Publications

RATIONALE: The mTORC1 (mechanistic target of rapamycin complex-1) controls metabolism and protein homeostasis and is activated following ischemia reperfusion (IR) injury and by ischemic preconditioning (IPC). However, studies vary as to whether this activation is beneficial or detrimental, and its influence on metabolism after IR is little reported. A limitation of prior investigations is their use of broad gain/loss of mTORC1 function, mostly applied before ischemic stress. This can be circumvented by regulating one serine (S1365) on TSC2 (tuberous sclerosis complex) to achieve bidirectional mTORC1 modulation but only with TCS2-regulated costimulation.

OBJECTIVE: We tested the hypothesis that reduced TSC2 S1365 phosphorylation protects the myocardium against IR and is required for IPC by amplifying mTORC1 activity to favor glycolytic metabolism.

METHODS AND RESULTS: Mice with either S1365A (TSC2SA; phospho-null) or S1365E (TSC2SE; phosphomimetic) knockin mutations were studied ex vivo and in vivo. In response to IR, hearts from TSC2SA mice had amplified mTORC1 activation and improved heart function compared with wild-type and TSC2SE hearts. The magnitude of protection matched IPC. IPC requited less S1365 phosphorylation, as TSC2SE hearts gained no benefit and failed to activate mTORC1 with IPC. IR metabolism was altered in TSC2SA, with increased mitochondrial oxygen consumption rate and glycolytic capacity (stressed/maximal extracellular acidification) after myocyte hypoxia-reperfusion. In whole heart, lactate increased and long-chain acylcarnitine levels declined during ischemia. The relative IR protection in TSC2SA was lost by lowering glucose in the perfusate by 36%. Adding fatty acid (palmitate) compensated for reduced glucose in wild type and TSC2SE but not TSC2SA which had the worst post-IR function under these conditions.

CONCLUSIONS: TSC2-S1365 phosphorylation status regulates myocardial substrate utilization, and its decline activates mTORC1 biasing metabolism away from fatty acid oxidation to glycolysis to confer protection against IR. This pathway is also engaged and reduced TSC2 S1365 phosphorylation required for effective IPC. Graphic Abstract: A graphic abstract is available for this article.

COVID-19 is one of the most consequential pandemics in the last century, yet the biological mechanisms that confer disease risk are incompletely understood. Further, heterogeneity in disease outcomes is influenced by race, though the relative contributions of structural/social and genetic factors remain unclear. Very recent unpublished work has identified two genetic risk loci that confer greater risk for respiratory failure in COVID-19: the ABO locus and the 3p21.31 locus. To understand how these loci might confer risk and whether this differs by race, we utilized proteomic profiling and genetic information from three cohorts including black and white participants to identify proteins influenced by these loci. We observed that variants in the ABO locus are associated with levels of CD209/DC-SIGN, a known binding protein for SARS-CoV and other viruses, as well as multiple inflammatory and thrombotic proteins, while the 3p21.31 locus is associated with levels of CXCL16, a known inflammatory chemokine. Thus, integration of genetic information and proteomic profiling in biracial cohorts highlights putative mechanisms for genetic risk in COVID-19 disease.

Risk assessments are integral for the prevention and management of cardiometabolic disease (CMD). However, individuals may develop CMD without traditional risk factors, necessitating the development of novel biomarkers to aid risk prediction. The emergence of omic technologies, including genomics, proteomics, and metabolomics, has allowed for assessment of orthogonal measures of cardiometabolic risk, potentially improving the ability for novel biomarkers to refine disease risk assessments. While omics has shed light on novel mechanisms for the development of CMD, its adoption in clinical practice faces significant challenges. We review select omic technologies and cardiometabolic investigations for risk prediction, while highlighting challenges and opportunities for translating findings to clinical practice.

PURPOSE OF REVIEW: To highlight updates on the use of extracorporeal membrane oxygenation (ECMO) and surgical embolectomy in the treatment of massive pulmonary embolism.

