMR over time was also similar with the two doses, with significant differences from resting values disappearing after five minutes of intracoronary papaverine administration. IMR increased with disrupted microcirculation in all animals (41±16 U, p=0.001). Conclusions: IMR provides invasive and real‐time assessment of coronary microcirculation. Disruption of the microvascular bed is associated with a significant increase in IMR. A 5‐mg dose of intracoronary papaverine is as effective as a 10‐mg dose in inducing maximal hyperemia. After five minutes of papaverine administration there is no significant difference from resting hemodynamic status. Palavras‐chave: Microcirculação coronária, Índice de resistência da microcirculação, Modelo animal, Keywords: Coronary microcirculation, Index of microcirculation resistance, Animal model

Resumo: A tomografia computorizada cardíaca (angioTC cardíaca) permite documentar a presença de doença coronária, independentemente do seu grau de estenose. Recentemente, foi validado o valor prognóstico da doença coronária não obstrutiva documentada por angioTC cardíaca. No entanto, não existem ainda recomendações claras acerca da abordagem destes doentes, nomeadamente sobre o início de medidas farmacológicas mais agressivas em prevenção primária. A abordagem destes doentes permanece controversa, sobretudo nos casos em que existe uma discrepância entre o risco cardiovascular e a carga aterosclerótica objetivada na angioTC.Os autores descrevem o caso de um doente com discrepância entre a extensão da aterosclerose coronária objetivada e a sua estimativa de acordo com os scores de probabilidade pré-teste e de eventos cardiovasculares. Tratando-se de um indivíduo com documentação de aterosclerose coronária acima do esperado - score de cálcio superior ao percentil 90 e doença coronária não obstrutiva na angioTC cardíaca, mas por outro lado, assintomático e sem fatores de risco nem antecedentes cardiovasculares, com uma estimativa de risco cardiovascular muito baixa e atleta de competição, torna-se difícil decidir acerca do risco/benefício de medidas farmacológicas de prevenção primária. Abstract: Cardiac computed tomography (CT) documents the presence of coronary artery disease, regardless of the degree of stenosis. The prognostic value of non-obstructive coronary artery disease documented by cardiac CT has recently been validated. However, there are still no clear guidelines on the management of such patients, particularly concerning initiation of more aggressive pharmacological measures for primary prevention. The approach to these patients remains controversial, especially in cases in which there is a discrepancy between cardiovascular risk and the atherosclerotic burden as documented by cardiac CT.The authors describe the case of a patient with a discrepancy between the extent of documented coronary atherosclerosis and that estimated according to pretest probability and cardiovascular risk scores. As this individual had more severe coronary atherosclerosis than expected (calcium score above the 90th percentile and non-obstructive coronary artery disease on cardiac CT) but was a competitive athlete and otherwise asymptomatic and without risk factors or cardiovascular history, with a very low estimated cardiovascular risk, it was difficult to decide on the risks and benefits of pharmacological primary prevention. Palavras-chave: Tomografia computorizada cardíaca, Doença coronária não obstrutiva, Exercício físico, Keywords: Cardiac computed tomography, Non-obstructive coronary artery disease, Physical exercise

Background: Treadmill exercise testing has low specificity for the detection of significant epicardial coronary artery disease (CAD). A possible mechanism to explain some of the false positives is transient subendocardial ischemia induced by intraventricular gradients (IVG) during stress. The development of IVG during dobutamine stress echocardiography (DSE) occurs in 8-38% of non-selected populations. Objectives: To determine: 1. the prevalence of IVG in a selected population of false positives on treadmill stress testing; 2. whether this prevalence is different from that described for non-selected populations; 3. whether patient characteristics are related to the presence of IVG; 4. the relation between the presence of IVG and the occurrence of ECG abnormalities, symptoms and blood pressure. Methods and Results: We evaluated 50 consecutive patients with false positive treadmill stress tests (normal CT coronary angiography, nuclear perfusion tests or angiography) with DSE (2D and Doppler evaluation). All DSE exams were negative for ischemia. Stress-induced IVG was seen in 34 of the 50 patients (68%) and 16 patients (32%) did not develop IVG (p 0.05). However, the presence of IVG was associated with the occurrence of ischemic ST depression during dobutamine stress echo (p 0,05). No entanto, a presença de GIV relacionou-se com a ocorrência de depressão do segmento ST durante o ecocardiograma de sobrecarga com dobutamina (p < 0,05). Conclusões: 1. A prevalência de GIV durante o ecocardiograma de stress com dobutamina em populações seleccionadas de falsos positivos de prova de esforço é muito elevada, ocorrendo em 2/3 dos doentes. 2. Esta prevalência é significativamente mais alta que a descrita para populações não seleccionadas. 3. Idade, género, factores de risco para DAC, terapêutica com beta-bloqueantes/antagonistas dos canais de cálcio, doença arterial significativa/HVE, sintomas e a pressão arterial durante a sobrecarga não se relacionam com a presença ou ausência de GIV. 4. A presença de GIV está relacionada com a ocorrência de alterações isquémicas do segmento ST durante a ecocardiografia de sobrecarga com dobutamina. Keywords: Treadmill stress tests, False positives, Stress echocardiography, Physical exercise, Intraventricular gradient, Palavras-chave: Prova de esforço, Falsos positivos, Ecocardiografia de sobrecarga, Exercício físico, Gradiente intraventricular

