Wild-Type Transthyretin Cardiac Amyloidosis is Not Rare in Elderly Subjects: the CATCH Screening Study.

BACKGROUND: Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) affects older adults and is currently considered as a rare disorder. OBJECTIVE: We investigated for the first time the prevalence of ATTRwt-CA in elderly individuals from the general population. METHODS: General practitioners from Pisa, Italy, proposed a screening for ATTRwt-CA to all their patients aged 65-90 years, until 1,000 accepted. The following red flags were searched: interventricular septal thickness ≥12 mm, any echocardiographic, ECG or clinical hallmark of CA, or high sensitivity-troponin T ≥14 ng/L. Individuals with at least one red flag (n=346) were asked to undergo the search for a monoclonal protein and bone scintigraphy, and 216 accepted. RESULTS: Four patients received a non-invasive diagnosis of ATTRwt-CA. All complained of dyspnea on moderate effort. A woman and a man aged 79 and 85 years, respectively, showed an intense cardiac tracer uptake (grade 3), left ventricular (LV) wall thickening, grade 2 to 3 diastolic dysfunction, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) >1,000 ng/L. Two other patients (a man aged 74 years and a woman aged 83 years) showed a grade 2 uptake, an increased LV septal thickness, but preserved diastolic function, and NT-proBNP <300 ng/L. The prevalence of ATTR-CA in subjects ≥65 years was calculated as 0.46% (i.e., 4 out of the 870 subjects completing the screening, namely 654 not meeting the criteria for Step 2 and 216 progressing to Step 2). CONCLUSIONS: ATTRwt-CA is uncommon in elderly subjects from the general population, but more frequent than expected for a rare disease.

Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is a heart condition mostly found in older adults. ATTRwt-CA is considered a rare disease, although no systematic screening have been performed yet. The study aimed to understand how common this disease is among the general population aged 65 to 90 years in Pisa, Italy. To do this, general practitioners offered screening for ATTRwt-CA to their patients within this age group. The initial step of the screening involved checking for certain warning signs (red flags), like abnormal thickness in a part of the heart called the interventricular septum, unusual heart function observed through various tests, or elevated levels of a specific heart protein. Out of 1,000 individuals who began the screening process, 346 showed at least one of these red flags and were further examined using bone scintigraphy (a type of imaging test) and tests for a specific protein related to this condition. Of these, 216 agreed to proceed with these additional tests. The results showed that four of these patients actually had ATTRwt-CA. Their conditions varied in severity, with some showing more intense signs of the disease on the heart scans, thicker heart walls, and higher levels of heart stress proteins. All four patients experienced mild difficulty in breathing during physical activity. Based on these findings, the study concluded that about 0.46% of elderly individuals in the general population might have ATTRwt-CA, indicating that the disease is somewhat more common in this age group than previously thought.

Bayesian Convolutional Neural Networks in Medical Imaging Classification: A Promising Solution for Deep Learning Limits in Data Scarcity Scenarios.

Deep neural networks (DNNs) have already impacted the field of medicine in data analysis, classification, and image processing. Unfortunately, their performance is drastically reduced when datasets are scarce in nature (e.g., rare diseases or early-research data). In such scenarios, DNNs display poor capacity for generalization and often lead to highly biased estimates and silent failures. Moreover, deterministic systems cannot provide epistemic uncertainty, a key component to asserting the model's reliability. In this work, we developed a probabilistic system for classification as a framework for addressing the aforementioned criticalities. Specifically, we implemented a Bayesian convolutional neural network (BCNN) for the classification of cardiac amyloidosis (CA) subtypes. We prepared four different CNNs: base-deterministic, dropout-deterministic, dropout-Bayesian, and Bayesian. We then trained them on a dataset of 1107 PET images from 47 CA and control patients (data scarcity scenario). The Bayesian model achieved performances (78.28 (1.99) % test accuracy) comparable to the base-deterministic, dropout-deterministic, and dropout-Bayesian ones, while showing strongly increased "Out of Distribution" input detection (validation-test accuracy mismatch reduction). Additionally, both the dropout-Bayesian and the Bayesian models enriched the classification through confidence estimates, while reducing the criticalities of the dropout-deterministic and base-deterministic approaches. This in turn increased the model's reliability, also providing much needed insights into the network's estimates. The obtained results suggest that a Bayesian CNN can be a promising solution for addressing the challenges posed by data scarcity in medical imaging classification tasks.

