Impact of the Noninvasive Diagnostic Algorithm on Clinical Presentation and Prognosis in Cardiac Amyloidosis.

Background: The introduction of a noninvasive diagnostic algorithm in 2016 led to increased awareness and recognition of cardiac amyloidosis (CA). Objectives: The purpose of this study was to analyze the impact of the introduction of the noninvasive diagnostic algorithm on diagnosis and prognosis in a multicenter Italian CA cohort. Methods: This was a retrospective analysis of 887 CA patients from 5 Italian Cardiomyopathies Referral Centers: 311 light-chain CA, 87 variant transthyretin (TTR)-related CA, 489 wild-type TTR-related CA. Clinical characteristics and outcomes (all-cause mortality and heart failure [HF] hospitalizations) were compared overall and for each CA subtype between patients diagnosed before versus after 2016. Outcomes were further compared by propensity score weighted Kaplan-Meier analysis and Cox regression analysis. Results: CA diagnoses increased after 2016, in particular for wild-type TTR-related CA. Patients diagnosed after versus before 2016 were older, had less frequently a history of HF prior to diagnosis, and NYHA functional class III-IV at diagnosis. Over a median follow-up of 18 months, 172 (86%) patients diagnosed before 2016 died or had an HF hospitalization, versus 300 (44%) diagnosed after 2016. Propensity score weighted Kaplan-Meier analysis showed worse outcomes (P < 0.001) for patients diagnosed before 2016. At Cox regression analysis, CA diagnosis after 2016 was an independent protective factor for the composite outcome (HR: 0.69; P = 0.001), with interaction by CA subtype (significant in TTR-related CA and null in light-chain). Conclusions: CA patients diagnosed after 2016 showed a less severe phenotype and a better prognosis. The impact of the noninvasive diagnostic algorithm on outcomes was particularly relevant in TTR-related CA.

Early diagnosis, disease stage and prognosis in wild-type transthyretin amyloid cardiomyopathy: The DIAMOND study.

AIMS: Disease staging and prognostic scoring in wild-type transthyretin-related cardiac amyloidosis (ATTRwt-CA) can be captured by two systems (NAC and Columbia scores). However, uncertainty remains as epidemiology of the disease is evolving rapidly. We evaluated features associated with staging systems across ATTRwt-CA patients from different diagnostic pathways, and their association with prognosis. METHODS: We performed an analysis on DIAMOND patients with available data to evaluate NAC and Columbia score. DIAMOND was a retrospective study from 17 Italian referral centres for CA, enrolling 1281 patients diagnosed between 2016 and 2021, and aimed at describing characteristics of pathways leading to ATTRwt-CA diagnosis. Of the original cohort, 811 patients were included in this analysis. Each patient had NAC and Columbia score calculated. Patients were grouped according to NAC and Columbia scoring classes. We described characteristics of patients according to staging classes and diagnostic pathways at diagnosis. Prevalence of early diagnoses, defined as NAC Ia, NYHA class I, no use of diuretics, no history of heart failure (HF) hospitalizations nor of atrial fibrillation prior to diagnosis, was investigated. Finally, prognostic variables were tested alone and grouped as NAC or Columbia scores in Cox univariate and multivariate regression analyses. Prognosis was investigated as all-cause mortality, in the whole population and dividing patients in HF versus other diagnostic pathways. RESULTS: Only 1% of the study population had an early ATTRwt-CA diagnosis. Distribution of prognostic variables and of NAC and Columbia classes was heterogeneous across diagnostic pathways. The prevalence of NAC III and Columbia III was higher in the HF diagnostic pathway, but all NAC and Columbia classes were present in all pathways. Both NAC and Columbia scores were associated with all-cause mortality at univariate Cox regression analysis in the whole population, in patients from the HF diagnostic pathway and in those from other pathways. At multivariate analysis, Columbia score remained significantly associated with the outcome, together with age at diagnosis, left ventricular ejection fraction and maximal wall thickness. CONCLUSIONS: In this contemporary nationwide cohort, an ATTRwt-CA early diagnosis was very rare. Disease staging with NAC and Columbia scoring systems determined classes of patients with heterogeneous features. Both scores were significantly associated with mortality, but other variables also had prognostic significance.

