Massimiliano Lorenzini

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.

Prognostic Implications of the Doppler Restrictive Filling Pattern in Hypertrophic Cardiomyopathy

The Doppler echocardiographic pattern of restrictive left ventricular (LV) filling has proved to be an important predictor of clinical course and prognosis in dilated cardiomyopathy. However, the relation between restrictive filling pattern and clinical course has not been systematically investigated in hypertrophic cardiomyopathy (HC). We assessed the prognostic implications of the Doppler restrictive filling pattern in 239 consecutive patients with HC in whom Doppler measurements of LV filling had been systematically recorded at initial evaluation and during follow-up. Restrictive LV filling was identified in 14 patients (5.9%) at initial evaluation and developed in 22 (9.2%) during follow-up. A close relation was identified between restrictive filling pattern and end-stage HC, with patients with restrictive filling showing a sixfold increase in risk of developing end-stage HC (hazard ratio 6.25, 95% confidence interval 1.90 to 20.57, p = 0.003). Over a median follow-up of 9.7 years, 22 patients (9.2%) died suddenly or received appropriate cardioverter-defibrillator interventions, and 54 (22.6%) had HC-related death or underwent heart transplantation. In a set of univariate and multivariate analyses including each of the generally accepted risk factors for cardiac death in HC, the restrictive filling pattern was a strong and independent marker of increased risk (hazard ratio for sudden cardiac events 3.51, 95% confidence interval 1.37 to 8.95, p = 0.009; hazard ratio for HC-related death or heart transplantation 3.54, 95% confidence interval 1.91 to 6.57, p <0.001) compared to patients without restrictive filling. In conclusion, in our study cohort, the Doppler pattern of restrictive LV filling proved to be a strong predictor of sudden death and HC-related death, independently of other markers for unfavorable prognosis in this disease.

Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis

Abstract The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one consisting of mainly intact ATTR (type B). The fibril types are correlated to phenotypic differences. Patients with ATTR fragments have a late onset and develop cardiomyopathy, while patients without fragments have an early onset and less myocardial involvement. The present study aimed to determine whether this correlation between fibril type and phenotype is valid for familial ATTR amyloidosis in general. Cardiac or adipose tissues from 63 patients carrying 29 different TTR non-V30M mutations as well as 13 Japanese ATTRV30M patients were examined. Fibril type was determined by western blotting and compared to the patients’ age of onset and degree of cardiomyopathy. All ATTR non-V30M patients had a fibril composition with ATTR fragments, except two ATTRY114C patients. No clear conclusions could be drawn about a phenotype to fibril type correlation among ATTR non-V30M patients. In contrast, Japanese ATTRV30M patients showed a similar correlation as previously described for Swedish ATTRV30M patients. This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis, and suggests that fibrils composed of only full-length ATTR is an exception found only in a subset of patients.

Significance of Magnetic Resonance Imaging in Apical Hypertrophic Cardiomyopathy

Apical hypertrophic cardiomyopathy (HC) is an uncommon variant of nonobstructive HC with peculiar characteristics. The investigators report a series of 13 consecutive Caucasian patients with a suspicion or diagnosis of apical HC on the basis of electrocardiographic and/or echocardiographic findings who prospectively underwent magnetic resonance imaging with late gadolinium enhancement (LGE) evaluation. All but 1 patient presented T-wave inversion in the anterolateral leads on electrocardiogram, with a mean maximum negative T wave of 7.0 +/- 3.9 mm. Echocardiography provided correct diagnoses in 9/13 patients (69%), while in 4 patients echocardiographic results were normal or inconclusive. Magnetic resonance imaging showed a spadelike morphology of the left ventricle in 6 patients and identified an apical aneurysm in 4. Eleven patients (85%) presented LGE with a mean percentage of 2.3 +/- 2.6% of total left ventricular mass. In 9 (69%) patients LGE was limited to the hypertrophic segments while in 6 (46%) patients it was also present in nonhypertrophic segments. In conclusion, magnetic resonance imaging in patients with apical HC showed a high incidence of apical aneurysms and a peculiar distribution of LGE, that was not limited to hypertrophic segments.

Cardiac amyloidosis: the great pretender

Cardiac amyloidosis (CA) is often misdiagnosed because of both physician-related and disease-related reasons including: fragmented knowledge among different specialties and subspecialties, shortage of centres and specialists dedicated to disease management, erroneous belief it is an incurable disease, rarity of the condition, intrinsic phenotypic heterogeneity, genotypic heterogeneity in transthyretin-related forms and the necessity of target organ tissue histological diagnosis in the vast majority of cases. Pitfalls, incorrect beliefs and deceits challenge not only the path to the diagnosis of CA but also the precise identification of aetiological subtype. The awareness of this condition is the most important prerequisite for the management of the risk of underdiagnoses and misdiagnosis. Almost all clinical, imaging and laboratory tests can be misinterpreted, but fortunately each of these diagnostic steps can also offer diagnostic “red flags” (i.e. highly suggestive findings that can foster the correct diagnostic suspicion and facilitate early, timely diagnosis). This is especially important because outcomes in CA are largely driven by the severity of cardiac dysfunction and emerging therapies are aimed at preventing further amyloid deposition.

