Advances in the Treatment of Cardiac Amyloidosis.

OPINION STATEMENT: Cardiac amyloidosis is associated with a high mortality rate, a long delay between the first signs and the diagnosis but a short interval between diagnosis and death. This scenario has changed recently due to improved disease awareness among doctors and significant progress in diagnosis thanks to multimodal imaging and a multidisciplinary approach. Therefore, during the last few years, we have had access to specific therapies for those patients. Those therapies are quite different depending on the type of amyloidosis, but there has been real progress. Systemic light chain amyloidosis (AL) with cardiac involvement is the most common form of cardiac amyloidosis. The severity of heart disease dictates the prognosis in AL amyloidosis. Advances in chemotherapy and immunotherapy that suppress light chain production have improved the outcomes. These recent improvements in survival rates have enabled therapies such as implanted cardiac defibrillators and heart transplantation that were usually not indicated for patients with advanced light chain amyloid cardiomyopathy to now be applied in selected patients. For transthyretin amyloidosis (ATTR), the second most common form of amyloidosis with cardiac involvement, there is also significant progress in treatment. Until recently, we had no specific therapy for ATTR cardiomyopathy (ATTR-CM), though now disease-modifying therapies are available. Therapies that stabilize transthyretin, such as tafamidis, have been shown to improve outcomes for patients with ATTR-CM. Modern treatments that stop the synthesis of TTR through gene silencing, such as patisiran and inotersen, have shown positive results for patients with TTR amyloidosis. Significant progress has been made in the treatment of amyloid cardiomyopathy, and hopefully, we will see even more progress with the spread of those treatments. We now can be optimistic about patients with this disease.

The Use of a Wheelchair Propulsion Field Test to Determine Peak Heart Rate in Children and Adolescents With Myelomeningocele.

PURPOSE: We analyzed the evolution and pattern of heart rate (HR) during the 12-minute wheelchair propulsion field test (WPFT) and compared the peak HR (HRpeak) from the WPFT to the HRpeak obtained in the progressive cardiopulmonary exercise test on arm cranking ergometer (ACT). We aimed to determine if the field test detects the HRpeak consistently and could be used in clinical practice. METHODS: Eleven wheelchair-using children and adolescents with myelomeningocele (aged 8-15 y) performed a maximal ACT and a 12-minute WPFT. HR was recorded continuously at rest, during each minute of the tests, and at recovery. Mixed analysis of variance was used to compare the variables at rest and peak. Bland-Altman plot and Lin's concordance correlation coefficient were used to show agreement between the tests. RESULTS: During minute 2 of the WPFT, participants reached 73%-96% of the HRpeak values recorded in the ACT. From minutes 4 to 12, participants reached HRpeak values ranging 86%-109% of the values recorded in the ACT. There is agreement between the ACT and the WPFT tests. CONCLUSION: WPFT with minimal duration of 4 minutes may be an alternative tool to obtain HRpeak in children and adolescents with myelomeningocele.

Comparative Analysis of ECG and Holter Monitoring in the Assessment of Heart Rate in Heart Failure with Reduced Ejection Fraction and Sinus Rhythm. / Análise Comparativa do ECG com o Holter na avaliação da Frequência Cardíaca na Insuficiência Cardíaca com Fração de Ejeção Reduzida e Ritmo Sinusal.

BACKGROUND: Heart rate (HR) has shown prognostic value in patients with heart failure with reduced ejection fraction (HFrEF) and sinus rhythm. However, the method of measurement is debated in the literature. OBJECTIVES: To compare HR on Holter with 3 resting electrocardiograms (ECG1, ECG2, and ECG3) in patients with HFrEF and sinus rhythm. METHODS: This was a cross-sectional study with 135 patients with heart failure with ejection fraction ≤ 40% and sinus rhythm. HR was assessed by ECG and Holter. Analyses included intraclass correlation coefficient (ICC), robust regression, root mean squared error, Bland-Altman, and area under the receiver operating characteristic (ROC) curve. A significance level of 0.05 and Bonferroni-Holm adjustment were adopted to minimize type I errors. RESULTS: The median [interquartile range] age and ejection fraction were 65 years [16] and 30% [11], respectively. The ICC of the 3 ECGs was 0.922 (95% confidence interval: 0.892; 0.942). The robust regression coefficients for ECG1 and ECG3 were 0.20 (95% confidence interval: 0.12; 0.29) and 0.21 (95% confidence interval: 0.06; 0.36). The robust R2 was 0.711 (95% confidence interval: 0.628; 0.76). In the Bland-Altman agreement analysis, the limits of agreement were -17.0 (95% confidence interval: -19.0; -15.0) and 32.0 (95% confidence interval: 30.0; 34.0). The area under the ROC curve was 0.896 (95% confidence interval: 0.865; 0.923). CONCLUSION: The HR on ECG showed high agreement with the HR on Holter, validating its clinical use in patients with HFrEF and sinus rhythm. However, agreement was suboptimal in one third of patients with HR below 70 bpm on ECG; thus, 24-hour Holter monitoring should be considered in this context.

