MET somatic activating mutations are responsible for lymphovenous malformation and can be identified using cell-free DNA next generation sequencing liquid biopsy.

OBJECTIVE: Germline mutations of either the endothelial cell-specific tyrosine kinase receptor TIE2 or the glomulin (GLMN) gene are responsible for rare inherited venous malformations. Both genes affect the hepatocyte growth factor receptor c-Met, inducing vascular smooth muscle cell migration. Germline mutations of hepatocyte growth factor are responsible for lymphatic malformations, leading to lymphedema. The molecular alteration leading to the abnormal mixed vascular anomaly defined as lymphovenous malformation has remained unknown. METHODS: A group of 4 patients with lymphovenous malformations were selected. Plasma was obtained from both peripheral and efferent vein samples at the vascular malformation site for cell-free DNA extraction. When possible, we analyzed tissue biopsy samples from the vascular lesion. RESULTS: We have demonstrated that in all four patients, an activating MET mutation was present. In three of the four patients, the same pathogenic activating mutation, T1010I, was identified. The mutation was found at the tissue level for the patient with tissue samples available, confirming its causative role in the lymphovenous malformations. CONCLUSIONS: In the present study, we have demonstrated that cell-free DNA next generation sequencing liquid biopsy is able to identify the MET mutations in affected tissues. Although a wider cohort of patients is necessary to confirm its causative role in lymphovenous malformations, these data suggest that lymphovenous malformations could result from postzygotic somatic mutations in genes that are key regulators of lymphatic development. The noninvasiveness of the method avoids any risk of bleeding and can be easily performed in children. We are confident that the present pioneering results have provided a viable alternative in the future for lymphovenous malformation diagnosis, allowing for subsequent therapy tailored to the genetic defect.

Psychosocial assessment of families caring for a child with acute lymphoblastic leukemia, epilepsy or asthma: Psychosocial risk as network of interacting symptoms.

The purpose of this study is to assess psychosocial risk across several pediatric medical conditions and test the hypothesis that different severe or chronic pediatric illnesses are characterized by disease specific enhanced psychosocial risk and that risk is driven by disease specific connectivity and interdependencies among various domains of psychosocial function using the Psychosocial Assessment Tool (PAT). In a multicenter prospective cohort study of 195 patients, aged 5-12, 90 diagnosed with acute lymphoblastic leukemia (ALL), 42 with epilepsy and 63 with asthma, parents completed the PAT2.0 or the PAT2.0 generic version. Multivariate analysis was performed with disease as factor and age as covariate. Graph theory and network analysis was employed to study the connectivity and interdependencies among subscales of the PAT while data-driven cluster analysis was used to test whether common patterns of risk exist among the various diseases. Using a network modelling approach analysis, we observed unique patterns of interconnected domains of psychosocial factors. Each pathology was characterized by different interdependencies among the most central and most connected domains. Furthermore, data-driven cluster analysis resulted in two clusters: patients with ALL (89%) mostly belonged to cluster 1, while patients with epilepsy and asthma belonged primarily to cluster 2 (83% and 82% respectively). In sum, implementing a network approach improves our comprehension concerning the character of the problems central to the development of psychosocial difficulties. Therapy directed at problems related to the most central domain(s) constitutes the more rational one because such an approach will inevitably carry over to other domains that depend on the more central function.

Impact of specific coronary lesions on regional ischemia at single photon emission computed tomography.

AIMS: Prior studies using stress myocardial perfusion imaging (MPI), which examined the association between obstructive epicardial coronary disease and presence of myocardial ischemia did not provide a detailed assessment on a regional level. We examined this relationship in a large population of patients in whom the coronary anatomy was defined by invasive coronary angiography. METHODS: We retrospectively extracted details on individuals undergoing MPI with single photon emission computed tomography (SPECT) who had coronary angiography within 12 months. A 17-segment model for native coronary anatomy and a 7-region model for myocardial perfusion were used with a dedicated matching algorithm. RESULTS: A total of 2564 patients were included, yielding a total of 6279 stenoses matched with 17 948 myocardial regions. From such a cohort, 151 (5.9%) patients had normal perfusion, 1878 (73.2%) had myocardial ischemia (reversible defects), 260 (10.1%) had myocardial necrosis (scar or fixed defects), and 275 (10.7%) had ischemia and necrosis. At per-patient analysis, significant angiographic disease was more common in the ischemic group (prevalence between 69.6 and 80.0%) than other groups. At per-region analysis, abnormal perfusion in the coronary-specific regions varied depending on location of stenosis; it was 96% for left main disease, 81% for proximal left anterior descending disease, 85% for proximal left circumflex disease, and 82% for proximal right coronary artery disease and <60% for posterior descending artery disease. CONCLUSION: The correlation between significant coronary stenosis and presence of corresponding regional perfusion abnormality depends on the location of the lesion and the corresponding myocardial region.