Identification of TTR-Related Subclinical Amyloidosis With 99mTc-DPD Scintigraphy

We have previously documented that 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) has a high affinity for transthyretin (TTR)-infiltrated myocardium, allowing a differential diagnosis with light-chain cardiac amyloidosis [(1)][1] and other non-amyloidotic cardiomyopathies with a

Defining the Diagnosis in Echocardiographically Suspected Senile Systemic Amyloidosis

Senile systemic amyloidosis (SSA) is a cardiomyopathy mainly affecting elderly men due to intramyocardial deposition of wild-type (nonmutant) transthyretin (TTR) ([1][1]). Since the heart is the only involved organ, SSA—which requires endomyocardial biopsy (EMB) for a definite diagnosis—is often

Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths

Aims Wild-type transthyretin amyloidosis (ATTRwt) is mostly considered a disease predominantly of elderly male, characterized by concentric LV hypertrophy, preserved LVEF, and low QRS voltages. We sought to describe the characteristics of a large cohort of ATTRwt patients to better define the disease. Methods and results Clinical findings of consecutive ATTRwt patients diagnosed at 2 centres were reviewed. ATTRwt was diagnosed histologically or non-invasively (LV hypertrophy ≥12 mm, intense cardiac uptake at 99mTc-DPD scintigraphy and AL exclusion). Mutations in TTR were excluded in all cases. The study cohort comprised 108 patients (78.6 ± 8 years); 67 (62%) diagnosed invasively and 41 (38%) non-invasively. Twenty patients (19%) were females. An asymmetric hypertrophy pattern was observed in 25 (23%) patients. Mean LVEF was 52 ± 14%, with 39 patients (37%) showing a LVEF < 50%. Atrial fibrillation (56%) and a pseudo-infarct pattern (63%) were the commonest ECG findings. Only 22 patients fulfilled QRS low-voltage criteria while 10 showed LV hypertrophy on ECG. Although heart failure was the most frequent profile leading to diagnosis (68%), 7% of individuals presented with atrioventricular block and 11% were diagnosed incidentally. Almost one third (35; 32%) were previously misdiagnosed. Conclusion The clinical spectrum of ATTRwt is heterogeneous and differs from the classic phenotype: women are affected in a significant proportion; asymmetric LV hypertrophy and impaired LVEF are not rare and only a minority have low QRS voltages. Clinicians should be aware of the broad clinical spectrum of ATTRwt to correctly identify an entity for which a number of disease-modifying treatments are under investigation.

Cardiac involvement in hereditary-transthyretin related amyloidosis

Hereditary transthyretin-related amyloidosis remains a widely underdiagnosed condition, owing to its extreme phenotypic variability: the clinical spectrum of the disease ranges from an almost exclusive neurologic involvement to strictly cardiac manifestations. This heterogeneity is linked to several factors including specific transthyretin mutations, geographic distribution and endemic vs. non-endemic aggregation type. The existence of exclusively or predominantly cardiac phenotypes makes the recognition of the disease very challenging since it can mimic other more common causes of left ventricular “hypertrophy”. Assessment of such patients should include an active search for possible red flags that can indicate the correct final diagnosis.

Effects of myocardial fibrosis assessed by MRI on dynamic left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy: a retrospective database analysis

Background While implications of myocardial fibrosis on left ventricular (LV) function at rest have been studied in hypertrophic cardiomyopathy (HCM), the pathophysiological consequences on dynamic LV outflow tract (LVOT) gradient have so far not been investigated in detail. Objective To evaluate the influence of myocardial fibrosis, detected by MRI as late-gadolinium enhancement (LGE), on LVOT gradient in HCM. Design Retrospective database analysis. Setting A single Italian cardiomyopathies referral centre. Patients Seventy-six HCM patients with normal ejection fraction at rest. Interventions Patients underwent cardiac MR and performed bicycle exercise echocardiogram within a month. Results LGE was present in 54 patients (71%), ranging from 0.2% to 32.4% of LV mass. There was a weak correlation between the amount of fibrosis and LVOT gradient variation during exercise in the overall population (r=−0.243, p=0.034) and a stronger correlation in patients with obstructive HCM at rest (r=−0.524, p=0.021). Patients with an LVOT gradient increase ≥50 mm Hg during exercise had a significantly lesser extent of fibrosis than those with an increase <50 mm Hg (0.7% (IQR 0–2.4) vs 3.2% (IQR 0.2–7.4), p=0.006). The extent of fibrosis was significantly lower among the highest quartiles of LVOT gradient increase (p=0.009). Conclusions In patients with HCM and normal ejection fraction at rest, myocardial fibrosis was associated with a lower increase in LVOT gradient during exercise, probably due to a lesser degree of myocardial contractility recruitment. This negative association was more evident in patients with an obstructive form at rest.