Standard Therapy in Cardiac Amyloidosis: What is Known, What is "Gray".

Amyloidosis is a systemic disease due to the accumulation of misfolded amyloid fibrils that damage the heart and worsen the prognosis. Heart failure (HF), a condition frequently linked with an advanced stage of this disease, is the most prevalent clinical manifestation that leads to its diagnosis. However, due to the growing awareness of the occurrence of cardiac amyloidosis (CA), it is now possible to perform an early diagnosis and have a positive impact on its natural course. This study aims to highlight the most compelling issues concerning patients' clinical management with HF and CA.

Screening for cardiac amyloidosis in patients with tenosynovial red flags: A collaboration between family medicine and cardiology.

BACKGROUND: Amyloid deposition in tenosynovial structures precedes cardiac involvement up to 20 years. Therefore, a cardiological screening in patients with a history of tenosynovial manifestations of cardiac amyloidosis (CA) could lead to an increased number of early diagnoses. METHODS: Patients with tenosynovial manifestations of CA (carpal tunnel syndrome, atraumatic biceps tendon rupture, lumbar spinal stenosis) have been identified by general practitioners and evaluated in a Referral Center for CA. Patients with a high suspicion of CA underwent the CA diagnostic pathway. RESULTS: Among 50 General Practitioners (GP) contacted, 10 (20%) agreed to participate in the study for a total of 5615 patients ≥60 years. One hundred forty-five patients met the inclusion criteria, 2 of them already had a diagnosis of CA, and 57 agreed to undergo a cardiological evaluation (electrocardiography, echocardiography, NTproBNP assay). The median age was 73 [67-80] years and 31 (54%) were women. Eight patients were suggested to start the CA diagnostic pathway, five of them underwent a complete diagnostic evaluation for CA, three refused to complete the diagnostic exams and no new diagnoses were made. CONCLUSION: A screening program for CA in patients with tenosynovial manifestations identified by general practitioners is feasible, but may not yield a high rate of new diagnosis. In this study, we identified two patients who already had a diagnosis of CA, and among patients at high risk for CA, 37% refused to complete the diagnostic pathway. Increased awareness of CA among patients might increase participation and diagnostic yield in screening studies. Further validation of this protocol is needed to evaluate its diagnostic performance.

Atrial electrofunctional predictors of incident atrial fibrillation in cardiac amyloidosis.

BACKGROUND: Atrial fibrillation (AF) is common in patients with cardiac amyloidosis (CA) and is a significant risk factor for heart failure hospitalization and thromboembolic events. OBJECTIVE: This study was designed to investigate the atrial electrofunctional predictors of incident AF in CA. METHODS: A multicenter, observational study was conducted in 4 CA referral centers including sinus rhythm patients with light-chain (AL) and transthyretin (ATTR) CA undergoing electrocardiography and cardiac magnetic resonance imaging. The primary end point was new-onset AF occurrence. RESULTS: Overall, 96 patients (AL-CA, n = 40; ATTR-CA, n = 56) were enrolled. During an 18-month median follow-up (Q1-Q3, 7-29 months), 30 patients (29%) had incident AF. Compared with those without AF, patients with AF were older (79 vs 73 years; P = .001). They more frequently had ATTR (87% vs 45%; P < .001); electrocardiographic interatrial block (IAB), either partial (47% vs 21%; P = .011) or advanced (17% vs 3%; P = .017); and lower left atrial ejection fraction (LAEF; 29% vs 41%; P = .004). Age (hazard ratio [HR], 1.059; 95% CI, 1.002-1.118; P = .042), any type of IAB (HR, 2.211; 95% CI, 1.03-4.75; P = .041), and LAEF (HR, 0.967; 95% CI, 0.936-0.998; P = .044) emerged as independent predictors of incident AF. Patients exhibiting any type of IAB, LAEF <40%, and age >78 years showed a cumulative incidence for AF of 40% at 12 months. This risk was significantly higher than that carried by 1 (8.5%) or none (7.6%) of these 3 risk factors. CONCLUSION: In patients with CA, older age, IAB on 12-lead electrocardiography, and reduced LAEF on cardiac magnetic resonance imaging are significant and independent predictors of incident AF. A closer screening for AF is advisable in CA patients carrying these features.