FUNDAMENTO: A frequência cardíaca (FC) na insuficiência cardíaca com fração de ejeção reduzida (ICFEr) e ritmo sinusal apresenta valor prognóstico. Entretanto, o método de mensuração é debatido na literatura. OBJETIVOS: Comparar em pacientes com ICFEr e ritmo sinusal a FC no Holter com três eletrocardiogramas de repouso: ECG1, ECG2 e ECG3. METODOLOGIA: Estudo transversal com 135 pacientes portadores de insuficiência cardíaca com fração de ejeção ≤ 40% e ritmo sinusal. A FC foi avaliada por ECG e Holter. Análises incluíram o coeficiente de correlação intraclasse (CCI), regressão robusta, raiz do erro quadrático médio, Bland-Altman e a área sobre a curva ROC. Adotou-se nível de significância de 0,05 e o ajuste de Bonferroni-Holm para minimizar erros tipo I. RESULTADOS: As medianas [intervalo interquartil] de idade e fração de ejeção foram de 65 anos [16] e 30% [11], respectivamente. O CCI dos 3 ECG foi de 0,922 (intervalo de confiança de 95%: 0,892; 0,942). Os coeficientes de regressão robusta para ECG1 e ECG3 foram 0,20 (intervalo de confiança de 95%: 0,12; 0,29) e 0,21 (intervalo de confiança de 95%: 0,06; 0,36). O R2 robusto foi de 0,711 (intervalo de confiança de 95%: 0,628; 0,76). Na análise de concordância de Bland-Altman, os limites de concordância foram de −17,0 (intervalo de confiança de 95%: −19,0; −15,0) e 32,0 (intervalo de confiança de 95%: 30,0; 34,0). A área sob a curva ROC foi de 0,896 (intervalo de confiança de 95%: 0,865; 0,923). CONCLUSÃO: A FC do ECG mostrou alta concordância com a FC do Holter, validando seu uso clínico em pacientes com ICFEr e ritmo sinusal. Contudo, a concordância foi subótima em um terço dos pacientes com FC inferior a 70 bpm pelo ECG, devendo ser considerada a realização de Holter neste contexto.

Clinical and genetic profiles of patients with hereditary and wild-type transthyretin amyloidosis: the Transthyretin Cardiac Amyloidosis Registry in the state of São Paulo, Brazil (REACT-SP).

BACKGROUND: Transthyretin amyloidosis (ATTR) is a multisystem disease caused by the deposition of fibrillar protein in organs and tissues. ATTR genotypes and phenotypes are highly heterogeneous. We present data on physical signs and symptoms, cardiac and neurological assessments and genetic profile of patients enrolled in the Transthyretin Cardiac Amyloidosis Registry of the State of São Paulo, Brazil. RESULTS: Six hundred-forty-four patients were enrolled, 505 with the variant form (ATTRv) and 139 with wild-type (ATTRwt). Eleven different mutations were detected, the most common being Val50Met (47.5%) and V142Ile (39.2%). Overall, more than half of the patients presented cardiac involvement, and the difference in this proportion between the ATTRv and ATTRwt groups was significant (43.9 vs. 89.9%; p < 0.001). The prevalence of the neurological phenotype also differed between ATTRv and ATTRwt (56.8 vs. 31.7%; p < 0.001). The mixed phenotype was found in 25.6% of the population, without a significant difference between ATTRv and ATTRwt groups. A group of patients remained asymptomatic (10.4%), with a lower proportion of asymptomatic ATTRwt patients. CONCLUSIONS: This study details the clinical and genetic spectrum of patients with ATTR in São Paulo, Brazil. This preliminary analysis highlights the considerable phenotypic heterogeneity of neurological and cardiac manifestations in patients with variant and wild-type ATTR.