The prevalence, complexity, clinical importance, heterogeneity and unpredictability of inherited cardiovascular diseases make the development of inherited cardiovascular disease centers an inevitability, with the ultimate goal of reducing the morbidity and mortality associated with these conditions. An inherited cardiovascular disease center may be seen as a subunit of a cardiology department, with health professionals specializing in these types of disorders, organized to provide excellence in all related areas, including diagnosis, treatment, follow-up, prevention, risk stratification and prognosis. Among its objectives are the development of action protocols and the creation of databases that enable patients to be included in national and international research networks. To achieve these objectives these centers should include functional units of clinical and basic sciences, research, training and education, acting in harmony in a holistic approach to patients and their families. As most experience on inherited cardiovascular diseases is based on hypertrophic cardiomyopathy and on “hypertrophic cardiomyopathy centers”, these centers represent an excellent opportunity to learn how to set up inherited cardiovascular disease centers. European centers will differ from country to country, reflecting the heterogeneity of national health systems, but will share a common core, presented in this document. Though we are aware that this ambitious project is not at all easy and may be difficult to implement in its entirety – in fact we consider it a major step – our position is that all the efforts to achieve it are worthwhile, considering that the main goal will always be the well-being of those affected by these particular disorders. Resumo: A prevalência, complexidade, importância clínica, heterogeneidade e imprevisibilidade das doenças cardíacas heredofamiliares torna a criação de Unidades de Doenças Cardíacas Hereditárias uma inevitabilidade, cujo objectivo final é reduzir a morbilidade e a mortalidade relacionadas com estas patologias. Uma Unidade de Doenças Cardíacas Hereditárias é uma subunidade de um departamento de Cardiologia constituída por profissionais de saúde especializados neste tipo de doenças, organizado de forma a proporcionar a excelência em todos as suas áreas, incluindo diagnóstico, tratamento, seguimento, prevenção, estratificação de risco e determinação de prognóstico. Alguns dos seus objectivos são o desenvolvimento de protocolos de actuação e a criação de bases de dados que permitam a inclusão de doentes em registos e redes de investigação nacionais e internacionais. Para atingir estes objectivos estes centros devem integrar Unidades Funcionais (clínica, ciências básicas, investigação, treino e educação), actuando harmonicamente numa abordagem holística de doentes e suas famílias. Como grande parte do conhecimento referente às doenças cardíacas hereditárias se baseia na miocardiopatia hipertrófica e na experiência adquirida com os “centros de miocardiopatia hipertrófica”, estes representam um excelente modelo para aprender como criar e desenvolver as Unidades de Doenças Cardíacas Hereditárias. A nível Europeu, as características destas Unidades serão diferentes de um país para outro, reflectindo a heterogeneidade dos diferentes sistemas e serviços nacionais de saúde, compartilhando no entanto um core comum, apresentado neste documento. Embora conscientes de que este projecto é ambicioso e de que a sua concretização como um todo não será uma tarefa fácil, consideramos a aplicação e divulgação deste conceito a nível nacional e Europeu um passo de grande importância. Assim, a nossa posição é que todos os esforços para atingir esta meta valem a pena, considerando que o principal objectivo será sempre o bem-estar dos doentes afectados por estas patologias. Keywords: Inherited cardiovascular diseases, Inherited cardiovascular disease centers, Hypertrophic cardiomyopathy, Hypertrophic cardiomyopathy centers, Palavras-chave: Doenças cardíacas hereditárias, Unidades de doenças cardíacas hereditárias, Miocardiopatia hipertrófica, Centros de miocardiopatia hipertrófica

