Early Diagnosis and Outcome in Patients With Wild-Type Transthyretin Cardiac Amyloidosis.

Whether diagnostic timing in transthyretin (TTR) cardiac amyloidosis (CA) predisposes patients to worse outcomes is unresolved. We aimed to describe the long-term association of diagnostic timing (time from first onset of symptoms consistent with CA leading to medical contact to definitive diagnosis) with mortality in patients with wild-type TTR-CA (ATTRwt-CA). Overall, we reviewed the medical records of 160 patients seen at a tertiary care amyloidosis unit from January 1, 2016, to January 1, 2020 (median [interquartile range] follow-up, 21 [10 to 34] months), and compared them by survival. Median diagnostic timing was 4 (2 to 12) months and was longer in nonsurvivors (9 [3 to 15] vs 3 [1 to 7] months; P<.001). Patients diagnosed 6 or more months after symptom onset had higher mortality, with a median survival of 30 months (95% CI, 22 to 37 months). On Cox multivariable analysis, timing was independently associated with all-cause mortality (hazard ratio per month increase, 1.049 [95% CI, 1.017 to 1.083]) together with age at diagnosis, disease stage, New York Heart Association class, and coronary artery disease. In conclusion, diagnostic timing of ATTRwt-CA is associated with mortality. Timely diagnosis is warranted whenever "red flags" are present.

Pathophysiology and Treatment of Hypertrophic Cardiomyopathy: New Perspectives.

PURPOSE OF REVIEW: We provide a state of the art of therapeutic options in hypertrophic cardiomyopathy (HCM), focusing on recent advances in our understanding of the pathophysiology of sarcomeric disease. RECENT FINDINGS: A wealth of novel information regarding the molecular mechanisms associated with the clinical phenotype and natural history of HCM have been developed over the last two decades. Such advances have only recently led to a number of controlled randomized studies, often limited in size and fortune. Recently, however, the allosteric inhibitors of cardiac myosin adenosine triphosphatase, countering the main pathophysiological abnormality associated with HCM-causing mutations, i.e. hypercontractility, have opened new management perspectives. Mavacamten is the first drug specifically developed for HCM used in a successful phase 3 trial, with the promise to reach symptomatic obstructive patients in the near future. In addition, the fine characterization of cardiomyocyte electrophysiological remodelling has recently highlighted relevant therapeutic targets. Current therapies for HCM focus on late disease manifestations without addressing the intrinsic pathological mechanisms. However, novel evidence-based approaches have opened the way for agents targeting HCM molecular substrates. The impact of these targeted interventions will hopefully alter the natural history of the disease in the near future.

Embolic risk stratification and prognostic impact of early surgery in left-sided infective endocarditis.

BACKGROUND: In patients with left-sided infective endocarditis (IE) and heart failure associated with large vegetations, early surgery prevents embolic events. However, optimal timing of surgery for other indications is still unresolved particularly when the presence of large vegetations represents the sole indication. METHODS: We retrospectively analyzed 308 consecutive patients admitted to our department with definite left-sided IE. Of these patients, 243 (79%) underwent cardiac surgery (complicated IE), 34 patients with uncomplicated IE received medical treatment, 24 were not operated due to prohibitive general conditions and 7 refused surgery. Long-term follow-up was obtained by structured telephone interviews. RESULTS: During the 6-year follow-up (average 121.8 weeks ± 76), patients not operated because of general conditions or refusal had the worst prognosis, while outcome in operated patients for complicated IE was comparable to that of uncomplicated IE treated medically. Early (<2 weeks from diagnosis) surgery was associated with better survival compared to delayed surgery (HR 0.58, p = 0.23). Embolic events were detected at admission in 38% of cases; Staphylococcus Aureus etiology and vegetation size were independently associated with embolism (OR 2.4, p = 0.01; OR 1, p=0.008 respectively). CONCLUSIONS: Compared to uncomplicated medically-treated patients, complicated IE showed comparable survival when managed aggressively by surgical intervention, whereas a conservative approach was associated with an adverse prognosis. Staphylococcus Aureus infection and vegetation size were independent predictors of systemic embolism. Our data support aggressive surgical management of complicated IE patients and highlight the importance of etiological characterization in clinical decision-making.

Intravascular lithotripsy for calcific coronary and peripheral artery stenoses.

