Letizia Riva

Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types.

Background— Most studies of amyloidotic cardiomyopathy consider as a single entity the 3 main systemic cardiac amyloidoses: acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt). In this study, we compared the diagnostic/clinical profiles of these 3 types of systemic cardiac amyloidosis. Methods and Results— We conducted a longitudinal study of 233 patients with clear-cut diagnosis by type of cardiac amyloidosis (AL, n=157; ATTRm, n=61; ATTRwt, n=15) at 2 large Italian centers providing coordinated amyloidosis diagnosis/management facilities since 1990. Average age at diagnosis was higher in AL than in ATTRm patients; all ATTRwt patients except 1 were elderly men. At diagnosis, mean left ventricular wall thickness was higher in ATTRwt than in ATTRm and AL. Left ventricular ejection fraction was moderately depressed in ATTRwt but not in AL or ATTRm. ATTRm patients less often displayed low QRS voltage (25% versus 60% in AL; P<0.0001) or low voltage-to-mass ratio (1.1±0.5 versus 0.9±0.5; P<0.0001). AL patients appeared to have greater hemodynamic impairment. On multivariate analysis, ATTRm was a strongly favorable predictor of survival, and ATTRwt predicted freedom from major cardiac events. Conclusions— AL, ATTRm, and ATTRwt should be considered 3 different cardiac diseases, probably characterized by different pathophysiological substrates and courses. Awareness of the diversity underlying the cardiac amyloidosis label is important on several levels, ranging from disease classification to diagnosis and clinical management.

Transthyretin-related amyloidoses and the heart: a clinical overview

A nonhereditary form of systemic amyloidosis associated with wild-type transthyretin causes heart involvement predominantly in elderly men (systemic senile amyloidosis, or SSA). However, hereditary transthyretin-related amyloidosis (ATTR) is the most frequent form of familial systemic amyloidosis, a group of severe diseases with variable neurological and organ involvement. ATTR remains a challenging and widely underdiagnosed condition, owing to its extreme phenotypic variability: the clinical spectrum of the disease ranges from an almost exclusive neurologic involvement to a strictly cardiac presentation. Such heterogeneity principally results from differential effects of the various reported transthyretin mutations, the geographic region the patient is from and, in the case of the most common mutation, Val30Met, whether or not large foci of cases occur (endemic versus nonendemic aggregation). Genetic or environmental factors (such as age, sex, and amyloid fibril composition) also contribute to the heterogeneity of ATTR, albeit to a lesser extent. The existence of exclusively or predominantly cardiac phenotypes should lead clinicians to consider the possibility of ATTR in all patients who present with an unexplained increase in left ventricular wall thickness at echocardiography. Assessment of such patients should include an active search for possible red flags that can point to the correct final diagnosis.

Non-invasive evaluation of the myocardial substrate of cardiac amyloidosis by gadolinium cardiac magnetic resonance

Objective: To investigate the prevalence and distribution of gadolinium (Gd) enhancement at cardiac magnetic resonance (CMR) imaging in patients with cardiac amyloidosis (CA) and to look for associations with clinical, morphological, and functional features. Patients and design: 21 patients with definitely diagnosed CA (nine with immunoglobulin light chain amyloidosis and 12 transthyretin related) underwent Gd-CMR. Results: Gd enhancement was detected in 16 of 21 (76%) patients. Sixty six of 357 (18%) segments were enhanced, more often at the mid ventricular level. Transmural extension of enhancement within each patient significantly correlated with left ventricular (LV) end systolic volume (r  =  0.58). The number of enhanced segments correlated with LV end diastolic volume (r  =  0.76), end systolic volume (r  =  0.6), and left atrial size (r  =  0.56). Segments with > 50% extensive transmural enhancement more often were severely hypokinetic or akinetic (p  =  0.001). Patients with > 2 enhanced segments had significantly lower 12 lead QRS voltage and Sokolow-Lyon index. No relation was apparent with any other clinical, morphological, functional, or histological characteristics. Conclusion: Gd enhancement is common but not universally present in CA, probably due to expansion of infiltrated interstitium. The segmental and transmural distribution of the enhancement is highly variable, and mid-ventricular regions are more often involved. Enhancement appears to be associated with impaired segmental and global contractility and a larger atrium.