Platypnea-orthodeoxia syndrome (POS) is an uncommon syndrome characterized by dyspnea and hypoxemia triggered by orthostatism and relieved by recumbency. It is often associated with an interatrial shunt through a patent foramen ovale (PFO). We report the case of a 92-year-old woman initially admitted in the setting of a traumatic femoral neck fracture (successfully treated with hip replacement surgery) in whom a reversible decline in transcutaneous oxygen saturation from 98% (in the supine position) to 84% (in the upright position) was noted early post-operatively. Thoracic multislice computed tomography excluded pulmonary embolism and severe parenchymal lung disease. The diagnosis of POS was confirmed by tilt-table contrast transesophageal echocardiography, which demonstrated a dynamic and position-dependent right-to-left shunt (torrential when semi-upright and minimal in the supine position) through a PFO. The patient underwent percutaneous closure of the PFO with an Amplatzer device, which led to prompt symptom relief and full functional recovery. Resumo: A síndrome platipneia-ortodeoxia (SPO) é uma entidade rara caracterizada por dispneia e hipoxemia desencadeadas pelo ortostatismo e aliviadas pelo decúbito. Está frequentemente associada à presença de um shunt inter-auricular através de um foramen ovale patente (FOP). Relata-se o caso de uma mulher de 92 anos, internada inicialmente por fratura traumática do colo do fémur. Foi submetida a artroplastia da anca sem complicações. No período pós operatório inicial observou-se um declínio reversível da saturação de oxigênio de 98% em decúbito dorsal para 84% na posição ortostática. A angio-tomografia computorizada do tórax excluiu trombo-embolia pulmonar e doença grave do parênquima pulmonar. O diagnóstico de SPO foi confirmado por ecocardiografia transesofágica contrastada (soro agitado) com inclinação na mesa de tilt, que demonstrou um shunt direito-esquerdo dinâmico e posicional (torrencial a 45° e mínimo a 0°) através de um FOP. A doente foi submetida a encerramento percutâneo do FOP com dispositivo Amplatzer, que proporcionou alívio sintomático imediato e permitiu uma recuperação funcional total. Keywords: Platypnea-orthodeoxia syndrome, Tilt table, Transesophageal echocardiography, Percutaneous closure, Patent foramen ovale, Palavras-chave: Síndrome platipneia-ortodeoxia, Inclinação dinâmica, Ecocardiografia transesofágica, Encerramento percutâneo, Foramen ovale patente

Keywords: Cardiology/education; Cardiovascular Diseases/ultrasonography; Cardiovascular Diseases/radiography; Diagnosis, Differential; Echocardiography; Education, Medical, Continuing.

Mesenchymal stem/stromal cells have unique properties favorable to their use in clinical practice and have been studied for cardiac repair. However, these cells are larger than coronary microvessels and there is controversy about the risk of embolization and microinfarctions, which could jeopardize the safety and efficacy of intracoronary route for their delivery. The index of microcirculatory resistance (IMR) is an invasive method for quantitatively assessing the coronary microcirculation status.To examine heart microcirculation after intracoronary injection of mesenchymal stem/stromal cells with the index of microcirculatory resistance.Healthy swine were randomized to receive by intracoronary route either 30x106 MSC or the same solution with no cells (1% human albumin/PBS) (placebo). Blinded operators took coronary pressure and flow measurements, prior to intracoronary infusion and at 5 and 30 minutes post-delivery. Coronary flow reserve (CFR) and the IMR were compared between groups.CFR and IMR were done with a variance within the 3 transit time measurements of 6% at rest and 11% at maximal hyperemia. After intracoronary infusion there were no significant differences in CFR. The IMR was significantly higher in MSC-injected animals (at 30 minutes, 14.2U vs. 8.8U, p = 0.02) and intragroup analysis showed a significant increase of 112% from baseline to 30 minutes after cell infusion, although no electrocardiographic changes or clinical deterioration were noted.Overall, this study provides definitive evidence of microcirculatory disruption upon intracoronary administration of mesenchymal stem/stromal cells, in a large animal model closely resembling human cardiac physiology, function and anatomy.