Prognostic impact of patients' management based on anatomic/functional phenotype: a study in patients with chronic coronary syndromes.

BACKGROUND: In stable coronary artery disease (CAD), the prognostic interaction between clinical variables and treatment appropriateness based on anatomic/functional phenotype needs to be evaluated. METHODS: 1585 consecutive patients underwent myocardial perfusion scintigraphy and coronary angiography within 90 days. Obstructive CAD (> 70% stenosis) with downstream moderate-to-severe ischemia (> 10%) was considered significant. Coronary revascularization was considered appropriate if all hemodynamically significant lesions were revascularized, while medical therapy only was deemed appropriate in the absence of hemodynamically significant CAD. RESULTS: Obstructive CAD and moderate-to-severe ischemia were documented in 1184 (75%) and 466 (29%) patients, respectively. Over mean follow-up of 4.7 ± 2.5 years, the primary endpoint (cardiac death and non-fatal myocardial infarction) occurred in 132 (8.2%) patients. Of patients with obstructive CAD, 797 (67%) were managed appropriately. Patients' management was inappropriate in 389 patients, because either non-hemodynamically significant lesions were revascularized (50%, including 2 patients with non-obstructive lesions being inappropriately revascularized) or ischemia-causing CAD was left untreated (50%). At multivariate analysis, an inappropriate management (P < .001) was correlated with the primary endpoint, together with previous myocardial infarction (P = .009), lower ejection fraction (P < .001) and higher glucose levels (P < .001). CONCLUSIONS: In stable CAD patients, management based on anatomic/functional phenotyping was correlated with a prognostic advantage at long-term follow-up. Correlation between treatment categories and patients' prognosis. A significantly higher event-rate was observed in patients where hemodynamically significant coronary lesions were left untreated-either because MT was not-adherently chosen or in the case of incomplete revascularization-than in those that were revascularized completely (17.6% vs 5.1%; P < .001). Conversely, the revascularization of non-hemodynamically significant CAD correlated with a higher event-rate than that of similar patients managed medically (13.8% vs 8.3%, P = .04). The event-rate of patients in whom coronary revascularization was performed in the presence of hemodynamically significant CAD ('appropriate revascularization') was similar to those with "No CAD/non-obstructive CAD" (5.1% vs 3.5%; P = NS).

Sex-specific associations of myocardial perfusion imaging with outcomes in patients with suspected chronic coronary syndrome.

BACKGROUND: Myocardial perfusion scintigraphy (MPS) is an established diagnostic technique for inducible ischemia in patients with suspected chronic coronary syndrome (CCS). Some MPS findings, most notably an ischemia extent>10% of the left ventricle (LV), hold prognostic significance and support maximization of anti-ischemic treatment. We aimed to assess sex-specific associations of MPS findings with cardiovascular (CV) events in a population at high risk of CCS. METHODS: In a prospective cohort study, 1,229 consecutive patients (age 70 ± 9.5 years, 73.5% males) without known CCS were referred to stress-rest MPS. All patients were followed for a median of 4.6 years for CV events. RESULTS: Men and women had comparable risk profiles and incidence rates of CV events (6.6% vs. 4.6% respectively, P = 0.186). A summed stress score (SSS) > 7 was associated with the primary endpoint, including CV death and/or nonfatal myocardial infarction (MI) (adjusted hazard ratio [HR], 3.13; 95% confidence interval [CI], 1.79-5.46; P = 0.001), all-cause mortality (HR, 3.01; 95% CI, 1.31-6.93; P = 0.01), and incidence of late revascularization (HR, 1.84; 95% CI, 1.22-2.78; P = 0.004) in men but not women. A summed difference score (SDS) > 6 was related to a higher rate of the primary endpoint only in men (adjusted HR, 1.97; 95% CI, 1.18-3.30; P = 0.009). CONCLUSIONS: Among patients undergoing a diagnostic workup for suspected CCS, stress perfusion and reversible ischemia abnormalities may independently predict worse survival and more CV events in men. However, the obtained results indicated the need for sex-specific cutoffs to refine risk stratification and assist in clinical decisions on anti-ischemic therapy beyond coronary artery anatomy.

Tissue Characterization in Cardiac Amyloidosis.