Heavily calcified lesions may be difficult to dilate adequately with conventional balloons and stents, which causes frequent periprocedural complications and higher rates of target lesion revascularisation (TLR). High-pressure non-compliant balloon angioplasty may be of insufficient force to modify calcium and, even when successful, may be limited in its ability to modify the entire calcified lesion. Scoring and cutting balloons hold theoretical value but data to support their efficacy are lacking and, because of their high lesion crossing profile, they often fail to reach the target lesion. Rotational and orbital atherectomy target superficial calcium; however, deep calcium, which may still impact on vessel expansion and luminal gain, is not affected. Intravascular lithotripsy (IVL), based on lithotripsy for renal calculi, is a new technology which uses sonic pressure waves to disrupt calcium with minimal impact to soft tissue. Energy is delivered via a balloon catheter, analogous to contemporary balloon catheters, with transmission through diluted ionic contrast in a semi-compliant balloon inflated at low pressure with sufficient diameter to achieve contact with the vessel wall. With coronary and peripheral balloons approved in Europe, peripheral balloons approved in the USA and multiple new trials beginning, we review the indications for these recently introduced devices, summarise the clinical outcomes of the available trials and describe the design of ongoing studies.

Comparison of long-term outcome in anthracycline-related versus idiopathic dilated cardiomyopathy: a single centre experience.

AIMS: Cardiac dysfunction is a severe complication of anthracycline-containing anticancer therapy. The outcome of anthracycline-induced cardiomyopathy (AICM) compared with other non-ischaemic causes of heart failure (HF), such as idiopathic dilated cardiomyopathy (IDCM), is unresolved. The aim of this study was to compare the survival of AICM patients with an IDCM cohort followed at our centre from 1990 to 2016. METHODS AND RESULTS: We included 67 patients (67% female, 50 ± 15 years) with AICM, defined as onset of otherwise unexplained left ventricular ejection fraction (LVEF) ≤50% following anthracycline therapy, and 488 IDCM patients (28% female, 55 ± 12 years). Patients were followed with constantly optimized HF therapy, for 7.6 ± 5.5 and 8.1 ± 5.5 years, respectively. In both cohorts, 25% of patients reached the combined endpoint of death/heart transplantation. Overall survival rates at 5 and 10 years were similar (AICM: 86% and 61%, IDCM: 88% and 75%; P = 0.61), and so was cardiovascular survival (AICM: 91% and 76%, IDCM: 91% and 80%; P = 0.373), also after 1:1 propensity matching (P = 0.27) and adjusting for age, LVEF and left ventricular size. A trend toward higher all-cause mortality was present in AICM patients [hazard ratio (HR) 1.67, 95% confidence interval (CI) 0.95-2.92, P = 0.076]. No differences were observed between AICM and IDCM with regard to pharmacological HF therapy, but AICM patients were less likely to receive devices (13% vs. 41.8% in IDCM, P < 0.001). CONCLUSION: Cardiovascular mortality in patients with AICM did not differ from that of a matched IDCM cohort, despite cancer-related morbidity and less prevalent use of devices. These data suggest that patients with AICM should be treated with appropriate guideline-directed medical therapies similar to other non-ischaemic dilated cardiomyopathies.

Abrupt Onset of Refractory Heart Failure Associated With Light-Chain Amyloidosis in Hypertrophic Cardiomyopathy.

Importance: The natural history of hypertrophic cardiomyopathy (HCM) is complex and may include progressive heart failure and severe left ventricular dysfunction. When disease progression is abrupt, however, other coexisting diseases should be ruled out. This may be difficult in the case of amyloidosis, which classically mimics HCM. Results: We present an example of severe clinical deterioration in a patient with HCM due to superimposed amyloid light-chain amyloidosis. A man in his 70s with a longstanding history of genetically confirmed HCM presented with rapid development of congestive heart failure over 6 months, in sharp contrast to a previously stable, asymptomatic clinical course. He was diagnosed as having the illness in his late 40s after a resuscitated cardiac arrest and regularly followed up on a yearly basis. His most recent electrocardiogram was profoundly changed from previous tracings, with marked and diffuse voltage reduction (QS in V1-V3) and inferolateral T-wave inversion. The echocardiogram showed an abrupt increase in the severity of left ventricular (LV) hypertrophy, with a concentric rather than asymmetric appearance, granular sparkling of the myocardium, biatrial enlargement, thickening of the mitral valve leaflets, and interatrial septum and mild pericardial effusion. Severe LV dysfunction with a restrictive LV filling pattern was evident, which is associated with LV outflow tract obstruction loss and right ventricle systolic impairment. Following hospital admission, multiple myeloma was diagnosed and confirmed by bone marrow biopsy and aspiration. Furthermore, abdominal fat aspiration showed amyloid deposition and confirmed the diagnosis of amyloid light-chain amyloidosis. Electrocardiograms, echocardiographic images, and videos presented in this report describe the abrupt and marked evolution of a sarcomeric to infiltrative cardiomyopathy, leading to an ominous outcome in which the patient died despite specific treatment. Conclusions and Relevance: While progression to the end-stage phase occurs over several years for patients with HCM and can be detected at relatively early stages, the abrupt onset of congestive heart failure is uncommon and should raise suspicion of other, superimposed cardiac diseases.

Defining phenotypes and disease progression in sarcomeric cardiomyopathies: contemporary role of clinical investigations.