RECENT FINDINGS: Outcomes for surgical embolectomy for massive pulmonary embolism have improved in the recent past. More contemporary therapeutic options include catheter embolectomy, which although offer less invasive means of treating this condition, need further study. The use of ECMO as either a bridge or mainstay of treatment in patients with contraindications to fibrinolysis and surgical embolectomy, or have failed initial fibrinolysis, has increased, with data suggesting improved outcomes with earlier implementation in selected patients.

SUMMARY: Although surgical embolectomy continues to be the initial treatment of choice in massive pulmonary embolism with contraindications or failed fibrinolysis, the use of ECMO in these high-risk patients provides an important tool in managing this often fatal condition.

Cardiac involvement in systemic amyloidosis (AL) occurs in  50% of all AL patients. However once symptomatic heart failure develops, therapeutic options are limited thereby conferring a poor overall prognosis. The median survival is <6 months when AL patients are untreated for the underlying plasma cell dyscrasia. We thus sought to identify risk factors of increased mortality in treatment-naïve, AL cardiac amyloidosis with heart failure. Patients with biopsy-proven AL cardiac amyloid, who presented with heart failure and did not received prior AL treatment, were enrolled between 2004-2014, at the initial visit to the Amyloidosis Center at Boston University Medical Center. Routine laboratory tests, physical examination and echocardiography data were collected. There were 165 predominantly white (76.4%), and male (61%) patients, with a mean age of 61.6 ± 9.5 years. Median survival was 10.9 months (95% CI 6.2-14.7). By multivariate analysis increased relative wall thickness (RWT) [HR 6.70; 95% CI 2.45-18.30), older age (HR 1.04; 95% CI 1.01-1.06), higher New York Heart Association (NYHA) functional class (HR 1.50; 95% CI 1.02-2.2), log brain natriuretic peptide (BNP) levels (HR 1.45; 95% CI 1.15-1.81) and C-reactive protein (CRP) levels (HR 1.02; 95% CI 1.00-1.04) were significant predictors for increased mortality. In conclusion, in treatment-naïve, AL cardiac amyloidosis patients with heart failure symptoms who lack these high-risk features may have a better outcome. These findings might allow for better risk stratification although outcomes are still poor.

Improved stent technologies have lead to reduced minimum durations of dual antiplatelet therapy (DAPT) to prevent stent thrombosis. However, the anti-ischemic benefits seen in extended DAPT in both stent and non-stent related lesions have called into question the optimum duration of DAPT after stent placement. Areas covered: We review the evidence for varying durations of DAPT after drug eluting stent placement including for patients on oral anticoagulation; decision tools available for clinicians to optimize patient selection for extended therapy and insight into application of these risk assessment tools in clinical practice. Expert commentary: The use of risk assessment tools in optimizing DAPT duration after stent placement provides an opportunity for improved outcomes by means of a personalized approach to care while allowing clinicians to engage with patients in shared-decision making.

OBJECTIVES: This study sought to identify clinical and procedural predictors of elevated radiation dose received by patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) and to determine if elevated radiation dose was predictive of mortality in this population.

BACKGROUND: Little data exist regarding the impact of excessive radiation burden on clinical outcomes in patients undergoing PCI.

METHODS: The study population included 1,039 patients who underwent PCI for an AMI between January 1, 2007 and December 31, 2008 at an academic tertiary care teaching hospital. Cumulative skin dose (measured in milligray [mGy]) was selected as a measurement of patient radiation burden. Clinical and procedural variables were analyzed in multiple logistic and linear regression models to determine predictors of higher skin dose, and its impact was evaluated on all-cause intermediate-term mortality at two years.

RESULTS: Median skin dose was 2120 mGy (IQR 1379-3190 mGy) in the overall population, of which 153 (20.8%) patients received an elevated skin dose (defined as a skin dose>4,000 mGy). Independent predictors of elevated skin dose included male gender, obesity, multivessel intervention, and presentation with a non-ST-elevation MI (NSTEMI) versus an ST-elevation MI (STEMI). Increased skin dose was not predictive of intermediate-term mortality by multivariate analysis in the overall population or in either subgroup of STEMI and NSTEMI.

CONCLUSIONS: In this contemporary observational study examining patients with AMI undergoing PCI, male gender, obesity, multivessel intervention, and presentation with a NSTEMI were associated with increased radiation exposure.