Assessment of the fate of myocardial necrosis by serial myocardial perfusion imaging.

BACKGROUND: Myocardial necrosis after myocardial infarction (MI) is common; extent and severity are however variable. The pattern is recognized by myocardial perfusion imaging (MPI) as fixed perfusion defects (FPD). The fate of such FPD is not well appraised. This study addressed this important issue in a large number of patients undergoing serial MPI in relation to type of intervening therapy. METHODS: Patients with prior MI or MPI-evidence of myocardial necrosis undergoing serial MPI without intervening acute coronary syndromes were included. The fate of necrosis by MPI on per-patient and per-region analysis was analyzed, factoring also the impact of intervening coronary revascularization (CR). RESULTS: A total of 3691 patients with 25,837 regions were identified, including 1413 (38.3%) subjects with 3358 (13.0%) regions exhibiting necrosis. Serial MPI after 29±21 months confirmed the persistent presence of myocardial necrosis FPD in the vast majority of patients and regions (86%); the consistency was even higher in the presence of moderate or severe necrosis (99%). Neither type nor site of CR significantly impacted on the presence and extent of myocardial necrosis at multivariable analysis. CONCLUSIONS: The finding of myocardial necrosis by MPI remains highly consistent over time, and is not significantly altered by CR.

Prognostic accuracy of myocardial perfusion imaging in octogenarians.

BACKGROUND: Myocardial perfusion imaging (MPI) has an established role in the work-up of coronary artery disease (CAD), but its comparative accuracy is debated in elderly patients. We examined a large administrative database to appraise the performance of MPI in octogenarians. METHODS: Our institutional database was queried for patients undergoing MPI without recent coronary revascularization or myocardial infarction (MI). We compared baseline, procedural, diagnostic, and prognostic features in patients aged < 80 vs ≥ 80 years with bivariate and propensity-adjusted analyses. RESULTS: From 13,254 patients, 12,737 (96.1%) were < 80 years old and 517 (3.9%) ≥ 80 years. Octogenarians were less likely to undergo exercise testing, had more severe and extensive myocardial ischemia (all P < 0.001), whereas CAD was more prevalent and diffuse in them (P = 0.012), and major adverse cardiac events more common during follow-up (P = 0.009). Diagnostic accuracy of MPI was similar or higher in octogenarians than in younger patients (e.g., sensitivity for three-vessel disease 92% in octogenarians vs 91% in younger patients), as was prognostic accuracy. Using propensity-matched analyses, MPI again yielded satisfactory prognostic accuracy in octogenarians. CONCLUSIONS: Use of MPI in octogenarians is associated with similar or better prognostic accuracy than in younger subjects.

Temporal Trends in the Prevalence, Severity, and Localization of Myocardial Ischemia and Necrosis at Myocardial Perfusion Imaging After Myocardial Infarction.

The definition, presentation, and management of myocardial infarction (MI) have changed substantially in the last decade. Whether these changes have impacted on the presence, severity, and localization of necrosis at myocardial perfusion imaging (MPI) has not been appraised to date. Subjects undergoing MPI and reporting a history of clinical MI were shortlisted. We focused on the presence, severity, and localization of necrosis at MPI with a retrospective single-center analysis. A total of 10,476 patients were included, distinguishing 5 groups according to the period in which myocardial perfusion scintigraphy had been performed (2004 to 2005, 2006 to 2007, 2008 to 2009, 2010 to 2011, 2012 to 2013). Trend analysis showed over time a significant worsening in baseline features (e.g., age, diabetes mellitus, and Q waves at electrocardiogram), whereas medical therapy and revascularization were offered with increasing frequency. Over the years, there was also a lower prevalence of normal MPI (from 16.8% to 13.6%) and ischemic MPI (from 35.6% to 32.8%), and a higher prevalence of ischemic and necrotic MPI (from 12.0% to 12.7%) or solely necrotic MPI (from 35.7% to 40.9%, p <0.001). Yet the prevalence of severe ischemia decreased over time from 11.4% to 2.0%, with a similar trend for moderate ischemia (from 15.9% to 11.8%, p <0.001). Similarly sobering results were wound for the prevalence of severe necrosis (from 19.8% to 8.2%) and moderate necrosis (from 8.5% to 7.8%, p = 0.028). These trends were largely confirmed at regional level and after propensity score matching. In conclusion, the outlook of stable patients with previous MI has substantially improved in the last decade, with a decrease in the severity of residual myocardial ischemia and necrosis, despite an apparent worsening in baseline features.

Impact of coronary revascularization on the clinical and scintigraphic outlook of patients with myocardial ischemia.