Serial Changes in Cardiopulmonary Exercise Testing Parameters in Untreated Patients With Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is associated with a progressive reduction of functional capacity. The progression of cardiopulmonary exercise testing (CPET) parameters over time is still unknown. METHODS: In this study, 55 patients with ATTR-CM underwent 2 serial cardiologic evaluations and CPETs in a national referral center for cardiac amyloidosis (Careggi University Hospital, Florence). RESULTS: Forty-three patients (78%) had wild-type ATTR. Median age was 80 years (interquartile range [IQR] 76-83 years), and 50 of the patients (91%) were men. At baseline, median peak oxygen consumption (pVO2) was 15 mL/kg/min (IQR 12-18 mL/kg/min), percentage of predicted pVO2 (%ppVO2) was 71% (IQR 60%-83%) and VE/VCO2 slope was 31 (IQR 26-34). After a median follow-up of 14 months (IQR 13-16 months), pVO2, %ppVO2 and VE/VCO2 slope were significantly worsened (-1.29 mL/kg/min [95% confidence interval (CI): -1.85 to -0.74; P < 0.01], -4.5% [95% CI: -6.9 to -2.02; P < 0.01], and 8.6 [95% CI 6-11; P < 0.01], respectively). Furthermore, exercise time (-39 s, 95% CI: -59 to -19; P < 0.01), exercise tolerance (-0.47 metabolic equivalents, 95% CI: -0.69 to -0.2; P < 0.01), and peak systolic pressure (-10.8 mm Hg, 95% CI: -16.2 to -5.4; P < 0.01) were significantly reduced. The worsening in CPET variables did not correspond with a significant change in echocardiographic parameters. CONCLUSIONS: Cardiorespiratory response to exercise significantly worsened over a short period of time in patients with ATTR-CM. Serial CPET may be useful to identify early disease progression.

[Therapeutic approaches in hypertrophic cardiomyopathy: from symptom relief to precision therapy]. / Approcci terapeutici nella cardiomiopatia ipertrofica: dal controllo dei sintomi alla terapia di precisione.

Hypertrophic cardiomyopathy is the most common genetic cardiomyopathy. Main complications include the development of arrhythmias and heart failure, and the latter may be triggered by left ventricular outflow tract obstruction. The treatment of left ventricular outflow tract obstruction includes pharmacological therapies (beta-blockers, calcium channel blockers, disopyramide) and septal reduction therapies (alcohol septal ablation, surgical myectomy). Myosin inhibitors represent a new therapeutic opportunity and in recent clinical trials proved effective in symptom relief, improvement of functional capacity and quality of life in patients with obstructive hypertrophic cardiomyopathy. In this narrative review we will summarize the available and under development therapeutic approaches for hypertrophic cardiomyopathy.

Stage-specific therapy for hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited myocardial disease and is defined by otherwise unexplained left ventricular hypertrophy. The main complications include heart failure and arrhythmias such as atrial fibrillation and ventricular arrhythmias. Current treatment rests on septal reduction therapies, prevention of sudden cardiac death through implantable cardioverter defibrillator, and use of drugs such as beta-blockers, calcium antagonists, or amiodarone. In the last years, new pharmacological agents specifically targeting the pathophysiology of the disease have been developed with encouraging results in terms of functional capacity and symptoms improvement from clinical trials. In this review, we summarize the possible treatment approaches for each phase of the natural history of the disease: pre-phenotype expression, classic phenotype, adverse remodelling, and overt dysfunction.

Prevalence of transthyretin-related amyloidosis in Tuscany: Data from the regional population-based registry.