Mutations in cardiac sarcomere protein genes are associated with a variety of clinical phenotypes, including hypertrophic (HCM), dilated (DCM), and restrictive (RCM) cardiomyopathy as well as left ventricular non-compaction, with the overlap of morpho-functional manifestations in individual patients and families. Over time, initial phenotypes may undergo profound changes which determine clinical course and disease progression. Although genetic defects causing HCM and DCM have opposite effects at the myofilament level, a number of downstream maladaptive mechanisms, ranging from microvascular dysfunction and ischaemia to myocardial fibrosis and from diastolic dysfunction to abnormal sympathetic activation and arrhythmogenesis, seem to recur in sarcomeric cardiomyopathies, independent of the presenting phenotype. The extent and rate at which each of these features occur and evolve may be radically different in each form of cardiomyopathy, determining a clinical heterogeneity that is not only cross-sectional, but also longitudinal, i.e. time-related. Timely and sensitive detection of these long-term modifications in the clinical setting is a key to preventing advanced disease and identifying novel therapeutic targets. The present review evaluates the contribution of contemporary technology to pre-clinical diagnosis, characterization of phenotypes, and assessment of disease progression in sarcomere cardiomyopathies, including echocardiography, positron emission tomography, magnetic resonance, pathology, and circulating biomarkers.

Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations.

BACKGROUND: Mild hypertrophy but increased arrhythmic risk characterizes the stereotypic phenotype proposed for hypertrophic cardiomyopathy (HCM) caused by thin-filament mutations. However, whether such clinical profile is different from more prevalent thick-filament-associated disease is unresolved. OBJECTIVES: This study aimed to assess clinical features and outcomes in a large cohort of patients with HCM associated with thin-filament mutations compared with thick-filament HCM. METHODS: Adult HCM patients (age >18 years), 80 with thin-filament and 150 with thick-filament mutations, were followed for an average of 4.5 years. RESULTS: Compared with thick-filament HCM, patients with thin-filament mutations showed: 1) milder and atypically distributed left ventricular (LV) hypertrophy (maximal wall thickness 18 ± 5 mm vs. 24 ± 6 mm; p < 0.001) and less prevalent outflow tract obstruction (19% vs. 34%; p = 0.015); 2) higher rate of progression to New York Heart Association functional class III or IV (15% vs. 5%; p = 0.013); 3) higher prevalence of systolic dysfunction or restrictive LV filling at last evaluation (20% vs. 9%; p = 0.038); 4) 2.4-fold increase in prevalence of triphasic LV filling pattern (26% vs. 11%; p = 0.002); and 5) similar rates of malignant ventricular arrhythmias and sudden cardiac death (p = 0.593). CONCLUSIONS: In adult HCM patients, thin-filament mutations are associated with increased likelihood of advanced LV dysfunction and heart failure compared with thick-filament disease, whereas arrhythmic risk in both subsets is comparable. Triphasic LV filling is particularly common in thin-filament HCM, reflecting profound diastolic dysfunction.

Coronary microvascular dysfunction is an early feature of cardiac involvement in patients with Anderson-Fabry disease.

AIMS: Male patients with Anderson-Fabry disease (AFD) often exhibit cardiac involvement, characterized by LV hypertrophy (LVH), associated with severe coronary microvascular dysfunction (CMD). Whether CMD is present in patients without LVH, particularly when female, remains unresolved. The aim of the study was to investigate the presence of CMD by positron emission tomography (PET) in AFD patients of both genders, with and without evidence of LVH. METHODS AND RESULTS: We assessed myocardial blood flow following dipyridamole infusion (Dip-MBF) with 13N-labelled ammonia by PET in 30 AFD patients (age 51 ± 13 years; 18 females) and in 24 healthy controls. LVH was defined as echocardiographic maximal LV wall thickness ≥13 mm. LVH was present in 67% of patients (n = 20; 10 males and 10 females). Dip-MBF was reduced in all patients compared with controls (1.8 ± 0.5 and 3.2 ± 0.5 mL/min/g, respectively, P < 0.001). For both genders, flow impairment was most severe in patients with LVH (1.4 ± 0.5 mL/min/g in males and 1.9 ± 0.5 mL/min/g in females), but was also evident in those without LVH (1.8 ± 0.3 mL/min/g in males and 2.1 ± 0.4 mL/min/g in females; overall P = 0.064 vs. patients with LVH). Analysis of variance (ANOVA) for the 17 LV segments showed marked regional heterogeneity of MBF in AFD (F = 4.46, P < 0.01), with prevalent hypoperfusion of the apical region. Conversely, controls showed homogeneous LV perfusion (F = 1.25, P = 0.23). CONCLUSIONS: Coronary microvascular function is markedly impaired in AFD patients irrespective of LVH and gender. CMD may represent the only sign of cardiac involvement in AFD patients, with potentially important implications for clinical management.