AIMS: The impact of coronary revascularization on outcomes and ischemic burden among patients with objective proof of ischemia is not yet established. We appraised the impact of revascularization on outcomes and residual ischemia in patients with objective evidence of ischemia at myocardial perfusion scintigraphy (MPS). METHODS: We queried our database for stable patients with myocardial ischemia at MPS, excluding those with prior myocardial infarction, systolic dysfunction, or cardiomyopathy. The impact of revascularization (defined as revascularization as first follow-up event) on outcomes and changes in myocardial ischemia at repeat MPS was appraised with propensity-matched analyses. RESULTS: From 6195 patients, propensity matching yielded 1262 pairs of patients undergoing revascularization versus not undergoing revascularization. After 35.2 ±â€Š23.9 months, revascularization was associated with lower risks of cardiac death [2 (0.2%) versus 10 (0.8%) in those not revascularized, P = 0.038] and of the composite of cardiac death or myocardial infarction [17 (1.3%) versus 37 (2.9%), P = 0.007]. In addition, revascularization was associated with a higher rate of improvement in ischemia degree after 28.1 ±â€Š20.7 months of follow-up (P < 0.001), with 257 (69.3%) patients with moderate or severe ischemia at baseline MPS improving after revascularization versus 136 (42.0%) in the nonrevascularization group. Conversely, revascularization did not prove impactful on follow-up MPS in patients with only minimal or mild ischemia at baseline MPS (P < 0.001). CONCLUSION: In a large series of patients with objective evidence of myocardial ischemia at MPS, especially when moderate or severe, revascularization was associated with a better clinical prognosis and a lower ischemic burden at repeat MPS.

Impact of coronary revascularization vs medical therapy on ischemia among stable patients with or suspected coronary artery disease undergoing serial myocardial perfusion scintigraphy.

BACKGROUND: Randomized trials have challenged the role of revascularization in stable coronary artery disease. We aimed to appraise the impact of revascularization on ischemia in patients undergoing serial myocardial perfusion scintigraphy (MPS). METHODS: We queried our institutional database for stable subjects undergoing serial MPS and appraised the impact of revascularization on changes in ischemia. RESULTS: A total of 3631 patients were included: 967 (27%) undergoing revascularization and 2664 (73%) receiving medical therapy only. Patients treated with revascularization had a significantly lower burden of myocardial ischemia at follow-up (odds ratio = 0.577 [95% confidence interval 0.483-0.689] vs medical therapy, P < .001). Among all those having moderate or severe ischemia at baseline, revascularization was associated with a follow-up prevalence of 80% for no, minimal, or mild ischemia and 20% for moderate or severe ischemia, vs 43% and 57% for medical therapy (P < .001). Even at multivariable analysis and propensity-adjusted, and propensity-matched analyses, revascularization was associated with a significantly lower prevalence of moderate or severe ischemia at follow-up (respectively P < .001, P = .001, and P = .042). CONCLUSIONS: Revascularization appears superior to medical therapy in reducing ischemic burden and normalizing myocardial perfusion among subjects with moderate or severe ischemia at baseline.

Comparative Impact of Hypoglycemic Agents on Severity and Extent of Myocardial Ischemia in Patients With Type 2 Diabetes Mellitus Undergoing Myocardial Perfusion Scintigraphy.

BACKGROUND: Hypoglycemic agents differ in mechanism, efficacy, and profile. However, there is uncertainty on their impact on myocardial perfusion. We thus aimed to investigate whether individuals with type 2 diabetes mellitus treated with different drug classes exhibit different perfusion patterns at myocardial perfusion scintigraphy (MPS). METHODS AND RESULTS: We queried our administrative database for patients with diabetes mellitus without prior or recent myocardial infarction. The primary objective was to compare the severity and extent of ischemia at MPS, distinguishing patients according to management strategy. A total of 7592 patients were included [2336 (31%) on diet, 3611 (48%) on metformin, 749 (10%) on sulfonylureas, 449 (6%) on metformin plus sulfonylureas, 447 (6%) on metformin plus insulin]. Unadjusted analyses and analyses adjusting for baseline features suggested that sulfonylureas alone or in combination were associated with more severe ischemia than nonsulfonylurea regimens (P < 0.05), whereas combination regimens including metformin were associated with more extensive myocardial ischemia than the other regimens (P < 0.05 for both). However, no significant difference disfavoring either metformin or sulfonylurea regimens persisted after multivariable adjustment for baseline, stress, and angiographic characteristics (all P > 0.05). CONCLUSION: Several significant differences in baseline, stress, and scintigraphic features appear evident in patients with diabetes mellitus receiving different hypoglycemic agents or regimens.

Prognostic impact of location and extent of vessel-related ischemia at myocardial perfusion scintigraphy in patients with or at risk for coronary artery disease.