Gender-related risk of myocardial involvement in systemic amyloidosis

To investigate associations between gender and myocardial involvement in systemic amyloidosis, we reviewed all patients presenting between 1994 and September 2006 in our institutional network (100 AL and 98 familial transthyretin-related amyloidosis (ATTR) patients, plus 12 elderly men with senile systemic amyloidosis). We focused on echocardiographic descriptors of myocardial involvement (height-indexed mean left ventricular (LV) wall thickness, LV mass index), and baseline LV function. Among familial ATTR patients, female prevalence was lower within the highest tertile of either echocardiographic indicator of myocardial involvement. Gender was independently associated with height-indexed mean LV wall thickness (as were gene mutations). Female prevalence appeared rather similar across the different neurological stages. Within the subgroup of familial ATTR patients with amyloidotic cardiomyopathy, women tended to display a considerably less severe morphological and functional echocardiographic profile. We explored the possible role of female sex hormones by considering menopausal status: women in the highest tertile of mean LV wall thickness index were more often postmenopausal than those in the other two tertiles and had a much higher (∼15 years) mean age; analogous age-related associations were not observable for men. In conclusion, these findings raise the hypothesis that some biological characteristic associated with female gender protects against myocardial involvement in familial ATTR.

Usefulness of 99mTc-DPD scintigraphy in cardiac amyloidosis.

In their useful state-of-the-art paper on the evaluation and management of cardiac amyloidosis, Selvanayagam et al. ([1][1]) rightly dedicate much space to noninvasive evaluation but make no mention of a relevant imaging tool: 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD)

Phenotypic and genotypic heterogeneity in transthyretin-related cardiac amyloidosis: Towards tailoring of therapeutic strategies?

Transthyretin-related hereditary amyloidosis (ATTR) is genotypically/phenotypically heterogeneous. We investigated myocardial involvement in ATTR in a cohort of patients with a wide range of mutations. Clinical/echocardiographic follow-up of 41 consecutive symptomatic ATTR patients from a single referral center was analyzed according to TTR mutation. Diagnosis was based on histology, immunohistochemistry and genotyping. Median follow up was 40 months (range 8–120). Among the 12 different mutations identified, Val30Met was found in 10 patients and Glu89Gln in seven. Compared with Val30Met, Glu89Gln was associated with higher LV mass index, lower left ventricular ejection fraction and shorter E-wave deceleration time. All Glu89Gln carriers had cardiomyopathy, which was more severe (for left ventricular thickness, left ventricular mass and restrictive pathophysiology) than in the six affected Val30Met patients. Glu89Gln was independently associated with higher risk of major cardiovascular events among cardiomyopathy patients. This follow-up study of ATTR patients carrying a wide range of mutations indicates that (1) cardiac involvement is a very important component of phenotypic expression; and (2) genotype is an important source of heterogeneity in myocardial involvement, with Glu89Gln being associated with a severe, heart-driven prognosis. We think that combined heart–liver transplantation could be considered for Glu89Gln carriers with established, morphologically severe cardiomyopathy.

Decision making for oral anticoagulants in atrial fibrillation: the ATA-AF study.

BACKGROUND Oral anticoagulants offer the best long-term protection against ischemic stroke in patients with atrial fibrillation (AF). However, vitamin K antagonists (VKA) are cumbersome to use and their prescription is far from guidelines recommendations. We report the results of a large survey on the attitudes of prescription of VKA in patients with AF. METHODS 7148 patients were enrolled by 196 Internal Medicine (MED) and 164 Cardiology (CARD) centers, and VKA specifically analyzed. Thrombotic and hemorrhagic risks were evaluated by means of CHADS2 and CHA2DS2VASc scores, and a study-specific bleeding score (modified HAS-BLED). RESULTS 63.9% of non-valvular patients had a CHADS2 score≥2 (MED: 75.3%-CARD: 53.1%), and 28.4% a bleeding score≥3 (41.9% MED-15.8% CARD). VKA were prescribed in 55.5% of non-valvular patients (46.3% MED and 64.2% CARD), in 81% of high-risk valvular patients and in 58.8% of the overall study population. Among patients at high risk of bleeding (score≥3), VKA were prescribed in 26.9% of subjects, while, in the subgroup at high risk of thrombosis (CHADS2 Score<2), these were prescribed in 54.4%. Age≥75, paroxysmal AF, cognitive impairment, need for assistance, CHADS2<2 and bleeding score≥3 were independent predictors of non-use of VKA. CONCLUSIONS Oral anticoagulants are more frequently used in CARD than in MED, plausibly due to greater complexity of MED patients. Stratification of thrombotic and hemorrhagic risk significantly drives the choice for VKA. However the fraction of patients in whom prescription or non-prescription is based on other individual characteristics is not negligible.