The limited available data regarding the prevalence of transthyretin amyloidosis, both for wild-type (ATTRwt) and hereditary form (ATTRv), is inferred from highly selected patients and subsequent extrapolations that limit the comprehension of the clinical disease impact. The Tuscan healthcare system in 2006 developed a web-based rare disease registry, to monitor and profile patients affected by rare diseases. Clinicians belonging to regional validated healthcare data centres can register patients at the diagnosis, with a rigorous approach and distinguishing the types of amyloidosis, i.e., ATTRwt versus ATTRv. Thanks to this data collection method, available from July 2006 and extended with electronic therapy plans related to a diagnosis since May 2017, we analysed prevalence and incidence of ATTR and its subtypes. On November 30th 2022, ATTRwt prevalence in Tuscany is 90.3 per 1,000,000 persons and ATTRv prevalence is 9.5 per 1,000,000 persons, whereas the annual incidence ranges from 14.4 to 26.7 per 1,000,000 persons and from 0.8 to 2.7 per 1,000,000 persons, respectively. The male gender is predominant in both forms. All except one patient showed evidence of cardiomyopathy. This epidemiological data requires attention, not only to increase the effort for the clinical management and earlier diagnosis, but also to underline the need for the disease-specific treatments.

Diagnostic pathways to wild-type transthyretin amyloid cardiomyopathy: a multicentre network study.

AIM: Epidemiology of wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) remains poorly defined. A better characterization of pathways leading to ATTRwt-CA diagnosis is of key importance, and potentially informative of disease course and prognosis. The aim of this study was to describe the characteristics of contemporary pathways leading to ATTRwt-CA diagnosis, and their potential association with survival. METHODS AND RESULTS: This was a retrospective study of patients diagnosed with ATTRwt-CA at 17 Italian referral centres for CA. Patients were categorized into different 'pathways' according to the medical reason that triggered the diagnosis of ATTRwt-CA (hypertrophic cardiomyopathy [HCM] pathway, heart failure [HF] pathway, incidental imaging or incidental clinical pathway). Prognosis was investigated with all-cause mortality as endpoint. Overall, 1281 ATTRwt-CA patients were included in the study. The diagnostic pathway leading to ATTRwt-CA diagnosis was HCM in 7% of patients, HF in 51%, incidental imaging in 23%, incidental clinical in 19%. Patients in the HF pathway, as compared to the others, were older and had a greater prevalence of New York Heart Association (NYHA) class III-IV and chronic kidney disease. Survival was significantly worse in the HF versus other pathways, but similar among the three others. In multivariate model, older age at diagnosis, NYHA class III-IV and some comorbidities but not the HF pathway were independently associated with worse survival. CONCLUSIONS: Half of contemporary ATTRwt-CA diagnoses occur in a HF setting. These patients had worse clinical profile and outcome than those diagnosed either due to suspected HCM or incidentally, although prognosis remained primarily related to age, NYHA functional class and comorbidities rather than the diagnostic pathway itself.

Anxious/Depressive Symptoms Alter the Subjective Perception of Heart Failure Severity in Transthyretin Cardiac Amyloidosis.

The subjective perception of cardiac symptom severity is considered a main treatment target in the management of transthyretin-related cardiac amyloidosis (CA), as opposed to objective prognostic markers such as N-terminal pro b-type natriuretic peptide (NT-proBNP), which objectively reflects the severity of heart disease. Nevertheless, anxious and depressive symptoms in patients with CA might affect subjects perceptions of disease, creating a potential gap between objective and subjective parameters. We assess the impact of such bias in consecutive patients with CA. A total of 60 patients aged 62 to 88 years with CA were recruited. The level of anxiety and depression was measured by the Hospital Anxiety and Depression Scale and the subjective perception of symptoms severity by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Finally, NT-proBNP plasma levels at rest and glomerular filtration rate were measured. Nearly 1/2 of the patients (48%) reported clinically relevant levels of psychologic symptoms. Higher levels of anxious and depressive symptoms were significantly linked to lower KCCQ scores. Furthermore, the relation between NT-proBNP and KCCQ was significant only when anxious and depressive symptoms were low (ß = -0.86, p = 0.002; ß = -0.86, p = 0.002, respectively) and medium (ß = -0.49, p = 0.004; ß = -0.45, p = 0.004, respectively) but was otherwise lost. Depression and anxiety in patients with transthyretin-related CA required assessment and management. In conclusion, patients with depression/anxiety have a clear disconnect between their personal assessment and objective measures of cardiac symptoms, with a major influence on the patients' wellbeing and on their subjective response to treatments in clinical trials.