BACKGROUND: Myocardial perfusion scintigraphy (MPS) has an established diagnostic and prognostic role in patients with or at risk for coronary artery disease, with ischemia severity and extent having already been identified as key predictors. Whether this is affected by the location of myocardial ischemia is uncertain. We aimed at comparing the prognostic outlook of patients undergoing MPS according to the site of ischemia. METHODS: Our institutional database was queried for subjects undergoing MPS, without myocardial necrosis or recent revascularization. We focused on the prognostic impact of location of vessel-related ischemia (VRI) at MPS, distinguishing four mutually exclusive groups: single-VRI involving left anterior descending (LAD), single-VRI not involving LAD, multi-VRI involving LAD, and multi-VRI not involving LAD. The primary outcome was the long-term (>1 year) rate of death or myocardial infarction (D/MI). RESULTS: A total of 13,254 patients were included. Moderate or severe VRI occurred in 2,627 (20%) patients. Clinical outcomes were significantly different among the groups of patients with moderate or severe VRI, including death, cardiac death, non-fatal myocardial infarction or their composites (overall P < .001). Specifically, and excluding subjects undergoing revascularization as first follow-up event, D/MI occurred in 8.4% of patients with single-VRI involving LAD, 5.5% of subjects with single-VRI not involving LAD, 16.5% of those with multi-VRI involving LAD, and 7.3% of patients with multi-VRI not involving LAD (overall P < .001). Even at incremental multivariable Cox proportional analysis, hierarchical VRI was independently associated with an increased risk of D/MI [hazard ratio = 1.17 (1.04-1.08) for each class increment, P = .010]. CONCLUSIONS: Location and extent of myocardial ischemia at MPS according to the VRI concept have a hierarchical predictive impact, with multi-VRI involving LAD being significantly and independently more prognostically ominous than other types of VRI.

Time to and risk of cardiac events after myocardial perfusion scintigraphy.

BACKGROUND: The burden of cardiovascular disease is increasing, yet it remains difficult to focus preventive strategies on populations at highest absolute and relative risks. We compared absolute and relative cardiovascular event counts, plus time to first event, among patients undergoing myocardial perfusion scintigraphy (MPS). METHODS AND RESULTS: Our database was queried to identify subjects without myocardial necrosis or recent revascularization, focusing on cardiac death (CD) or myocardial infarction (MI). A total of 13,254 patients were included, 5436 (41%) without, and 7818 (59%) with ischemia. After 32±21 months, subjects without ischemia, compared to those with ischemia, had lower absolute (16 vs 75 events, 18% vs 82%, p<0.001) and relative (0.3% vs 1.3%, p<0.001) risk of CD. Similar findings were obtained for MI (52 vs 81 events, 39% vs 61%, p<0.001, with corresponding rates of 1.0% vs 1.4%, p<0.001, respectively). Medical therapy appeared associated with fewer outcomes in those without ischemia, with the opposite occurring for subjects with ischemia (p<0.001). Median times to event ranged between 13 and 25 months in patients without ischemia vs 2 and 14 months in those with ischemia (p<0.001 for all comparisons). Multivariable-adjusted and propensity matched analyses confirmed the independent prognostic role of myocardial ischemia and, apparently, revascularization. CONCLUSION: Most fatal and non-fatal cardiac events appear to occur in patients with evidence of myocardial ischemia at MPS, especially those with moderate or severe ischemia not receiving revascularization during follow-up.

A novel clinically relevant segmentation method and corresponding maximal ischemia score to risk-stratify patients undergoing myocardial perfusion scintigraphy.

BACKGROUND: Myocardial perfusion scintigraphy (MPS) represents a key prognostic tool, but its predictive yield is far from perfect. We developed a novel clinically relevant segmentation method and a corresponding maximal ischemia score (MIS) in order to risk-stratify patients undergoing MPS. METHODS: Patients referred for MPS were identified, excluding those with evidence of myocardial necrosis or prior revascularization. A seven-region segmentation approach was adopted for left ventricular myocardium, with a corresponding MIS distinguishing five groups (no, minimal, mild, moderate, or severe ischemia). The association between MIS and clinical events was assessed at 1 year and at long-term follow-up. RESULTS: A total of 8,714 patients were included, with a clinical follow-up of 31 ± 20 months. Unadjusted analyses showed that subjects with a higher MIS were significantly different for several baseline and test data, being older, having lower ejection fraction, and achieving lower workloads (P < .05 for all). Adverse outcomes were also more frequent in patients with higher levels of ischemia, including cardiac death, myocardial infarction (MI), and their composites (P < .05 for all). Differences in adverse events remained significant even after extensive multivariable adjustment (hazard ratio for each MIS increment = 1.57 [1.29-1.90], P < .001 for cardiac death; 1.19 [1.04-1.36], P = .013 for MI; 1.23 [1.09-1.39], P = .001 for cardiac death/MI). CONCLUSIONS: Our novel segmentation method and corresponding MIS efficiently yield satisfactory prognostic information.