Age-dependent impairment in antibody responses elicited by a homologous CoronaVac booster dose.

The emergence of the SARS-CoV-2 Omicron sublineages resulted in increased transmission rates and reduced protection from vaccines. To counteract these effects, multiple booster strategies were used in different countries, although data comparing their efficiency in improving protective immunity remain sparse, especially among vulnerable populations, including older adults. The inactivated CoronaVac vaccine was among the most widely distributed vaccine worldwide and was essential in the early control of SARS-CoV-2-related hospitalizations and deaths. However, it is not well understood whether homologous versus heterologous booster doses in those fully vaccinated with CoronaVac induce distinct humoral responses or whether these responses vary across age groups. We analyzed plasma antibody responses from CoronaVac-vaccinated younger or older individuals who received a homologous CoronaVac or heterologous BNT162b2 or ChAdOx1 booster vaccine. All three evaluated boosters resulted in increased virus-specific IgG titers 28 days after the booster dose. However, we found that both IgG titers against SARS-CoV-2 Spike or RBD and neutralization titers against Omicron sublineages were substantially reduced in participants who received homologous CoronaVac compared with the heterologous BNT162b2 or ChAdOx1 booster. This effect was specifically prominent in recipients >50 years of age. In this group, the CoronaVac booster induced low virus-specific IgG titers and failed to elevate neutralization titers against any Omicron sublineage. Our results point to the notable inefficiency of CoronaVac immunization and boosting in mounting protective antiviral humoral immunity, particularly among older adults, during the Omicron wave. These observations also point to benefits of heterologous regimens in high-risk populations fully vaccinated with CoronaVac.

Circulatory and ventilatory power in diabetic patients: Secondary analysis of a randomized controlled trial.

BACKGROUND: Circulatory (CP) and ventilatory power (VP) have been used to improve the prognostic accuracy of cardiopulmonary exercise tests in cardiovascular disease, such as coronary artery disease. However, the effects of combined resistance and aerobic exercise program on VP and CP, especially in type 2 diabetes patients, have not been adequately investigated. Thus, this new parameter can be useful to prescribe exercise programs more assertive for this population. The present study aimed to assess the effect of 3 months of combined resistance and aerobic exercise training (CET) on CP and VP in patients with type 2 diabetes. METHODS: A randomized controlled trial was conducted involving 48 diabetic patients with an average age of 52.4 (±8.01) years old. The subjects were randomized into two groups: sedentary (SG, n = 15) and the CET group (n = 19). Cardiopulmonary exercise testing (symptom-limited incremental) was performed on a cycle ergometer, and the following parameters were measured: relative VO2 , VE /VCO2 slope, linear relationship between oxygen uptake and minute ventilation, and VCO2 . CET was performed with 30-min aerobic and 30-min resistance exercises three times a week for 12 weeks. RESULTS: Significant (p < .05) and clinical (d ≥ .80) differences were observed that favoured CET compared with SG for the following variables: heart rate, workload, VO2 relative peak, circulatory power peak, and VCO2 peak. Although no statistical difference was observed for ventilatory power, there was a clinical difference (p > .05 and d ≥ 0.80) that favoured CET. CONCLUSION: Three months of combined exercise training improved VP and CP indices in patients with type 2 diabetes when compared with a sedentary group.

A normal sodium diet preserves serum sodium levels during treatment of acute decompensated heart failure: A prospective, blind and randomized trial.