Cardiac amyloidosis (CA) has long been considered a rare disease, but recent advancements in diagnostic tools have led to a reconsideration of the epidemiology of CA. Amyloid light-chain (AL) and transthyretin (ATTR) amyloidoses are the most common forms of cardiac amyloidosis. Due to the distinct treatments and the different prognoses, amyloid typing is crucial. Although a non-biopsy diagnosis can be obtained in ATTR amyloidosis when certain diagnostic criteria are fulfilled, tissue characterization still represents the gold standard for the diagnosis and typing of CA, particularly in AL amyloidosis. The present review focuses on the status of tissue characterization in cardiac amyloidosis, from histochemistry to immunohistochemistry and mass spectrometry, as well as on its future directions.

The role of cardiovascular magnetic resonance in the evaluation of acute myocarditis and inflammatory cardiomyopathies in clinical practice - a comprehensive review.

Inflammatory cardiomyopathy (I-CMP) is defined as myocarditis in association with cardiac dysfunction and/or ventricular remodelling. It is characterized by inflammatory cell infiltration into the myocardium and has heterogeneous infectious and non-infectious aetiologies. A complex interplay of genetic, autoimmune, and environmental factors contributes to the substantial risk of deteriorating cardiac function, acute heart failure, and arrhythmia as well as chronic dilated cardiomyopathy and its sequelae. Multi-parametric cardiovascular magnetic resonance (CMR) imaging is sensitive to many tissue changes that occur during myocardial inflammation, regardless of its aetiology. In this review, we summarize the various aetiologies of I-CMP and illustrate how CMR contributes to non-invasive diagnosis.

Amyloid Deposits and Fibrosis on Left Ventricular Endomyocardial Biopsy Correlate With Extracellular Volume in Cardiac Amyloidosis.

Background The relative contribution of amyloid and fibrosis to extracellular volume expansion in cardiac amyloidosis (CA) has never been defined. Methods and Results We included all patients diagnosed with amyloid light-chain (AL) or transthyretin cardiac amyloidosis at a tertiary referral center between 2014 to 2020 and undergoing a left ventricular endomyocardial biopsy. Patients (n=37) were more often men (92%), with a median age of 72 years (interquartile range, 68-81). Lambda-positive AL was found in 14 of 19 AL cases (38%) and kappa-positive AL in 5 of 19 (14%), while transthyretin was detected in the other 18 cases (48%). Amyloid deposits accounted for 15% of tissue sample area (10%-30%), without significant differences between AL and transthyretin amyloidosis. All patients displayed myocardial fibrosis, with a median extent of 15% of tissue samples (10%-23%; range, 5%-60%), in the absence of spatial overlap with amyloid deposits. Interstitial fibrosis was often associated with mild and focal subendocardial fibrosis. The extent of fibrosis or the combination of amyloidosis and fibrosis did not differ significantly between transthyretin amyloidosis and AL subgroups. In 20 patients with myocardial T1 mapping at cardiac magnetic resonance, the combined amyloid and fibrosis extent displayed a modest correlation with extracellular volume (r=0.661, P=0.001). The combined amyloid and fibrosis extent correlated with high-sensitivity troponin T (P=0.035) and N-terminal pro-B-type natriuretic peptide (P=0.002) serum levels. Conclusions Extracellular spaces in cardiac amyloidosis are enlarged to a similar extent by amyloid deposits and fibrotic tissue. Their combination can better explain the increased extracellular volume at cardiac magnetic resonance and circulating biomarkers than amyloid extent alone.

Have Volume-based Parameters of Positron Emission Tomography/Computed Tomography Prognostic Relevance for Patients With Potentially Platinum-responsive Recurrent Ovarian Cancer? A Single Center Italian Study.

BACKGROUND/AIM: To assess the prognostic relevance of volume-based parameters [whole body (wb)-metabolic tumor volume (MTV) and wb-total lesion glycolysis (TLG)] of pretreatment PET/CT in patients with potentially platinum-responsive recurrent ovarian cancer. PATIENTS AND METHODS: This retrospective investigation analyzed 67 patients at first relapse. RESULTS: At univariate analysis, post-relapse survival and overall survival correlated with residual disease after primary surgery (RD) (p=0.015 and 0.049, respectively), time to recurrence (p=0.005 and p=0.0003), number of recurrence sites (p=0.001 and p=0.0005), treatment at recurrence (p=0.044 and 0.043) and wb-MTV (p=0.023 and 0.021) but not with wb-TLG. RD, time to recurrence and number of recurrence sites, but not wb-MTV, were independent prognostic variables for post-relapse survival, and time to recurrence and number of recurrence sites, but not wb-MTV, were independent prognostic factors for overall survival. CONCLUSION: Volume-based parameters of PET/CT are not independent predictors of clinical outcome in potentially platinum-responsive recurrent ovarian cancer.

