Deposition of amyloidogenic proteins leading to the formation of amyloid fibrils in the myocardium cause cardiac amyloidosis. Although any form of systemic amyloidosis can affect the heart, light-chain (AL) or transthyretin amyloidosis (ATTR) account for the majority of diagnosed cardiac amyloid deposition. The extent of cardiac disease independently predicts mortality. The reversal or arrest of adverse cardiac remodeling is the target of current therapies, as cardiac-related mortality worsens prognosis in patients where the underlying systemic amyloidosis was successfully treated. Here, we provide a condensed overview on the pathophysiology of AL and ATTR cardiac amyloidoses and describe treatments that are currently used or investigated in clinical or preclinical trials. We also briefly touch on acquired amyloid deposition in cardiovascular disease other than AL or ATTR.
Background/PurposeThis study aims to quantify the utility of monitoring LVEF, hs-cTnT, and NT-proBNP for dynamic cardiotoxicity risk assessment in women with HER2+ early breast cancer undergoing neoadjuvant/adjuvant trastuzumab-based therapy.Materials and methodsWe used joint models of longitudinal and time-to-event data to analyze 1,136 echocardiography reports and 326 hs-cTnT and NT-proBNP measurements from 185 women. Cardiotoxicity was defined as a 10% decline in LVEF below 50% and/or clinically overt heart failure.ResultsMedian pre-treatment LVEF was 64%, and 19 patients (10%) experienced cardiotoxicity (asymptomatic n = 12, during treatment n = 19). The pre-treatment LVEF strongly predicted for cardiotoxicity (subdistribution hazard ratio per 5% increase in pre-treatment LVEF = 0.68, 95%CI: 0.48–0.95, p = 0.026). In contrast, pre-treatment hs-cTnT and NT-proBNP were not consistently associated with cardiotoxicity. During treatment, the longitudinal LVEF trajectory dynamically identified women at high risk of developing cardiotoxicity (hazard ratio per 5% LVEF increase at any time of follow-up = 0.36, 95% CI: 0.2–0.65, p = 0.005). Thirty-four patients (18%) developed an LVEF decline ≥ 5% from pre-treatment to first follow-up (“early LVEF decline”). One-year cardiotoxicity risk was 6.8% in those without early LVEF decline and pre-treatment LVEF ≥ 60% (n = 117), 15.9% in those with early LVEF decline or pre-treatment LVEF < 60% (n = 65), and 66.7% in those with early LVEF decline and pre-treatment LVEF < 60% (n = 3), (Gray’s test p < 0.0001).ConclusionCardiotoxicity risk is low in two thirds of women with HER2+ early breast cancer who have pre-treatment LVEF ≥ 60% and no early LVEF decline > 5% during trastuzumab-based therapy. The longitudinal LVEF trajectory but not hs-cTnT or NT-proBNP allows for a dynamic assessment of cardiotoxicity risk in this setting.
The novel LMNA nonsense mutation c.544C>T causes a severe arrhythmogenic phenotype manifesting with high incidence of SCD in most patients; and in one sub-family, a distinct phenotype with fast progressing heart failure, indicating the need for early consideration of ICD-implantation and listing for heart-transplantation.
PurposeAccumulating evidence points towards a close relationship between cardiovascular, endocrine and metabolic diseases. The BioPersMed Study (Biomarkers of Personalised Medicine) is a single-centre prospective observational cohort study with repetitive examination of participants in 2-year intervals. The aim is to evaluate the predictive impact of various traditional and novel biomarkers of cardiovascular, endocrine and metabolic pathways in asymptomatic individuals at risk for cardiovascular and/or metabolic disease.ParticipantsBetween 2010 and 2016, we recruited 1022 regional individuals into the study. Subjects aged 45 years or older presenting with at least one traditional cardiovascular risk factor or manifest type 2 diabetes mellitus (T2DM) were enrolled. The mean age of the participants was 57±8 years, 55% were female, 18% had T2DM, 33% suffered from arterial hypertension, 15% were smokers, 42% had hyperlipidaemia, and only 26% were at low cardiovascular risk according to the Framingham ‘Systematic COronary Risk Evaluation’.Findings to dateStudy procedures during screening and follow-up visits included a physical examination and comprehensive cardiovascular, endocrine, metabolic, ocular and laboratory workup with biobanking of blood and urine samples. The variety of assessed biomarkers allows a full phenotyping of individuals at cardiovascular and metabolic risk. Preliminary data from the cohort and relevant biomarker analyses were already used as control population for genomic studies in local and international research cooperation.Future plansParticipants will undergo comprehensive cardiovascular, endocrine and metabolic examinations for the next decades and clinical outcomes will be adjudicated prospectively.
Background Monitoring left-ventricular ejection fraction (LVEF) is a routinely-practiced strategy to survey patients with breast cancer (BC) towards cardiotoxic treatment effects. However, whether the LVEF as a single measurement or as a trajectory over time is truly sufficient to identify patients at high risk for cardiotoxicity is currently debated. Purpose To quantify the prognostic impact of LVEF and its change over time for predicting cardiotoxicity in women with HER2+ early BC. Methods We analyzed 1,136 echocardiography reports from 185 HER2+ early BC patients treated with trastuzumab ± chemoimmunoendocrine therapy in the neoadjuvant/adjuvant setting (Table 1). Cardiotoxicity was defined as a 10% decline in LVEF below 50%. Results Median baseline LVEF was 64% (25th-75th percentile: 60–69). Nineteen patients (10%) experienced cardiotoxicity (asymptomatic n=12, symptomatic n=7, during treatment n=19, treatment modification/termination n=14), Median time to cardiotoxicity was 6.7 months, and median LVEF decline in patients with cardiotoxicity was 18%. One-year cardiotoxicity risk was 7.6% in the 35 patients with a baseline LVEF≥60% and 24.5% in the 150 patients with a baseline LVEF<60% (Hazard Ratio (HR)=3.45, 95% CI: 1.35–8.75, Figure 1). During treatment, LVEF declined significantly faster in patients who developed cardiotoxicity than in patients without cardiotoxicity (1.3%/month vs. 0.1%/month, p<0.0001). A higher rate of LVEF decrease predicted for higher cardiotoxicity risk (HR per 0.1%/month higher LVEF decrease/month=2.50, 95% CI: 1.31–4.76, p=0.005), and cardiotoxicity risk increased by a factor of 1.7 per 5% absolute LVEF decline from baseline to first follow-up (HR=1.70, 95% CI: 1.30–2.38, p<0.0001). Thirty-six patients (19%) developed an LVEF decline of at least 5% from baseline to first follow-up (“early LVEF decline”). One-year cardiotoxicity risk was 6.8% in those without early LVEF decline and a baseline LVEF≥60% (n=117), 15.7% in those without an early LVEF decline and a baseline LVEF<60% (n=65), and 66.7% in those with an early LVEF decline and a baseline LVEF<60% (n=3), respectively (log-rank p<0.0001). Table 1. Baseline characteristics Age (years, median [IQR]) 55 [49–65] Estrogen receptor positive (n, %) 124 (67%) Neoadjuvant setting (n, %) 103 (56%) Figure 1. Risk of Cardiotoxicity. Conclusion Both a single LVEF measurement and the rate of LVEF decrease strongly predict cardiotoxicity in early BC patients undergoing HER2-targeted therapy. Routine LVEF monitoring identifies individuals at high risk of cardiotoxicity that may benefit from more sensitive screening techniques such as strain imaging.
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