Prognostic value of cardiopulmonary exercise testing in patients with transthyretin cardiac amyloidosis.

The aim of this study is to evaluate the prognostic value of cardiopulmonary testing (CPET) in a cohort of patients with transthyretin cardiac amyloidosis (ATTR-CA). ATTR-CA is associated with a progressive reduction in functional capacity. The prognostic role of CPET parameters and in particular of normalized peak VO2 (%ppVO2) remains to be thoroughly evaluated. In this study, 75 patients with ATTR-CA underwent cardiological evaluation and CPET in a National Referral Center for cardiac amyloidosis (Careggi University Hospital, Florence). Fifty-seven patients (76%) had wild-type ATTR. Median age was 80 (75-83) years, 68 patients (91%) were men. Peak oxygen consumption (14.1 ± 4.1 ml/kg/min) and %ppVO2 (68.4 ± 18.8%) were blunted. Twenty-seven (36%) patients had an abnormal pressure response to exercise. After a median follow-up of 25 (12-31) months, the composite outcome of death or heart failure hospitalization was registered in 19 (25.3%) patients. At univariate analysis %ppVO2 was a stronger predictor for the composite outcome than peak VO2. %ppVO2 and NT-proBNP remained associated with the composite outcome at multivariate analysis. The optimal predictive threshold for %ppVO2 was 62% (sensitivity: 71%; specificity: 68%; AUC: 0.77, CI 0.65-0.88). Patients with %ppVO2 ≤ 62%and NT-proBNP > 3000 pg had a worse prognosis with 1- and 2-year survival of 69 ± 9% and 50 ± 10%, respectively. CPET is a safe and useful prognostic tool in patients with ATTR-CA. CPET may help to identify patients with advanced disease that may benefit from targeted therapy.

Arrhythmic Burden in Cardiac Amyloidosis: What We Know and What We Do Not.

Cardiac amyloidosis (CA), caused by the deposition of insoluble amyloid fibrils, impairs different cardiac structures, altering not only left ventricle (LV) systo-diastolic function but also atrial function and the conduction system. The consequences of the involvement of the cardiac electrical system deserve more attention, as well as the study of the underlying molecular mechanisms. This is an issue of considerable interest, given the conflicting data on the effectiveness of conventional antiarrhythmic strategies. Therefore, this review aims at summarizing the arrhythmic burden related to CA and the available evidence on antiarrhythmic treatment in this population.

Red flags for the diagnosis of cardiac amyloidosis: simple suggestions to raise suspicion and achieve earlier diagnosis.

Cardiac amyloidosis is an infiltrative disease characterized by extracellular deposition of insoluble amyloid fibrils in the heart leading to organ dysfunction. Despite recent diagnostic advances, the diagnosis of cardiac amyloidosis is often delayed or even missed. Furthermore, a long diagnostic delay is associated with adverse outcomes, with the early diagnosed patients showing the longest survival. In this narrative review we aimed to summarize the 'red flags' that may facilitate the correct diagnosis. The red flags may be classified as clinical, biohumoral, electrocardiographic, echocardiographic, and cardiac magnetic resonance features and should promptly raise the suspicion of cardiac amyloidosis in order to start a correct diagnostic pathway and targeted treatment strategies that may improve patients' outcomes.

Prevalence of anxiety and depression symptoms in a sample of outpatients with ATTR cardiac amyloidosis.