Deep-learning-based cardiac amyloidosis classification from early acquired pet images.

The objective of the present work was to evaluate the potential of deep learning tools for characterizing the presence of cardiac amyloidosis from early acquired PET images, i.e. 15 min after [18F]-Florbetaben tracer injection. 47 subjects were included in the study: 13 patients with transthyretin-related amyloidosis cardiac amyloidosis (ATTR-CA), 15 patients with immunoglobulin light-chain amyloidosis (AL-CA), and 19 control-patients (CTRL). [18F]-Florbetaben PET/CT images were acquired in list mode and data was sorted into a sinogram, covering a time interval of 5 min starting 15 min after the injection. The resulting sinogram was reconstructed using OSEM iterative algorithm. A deep convolutional neural network (CAclassNet) was designed and implemented, consisting of five 2D convolutional layers, three fully connected layers and a final classifier returning AL, ATTR and CTRL scores. A total of 1107 2D images (375 from AL-subtype patients, 312 from ATTR-subtype, and 420 from Controls) have been considered in the study and used to train, validate and test the proposed network. CAclassNet cross-validation resulted with train error mean ± sd of 2.001% ± 0.96%, validation error of 4.5% ± 2.26%, and net accuracy of 95.49% ± 2.26%. Network test error resulted in a mean ± sd values of 10.73% ± 0.76%. Sensitivity, specificity, and accuracy evaluated on the test dataset were respectively for AL-CA sub-type: 1, 0.912, 0.936; for ATTR-CA: 0.935, 0.897, 0.972; for control subjects: 0.809, 0.971, 0.909. In conclusion, the proposed CAclassNet model seems very promising as an aid for the clinician in the diagnosis of CA from cardiac [18F]-Florbetaben PET images acquired a few minutes after the injection.

[18F]-Florbetaben PET/CT for Differential Diagnosis Among Cardiac Immunoglobulin Light Chain, Transthyretin Amyloidosis, and Mimicking Conditions.

OBJECTIVES: This study aimed to test the diagnostic value of [18F]-florbetaben positron emission tomography (PET) in patients with suspicion of CA. BACKGROUND: Diagnosis of cardiac involvement in immunoglobulin light-chain-derived amyloidosis (AL) and transthyretin-related amyloidosis (ATTR), which holds major importance in risk stratification and decision making, is frequently delayed. Furthermore, although diphosphonate radiotracers allow a noninvasive diagnosis of ATTR, demonstration of cardiac amyloidosis (CA) in AL may require endomyocardial biopsy. METHODS: Forty patients with biopsy-proven diagnoses of CA (20 ALs, 20 ATTRs) and 20 patients referred with the initial clinical suspicion and later diagnosed with non-CA pathology underwent a cardiac PET/computed tomography scan with a 60-min dynamic [18F]-florbetaben PET acquisition, and 4 10-min static scans at 5, 30, 50, and 110 min after radiotracer injection. RESULTS: Visual qualitative assessment showed intense early cardiac uptake in all subsets. Patients with AL displayed a high, persistent cardiac uptake in all the static scans, whereas patients with ATTR and those with non-CA showed an uptake decrease soon after the early scan. Semiquantitative assessment demonstrated higher mean standardized uptake value (SUVmean) in patients with AL, sustained over the whole acquisition period (early SUVmean: 5.55; interquartile range [IQR]: 4.00 to 7.43; vs. delayed SUVmean: 3.50; IQR: 2.32 to 6.10; p = NS) compared with in patients with ATTR (early SUVmean: 2.55; IQR: 1.80 to 2.97; vs. delayed SUVmean: 1.25; IQR: 0.90 to 1.60; p < 0.001) and in patients with non-CA (early SUVmean: 3.50; IQR: 1.60 to 3.37; vs. delayed SUVmean: 1.40; IQR: 1.20 to 1.60; p < 0.001). Similar results were found comparing heart-to-background ratio and molecular volume. CONCLUSIONS: Delayed [18F]-florbetaben cardiac uptake may discriminate CA due to AL from either ATTR or other mimicking conditions. [18F]-florbetaben PET/computed tomography may represent a promising noninvasive tool for the diagnosis of AL amyloidosis, which is still often challenging and delayed. (A Prospective Triple-Arm, Monocentric, Phase-II Explorative Study on Evaluation of Diagnostic Efficacy of the PET Tracer [18F]-Florbetaben [Neuraceq] in Patients With Cardiac Amyloidosis [FLORAMICAR2]; EudraCT number: 2017-001660-38).