BACKGROUND: We tested the hypothesis that a normal sodium diet could be associated with preservation of serum sodium during treatment of acute decompensated heart failure (ADHF). METHODS AND RESULTS: Forty-four patients hospitalized for ADHF were blindly randomized by using block method to a low sodium diet (LS: 3 g/day of dietary sodium chloride; n = 22, 59.5 ± 11.9 y.o., 50% males. LVEF = 30.0 ± 13.6%); and a normal sodium diet (NS: 7 g/day; n = 22, 56.4 ± 10.3 y.o., 68% males; LVEF = 27.8 ± 11.7%), and both groups were submitted to fluid restriction of 1.000 mL/day. At the 7th day of intervention 16 patients of LS group and 15 patients of NS group were assessed for difference in serum sodium. Both groups had equivalent decongestion, reflected by similar percent reduction of body weight (LS: -5.0 ± 4.7% vs NS: -4.5 ± 5.2%. p = 0.41). Reduction of the N terminal fragment of type B natriuretic peptide (NT-proBNP) was significant only in the NS (-1497.0 [-18843.0 - 1191.0]. p = 0.04). The LS group showed lower levels of serum sodium (135.4 ± 3.5 mmol/L) compared to the NS group (137.5 ± 1.9 mmol/L; p = 0.04). Four cases of hyponatremia were observed only in the LS group (22%). The NS group exhibited higher mean blood pressure values (79.4 ± 2.4 mmHg vs 75.5 ± 3.0 mmHg. p = 0.03), and lower heart rate (73.2 ± 1.6 bpm vs 75.5 ± 2.1 bpm. p = 0.02). CONCLUSIONS: These results suggest that a normal sodium diet, when compared to a low sodium diet, is associated with similar degrees of decongestion, but with higher levels of natremia, blood pressure and lower neurohormonal activation during ADHF treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier no. NCT03722069.

Análise Comparativa do ECG com o Holter na avaliação da Frequência Cardíaca na Insuficiência Cardíaca com Fração de Ejeção Reduzida e Ritmo Sinusal / Comparative Analysis of ECG and Holter Monitoring in the Assessment of Heart Rate in Heart Failure with Reduced Ejection Fraction and Sinus Rhythm

Resumo Fundamento A frequência cardíaca (FC) na insuficiência cardíaca com fração de ejeção reduzida (ICFEr) e ritmo sinusal apresenta valor prognóstico. Entretanto, o método de mensuração é debatido na literatura. Objetivos Comparar em pacientes com ICFEr e ritmo sinusal a FC no Holter com três eletrocardiogramas de repouso: ECG1, ECG2 e ECG3. Metodologia Estudo transversal com 135 pacientes portadores de insuficiência cardíaca com fração de ejeção ≤ 40% e ritmo sinusal. A FC foi avaliada por ECG e Holter. Análises incluíram o coeficiente de correlação intraclasse (CCI), regressão robusta, raiz do erro quadrático médio, Bland-Altman e a área sobre a curva ROC. Adotou-se nível de significância de 0,05 e o ajuste de Bonferroni-Holm para minimizar erros tipo I. Resultados As medianas [intervalo interquartil] de idade e fração de ejeção foram de 65 anos [16] e 30% [11], respectivamente. O CCI dos 3 ECG foi de 0,922 (intervalo de confiança de 95%: 0,892; 0,942). Os coeficientes de regressão robusta para ECG1 e ECG3 foram 0,20 (intervalo de confiança de 95%: 0,12; 0,29) e 0,21 (intervalo de confiança de 95%: 0,06; 0,36). O R2 robusto foi de 0,711 (intervalo de confiança de 95%: 0,628; 0,76). Na análise de concordância de Bland-Altman, os limites de concordância foram de −17,0 (intervalo de confiança de 95%: −19,0; −15,0) e 32,0 (intervalo de confiança de 95%: 30,0; 34,0). A área sob a curva ROC foi de 0,896 (intervalo de confiança de 95%: 0,865; 0,923). Conclusão A FC do ECG mostrou alta concordância com a FC do Holter, validando seu uso clínico em pacientes com ICFEr e ritmo sinusal. Contudo, a concordância foi subótima em um terço dos pacientes com FC inferior a 70 bpm pelo ECG, devendo ser considerada a realização de Holter neste contexto.