Patients with ATTR cardiac amyloidosis (ATTR-CA) face rare disease that could negatively influence psychological well-being with consequences on the course of the disease and quality of life. However, to date, no study analyzed the prevalence of anxiety and depression in patients with ATTR-CA and which clinical and sociodemographic characteristics are linked with these psychopathological conditions. A total of 109 consecutive patients (83% males) aged 62-90 years with ATTR-CA were recruited. In order to better understand the prevalence of anxiety and depression in ATTR-CA, a control group composed by 33 individuals equaling gender, education, and age were recruited. The level of anxiety and depression was measured using the Italian version of the Hospital Anxiety and Depression Scale (HADS). Sociodemographic and clinic characteristics were registered. Almost half of patients (49%) reported a clinical level of depression or anxiety, or both. ATTR-CA patients reported higher levels of anxiety and depression than control group. Results showed that older patients with ATTR-CA, especially females, with more advanced disease could be more at risk to develop an anxious disorder. Furthermore, being a woman, and presenting with a greater severity of symptoms, would appear to be a risk factor for developing a depressive disorder. Overall, these results highlighted the high presence of anxiety and depression in ATTR-CA patients, suggesting to physicians to pay attention to the psychological well-being of ATTR-CA patients. In fact, a psychological support for patients with high level of psychopathological disease could reduce disease burden and improve quality of life in ATTR-CA population.

ST-segment elevation myocardial infarction due to septic coronary embolism: a case report.

BACKGROUND: Coronary artery embolism is an infrequent cause of type 2 myocardial infarction which can be due to arterial thromboembolism or septic embolism. While systemic embolization is one of the most acknowledged and threatened complications of infective endocarditis, coronary localization of the emboli causing acute myocardial infarction is exceedingly rare occurring in <1% of cases. CASE SUMMARY: A 52-year-old man with a history of Bentall procedure and redo aortic valve replacement due to prosthetic degeneration (11 years prior to the current presentation) presented to the emergency department with high-grade fever and myalgias. Shortly after his arrival, he experienced typical chest pain and an electrocardiogram demonstrated signs of inferior ST-elevation myocardial infarction: coronary angiography showed a lesion of presumed embolic origin at the level of the mid-distal circumflex coronary artery which was treated with embolectomy. Transthoracic and transoesophageal echocardiography highlighted the presence of a periaortic abscess. The final diagnosis of infective endocarditis as the cause of septic coronary artery embolization was confirmed with a Positron Emission Tomography-Computed Tomography (PET-CT) exam and by the growth of Staphylococcus lugdunensis on repeated blood cultures. The patient underwent successful redo Bentall surgery the good outcome was confirmed at 1-month follow-up. DISCUSSION: Type 2 myocardial infarction caused by coronary embolism is a rare presentation of infective endocarditis and requires a high level of suspicion for its diagnosis. Prosthetic heart valves are a predisposing factor for infective endocarditis: aortic root abscess requires surgery as it rarely regresses with antibiotic therapy.

Cardiac involvement in Behçet disease presenting as non-bacterial thrombotic endocarditis: A case report.

Behçet disease (BD) is a form of widespread vasculitis that involves both arteries and veins. Cardiac involvement in BD is exceedingly rare and can present as a form of non-bacterial- thrombotic-endocarditis (NBTE). A 54-year-old man with Behçet disease was admitted to our hospital after presenting with abdominal pain and fever. He had been recently discharged from a hospital in another country with the diagnosis of infective endocarditis of the mitral valve and mycotic embolization to the superior mesenteric artery. At presentation, oral and genital ulcers were present, raising the suspicion of a flare of BD. Transesophageal echocardiography showed a small vegetation on the anterior leaflet of the mitral valve. Blood cultures results were negative. Computed tomography of the abdomen showed extensive inferior vena cava thrombosis. The aneurysm and thrombotic phenomena were interpreted as related to BD: the vegetation on the mitral valve was diagnosed as NBTE of which BD is a recognized cause. With corticosteroid and anticoagulant therapy, the patient's symptoms steadily improved. NBTE is a rare manifestation of BD; differential diagnosis with infective endocarditis can be challenging and should be focused on identifying predisposing conditions. The mainstay of treatment in NBTE is medical therapy with anticoagulation and treatment of the underlying disease. .