Myocardial salvage is increased after sympathetic renal denervation in a pig model of acute infarction.

RATIONALE: Despite advances in treatment of acute myocardial infarction (AMI), many patients suffer significant myocardial damage with cardiac dysfunction. Sympathetic renal denervation (RD) may reduce adrenergic activation following AMI. OBJECTIVE: To investigate the potential role of RD limiting myocardial damage and remodeling when performed immediately after AMI. METHODS AND RESULTS: Sixteen farm pigs underwent 90 min left anterior descending artery balloon occlusion. Eight pigs underwent RD immediately after reperfusion. LV function, extent of myocardium at risk, and myocardial necrosis were quantified by cardiac magnetic resonance 5 and 30 days after AMI. 123I-MIBG scintigraphy was performed 31 days after AMI to image myocardial sympathetic innervation. Heart norepinephrine was quantified (from necrotic, border and remote zone). RD and control did not differ in myocardium at risk extent (59 ± 9 vs 55 ± 11% of LV mass) at 5 days. At 30 days CMR, RD pigs had smaller necrotic areas than control as assessed by gadolinium delay enhancement (18 ± 7 vs 30 ± 12% of LV mass, p = 0.021) resulting in improved myocardial salvage index (60 ± 11 vs 44 ± 27%, p < 0.001). RD pigs had higher cardiac output (3.7 ± 0.8 vs 2.66 ± 0.7 L/min, p < 0.001) and lower LV end diastolic volume (98 ± 16 vs 113 ± 31 ml, p = 0.041). 123I-MIBG defect extension was smaller in RD than control (60 ± 28 vs 78 ± 17%, p < 0.05) with significant reduction in the difference between innervation and perfusion defects (25 ± 12 vs 36 ± 30%, p = 0.013). NE content from necrotic area (238; IQR 464 vs 2546; IQR 1727 ng/g in RD and control, respectively, p < 0.001) and from border zone (295; IQR 264 vs 837; IQR 207 in RD and control, respectively, p = 0.031) was significantly lower in RD than control. CONCLUSIONS: RD results in increased myocardial salvage and better cardiac function, when performed immediately after AMI. Reduction of sympathetic activation with preservation of cardiac sympathetic functionality warranted by RD may sustain these effects.

The Role of 18FDG PET/CT in the Assessment of Endocarditis, Myocarditis and Pericarditis.

Endocarditis, myocarditis and pericarditis are a heterogeneous group of phenotypic syndromes where the culprit area of inflammation is the heart. Inflammation may be determined by an infective agent, toxins, drugs or an activated immune system. Clinical manifestations can be subtle and diagnosis remains a challenge for cardiologists, requiring high level of suspicion and advanced multimodal cardiac imaging to avoid life-threatening consequences. The purpose of this review is to report the recent advances of PET/CT imaging with 18FDG in helping the management of patients affected by inflammatory heart disease. Two independent reviewers searched in PubMed articles published before or in June 2019 and final decisions on the inclusion of references were done in consensus with a third reviewer. At the end of the selection process 23/206 articles on "cardiac inflammation"; 26/235 articles on "endocarditis", "prosthetic heart valve", "pacemaker", "implantable cardiac device"; 7/103 articles on "myocarditis"; 13/330 articles on sarcoidosis" and 2/19 articles on "pericarditis" were included. Compared with the conventional methods, molecular imaging has the advantage to non-invasively and directly trace the inflammatory process, and to identify earlier the presence and the extent of intra-cardiac and extra-cardiac involvement, to enable quantification of disease activity, guide therapeutic interventions, and monitor treatment success.