Abstract Background Heart rate (HR) has shown prognostic value in patients with heart failure with reduced ejection fraction (HFrEF) and sinus rhythm. However, the method of measurement is debated in the literature. Objectives To compare HR on Holter with 3 resting electrocardiograms (ECG1, ECG2, and ECG3) in patients with HFrEF and sinus rhythm. Methods This was a cross-sectional study with 135 patients with heart failure with ejection fraction ≤ 40% and sinus rhythm. HR was assessed by ECG and Holter. Analyses included intraclass correlation coefficient (ICC), robust regression, root mean squared error, Bland-Altman, and area under the receiver operating characteristic (ROC) curve. A significance level of 0.05 and Bonferroni-Holm adjustment were adopted to minimize type I errors. Results The median [interquartile range] age and ejection fraction were 65 years [16] and 30% [11], respectively. The ICC of the 3 ECGs was 0.922 (95% confidence interval: 0.892; 0.942). The robust regression coefficients for ECG1 and ECG3 were 0.20 (95% confidence interval: 0.12; 0.29) and 0.21 (95% confidence interval: 0.06; 0.36). The robust R2 was 0.711 (95% confidence interval: 0.628; 0.76). In the Bland-Altman agreement analysis, the limits of agreement were −17.0 (95% confidence interval: −19.0; −15.0) and 32.0 (95% confidence interval: 30.0; 34.0). The area under the ROC curve was 0.896 (95% confidence interval: 0.865; 0.923). Conclusion The HR on ECG showed high agreement with the HR on Holter, validating its clinical use in patients with HFrEF and sinus rhythm. However, agreement was suboptimal in one third of patients with HR below 70 bpm on ECG; thus, 24-hour Holter monitoring should be considered in this context.

Avaliação e manejo clínico da disfunção de ventrículo direito na insuficiência cardíaca refratária / Assessment and clinical management of right ventricular dysfunction in advanced heart failure

A Insuficiência Cardíaca (IC) refratária pode ser definida como uma condição clínica crônica, como sintomas limitantes, acentuando comprometimento hemodinâmico e elevada mortalidade. Nesse contexto, a disfunção Ventricular Direita (VD)pode ser um aspecto clínico saliente, comumente dominando o quadro clínico. Em contraste com a falência ventricular esquerda, a disfunção do VD permanece praticamente ignorada, com escassas orientações em diretrizes para o manejo dessa condição clínica. Um dos mais importantes fatores determinantes da disfunção ventricular direita neste cenário é o aumento da pós-carga ventricular direita devido à hipertensão arterial pulmonar, que, por sua vez, é secundária à congestão pulmonar venosa crônica atribuída à falência ventricular esquerda. Essa disfunção de VD possui forte correlação com aumento da mortalidade. Apesar da falta de recomendações nas diretrizes, é um conceito embasado em aspectos clínicos e fisiopatológicos que o tratamento otimizado da IC esquerda é o primeiro passo necessário no manejo da disfunção do VD. Não existe terapia especificamente direcionada para o tratamento da insuficiência cardíaca direita, mas a terapêutica recomendada para o tratamento da disfunção do VE promove redução da pressão capilar pulmonar, da pressão da artéria pulmonar e consequente melhora da disfunção do VD, sendo estes pontos mais efetivos do tratamento. O racional do tratamento da disfunção do VD contempla três elementos da fisiologia cardiovascular: a pré-carga, a contratilidade e a pós-carga. Além disso, novas alternativas terapêuticas têm emergido, como inibidores de fosfodiesterase-5, terapia de ressincronização e dispositivos de assistência ventricular, mas que ainda carecem de estudos mais amplos para a implementação na prática clínica.

Advanced Heart Failure (HF) can be defined as a chronic medical, conditions, whit limiting symptons, severe hemodynamic impairment and high mortality. In this context, the Right Ventricular (RV) dysfunction can be a salient clinical aspect, and commonly dominate the clinical scenario. In contrast to left ventricular failure, RV dysfunction remains largely ignored, with little recommendations in the guidelines for the management of this conditions. one of the most important determinats of right ventricular dysfunction in this scenario is the increased right ventricular afterload due to pulmonary arterial hypertension, which is secondary to chronic pulmonary venous congestion attribuited to left ventricular failure. This form of RV dysfunction is strongly carrelated with increased mortality. Despite the lack of recommendations in the guidelines, it is a concept based on clinical and pathophysiological aspects that optimal treatment of left ventricular failure is the first necessary step in the management of RV failure. There is no specifically targeted for the treatment of right heart failure, but the recommended therapy for the treatment of LV dysfunction causes a reduction in pulmonary capillary wedge pressure, pulmonary artery pressure and consequent improvement in RV dysfunction, which are the most effective points of the treatment of RV dysfunction has three elements of cardiovascular physiology: the preload, contractility and afterload. Furthermore, new therapieshave recently emerged such as phosphodiesterase-5 inhibitors, cardiac resynchronization therapy and ventricular assist devices, but they still require further studies for implementation in clinical practice.