Novel oral anticoagulants and valvular atrial fibrillation: are they always contraindicated?

Atrial fibrillation (AF) is the most common sustained cardiac dysrhythmia, and is associated with an increased risk of death, stroke, and other thromboembolic events. Valvular heart disease (VHD) frequently coexists with AF, mostly in elderly patients. After the introduction of novel oral anticoagulants (NOACs) approved for the prevention of stroke in non-valvular atrial fibrillation (NVAF) on the basis of recent trials, the importance of a universal definition of NVAF was raised in clinical practice. In the most recent guidelines, the term valvular AF is used to imply that AF is related to rheumatic valvular disease (predominantly mitral stenosis), or prosthetic heart valves. In all the trials comparing NOACs and warfarin, a significant percentage of patients presented any type of VHD, excluding rheumatic mitral stenosis and mechanical heart valve. The subgroups analysis performed, so far showed no significant differences in terms of efficacy in the VHD subgroup compared to the general AF population. A restrictive definition of valvular AF (i.e., rheumatic mitral stenosis and mechanical heart valve) seems to be the most appropriate to contraindicate treatment with NOACs for AF thromboprophylaxis. In the remaining AF patients with significant valvular disease who per se would not require oral anticoagulation, NOACs should be allowed.

Indagine Censis sulla conoscenza in Italia della fibrillazione atriale a livello dei cittadini, dei medici di medicina generale e dei pazienti

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, particularly in the elderly. AF is considered an independent predictor of mortality and risk factor for stroke. AF-related stroke is usually severe and associated with a high rate of mortality and disability. Despite its prevalence, AF is a poorly known disease and it is underestimated by the general population. The aim of the Censis survey was to analyze the levels of AF knowledge and information in the Italian population and the level of AF risk awareness by general practitioners and AF patients. METHODS: The survey included structured interviews with a sample of 1000 Italian citizens aged ≥18 years, 300 general practitioners, and 1200 AF patients. RESULTS: The analysis confirmed low levels of knowledge of AF. In particular, the results showed that only one third of Italians know AF that is however perceived as a severe disease. In this subgroup, the risk of stroke associated with AF is known by 65%, but it is also widespread the wrong concept that AF is associated with an increased risk of myocardial infarction. The lack of knowledge of AF and its complications by the Italian population is due to educational gaps of general practitioners. In particular, only 50% of the Italian general practitioners perceive the thromboembolic risk of paroxysmal AF as comparable to that of permanent AF. In addition, there is an underuse of the scores for thromboembolic and hemorrhagic risk stratification recommended by current guidelines and a frequent use of antiplatelet therapy rather than oral anticoagulant therapy. There is also a low level of knowledge and awareness of the disease among AF patients. However, the majority of AF patients are aware of the importance of antithrombotic prophylaxis for stroke prevention. CONCLUSIONS: This study demonstrates limited knowledge and awareness of AF in the general population and also among general practitioners and affected patients.

Antithrombotic therapy for patients with an indication for oral anticoagulation undergoing percutaneous coronary intervention with stent: The case of venous thromboembolism

The management of antithrombotic therapy in patients on oral anticoagulation (OAC) for atrial fibrillation (AF) undergoing percutaneous coronary intervention with stent (PCI) is currently addressed by expert consensus documents and official Guidelines. No specific data, nor management suggestions, are available for OAC patients undergoing PCI in whom the indication for OAC is venous thromboembolism (VTE). In this article, the available evidence on VTE patients undergoing PCI, as obtained from studies where patients with various indications for PCI were included, is evaluated, and an algorithm for the management of antithrombotic therapy in this unique population is proposed.