18-FDG PET for large vessel vasculitis diagnosis and follow-up.

OBJECTIVES: Large vessel vasculitis (LVV) are chronic inflammatory diseases that affect arteries. While a mere clinical-serological approach does not seem sensitive either in the initial evaluation nor in long-term monitoring, 18-FDG positron emission tomography (18-FDG PET) is currently considered a useful assessment tool in LVV. We aimed at exploring the utility of 18-FDG, compared with traditional assessments, in the short- and long-term follow-up of patients with LVV. In addition, we compared patterns of vascular involvement in patients with Takayasu's arteritis (TAK) and giant cell arteritis (GCA). METHODS: We retrospectively analysed 47 patients affected by LVV, evaluating clinics, blood chemistry and 18-FDG PET results, at two time points, short-term (average 8 months after diagnosis) and long-term (average 29 months). RESULTS: 18-FDG PET uptake, expressed as mean value of SUV max, decreased significantly during follow-up in all the patients. A low concordance between 18-FDG PET and acute phase reactants levels was observed, but also a good sensitivity in detecting the response to treatment. CONCLUSIONS: The results confirm the role of 18-FDG PET as a powerful tool in the evaluation of LVV, both at the time of diagnosis and during monitoring. Furthermore, the data confirm that GCA and TAK are part of the same disease spectrum.

Negative binomial maximum likelihood expectation maximization (NB-MLEM) algorithm for reconstruction of pre-corrected PET data.

PURPOSE: Positron emission tomography (PET) image reconstruction is usually performed using maximum likelihood (ML) iterative reconstruction methods, under the assumption of Poisson distributed data. Pre-correcting raw measured counts, this assumption is no longer realistic. The goal of this work is to develop a reconstruction algorithm based on the Negative Binomial (NB) distribution, which can generalize over the Poisson distribution in case of over-dispersion of raw data, that may occur if sinogram pre-correction is used. METHODS: The mathematical derivation of a Negative Binomial Maximum Likelihood Expectation-Maximization (NB-MLEM) algorithm is presented. A simulation study to compare the performance of the proposed NB-MLEM algorithm with respect to a Poisson-based MLEM (P-MLEM) method was performed, in reconstructing PET data. The proposed NB-MLEM reconstruction was tested on a real phantom and human brain data. RESULTS: For the property of NB distribution, it is a generalization of the conventional P-MLEM: for not over dispersed data, the proposed NB-MLEM algorithm behaves like the conventional P-MLEM; for over-dispersed PET data, the additional evaluation of the dispersion parameter after each reconstruction iteration leads to a more accurate final image with respect to P-MLEM. CONCLUSIONS: A novel approach for PET image reconstruction from pre-corrected data has been developed, which exhibits a statistical behavior that deviates from the Poisson distribution. Simulation study and preliminary tests on real data showed how the NB-MLEM algorithm, being able to explain the over-dispersion of pre-corrected data, can outperform other algorithms that assume no over-dispersion of pre-corrected data, while still not accounting for the presence of negative data, such as P-MLEM.

Altered adipocyte differentiation and unbalanced autophagy in type 2 Familial Partial Lipodystrophy: an in vitro and in vivo study of adipose tissue browning.

Type-2 Familial Partial Lipodystrophy is caused by LMNA mutations. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Several studies have demonstrated that autophagy is involved in the regulation of adipocyte differentiation and the maintenance of the balance between white and brown adipose tissue. We identified deregulation of autophagy in laminopathic preadipocytes before induction of differentiation. Moreover, in differentiating white adipocyte precursors, we observed impairment of large lipid droplet formation, altered regulation of adipose tissue genes, and expression of the brown adipose tissue marker UCP1. Conversely, in lipodystrophic brown adipocyte precursors induced to differentiate, we noticed activation of autophagy, formation of enlarged lipid droplets typical of white adipocytes, and dysregulation of brown adipose tissue genes. In agreement with these in vitro results indicating conversion of FPLD2 brown preadipocytes toward the white lineage, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. Moreover, in vivo morpho-functional evaluation of fat depots in the neck area of three FPLD2 patients by PET/CT analysis with cold stimulation showed the absence of brown adipose tissue activity. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and show that both impaired white adipocyte turnover and failure of adipose tissue browning contribute to disease.