Significance: Failure to maintain mitochondrial DNA (mtDNA) has been implicated in a variety of mitochondrial disorders and human diseases. mtDNA degradation is an important process for mtDNA maintenance and stress response; nevertheless, the mechanism by which mtDNA is degraded remains partially understood. We demonstrate that mitochondrial transcription factor A (TFAM) facilitates damaged DNA degradation by accelerating strand cleavage at abasic sites, reducing the half-life of abasic DNA by 2 to 3 orders of magnitude relative to free DNA. The TFAM-catalyzed AP-lesion destabilization occurs with nonspecific DNA or mitochondrial light-strand promoter sequence, facilitated by lysine residues of TFAM to form Schiff base intermediates. The catalytic effect of TFAM on abasic DNA suggests a novel role of TFAM in mtDNA metabolism.

Background: The factors associated with unplanned higher-level re-amputation (UHRA) and one-year mortality among patients with chronic limb-threatening ischemia (CLTI) after lower extremity amputation are poorly understood. Methods: This was a single-center retrospective study of patients who underwent amputations for CLTI between 2014 and 2017. Unadjusted bivariate analyses and adjusted odds ratios (AOR) from logistic regression models were used to assess associations between pre-amputation risk factors and outcomes (UHRA and one-year mortality). Results: We obtained data on 203 amputations from 182 patients (median age 65 years [interquartile range (IQR) 57, 75]; 70.7% males), including 118 (58.1%) toe, 20 (9.9%) transmetatarsal (TMA), 37 (18.2%) below-knee (BKA), and 28 (13.8%) amputations at or above the knee. Median follow-up was 285 days (IQR 62, 1348). Thirty-six limbs (17.7%) had a UHRA, and the majority of these (72.2%) were following index forefoot amputations. Risk factors for UHRA included non-ambulatory status (AOR 6.74, 95% confidence interval (CI) 1.74–26.18; p < 0.10) and toe pressure < 30 mm Hg (AOR 4.89, 95% CI 1.52–15.78; p < 0.01). One-year mortality was 17.2% (n = 32), and risk factors included coronary artery disease (AOR 3.93, 95% CI 1.56–9.87; p < 0.05), congestive heart failure (AOR 4.90, 95% CI 1.96–12.29; p = 0.001), end-stage renal disease (AOR 7.54, 95% CI 3.10–18.34; p < 0.001), and non-independent ambulation (AOR 4.31, 95% CI 1.20–15.49; p = 0.03). Male sex was associated with a reduced odds of death at 1 year (AOR 0.37, 95% CI 0.15–0.89; p < 0.05). UHRA was not associated with one-year mortality. Conclusions: Rates of UHRA after toe amputations and TMA are high despite revascularization and one-year mortality is high among patients with CLTI requiring amputation.

Background: Alkaptonuria is a rare metabolic disease that causes an increase in homogentisic acid (HGA) due to a lack of enzymatic activity. Commonly, accumulation of HGA presents with dark discoloration of skin and other tissues, also known as ochronosis. Additionally, alkaptonuria can result in other clinical manifestations, including arthritis and cardiac disease. This case highlights alkaptonuria-related cardiac disease and challenges that cardiac surgery teams may face when treating this patient population. Case summary: A 62-year-old male with a history of alkaptonuria, Hodgkin’s lymphoma treated with chemoradiation, hypertension, and hyperlipidaemia originally presented with shortness of breath in the setting of known cardiac disease. Cardiac work-up demonstrated aortic stenosis, mitral stenosis, and multivessel coronary artery disease requiring aortic valve replacement, mitral valve replacement, and coronary artery bypass grafting. During the operation, significant discoloration of tissue was observed. This correlated with areas of severe calcification, which was noted throughout both valves. Extensive debridement was required prior to proceeding to valve replacements. Additionally, near-infrared spectroscopy failed to provide accurate measurements of cerebral oxygenation. Discussion: Alkaptonuria is correlated with cardiovascular disease, particularly valvular disease. Intraoperatively, these patients may exhibit noticeable discoloration and severe calcification of various tissues. Additionally, traditional infrared-based methods of cerebral oxygenation monitoring may not be reliable; however, other options of cerebral monitoring may be feasible. With proper pre-operative planning, however, patients with alkaptonuria may safely undergo cardiac surgery.

Background: Patients born with single ventricle anatomy palliated with the Fontan procedure are at risk of lymphatic complications (LC), including plastic bronchitis, protein losing enteropathy, and ascites. The mechanism of LC, associated risk factors, and impact on end organ dysfunction and mortality are not well understood. Methods: We performed a single‐center, retrospective, cross‐sectional cohort study of patients with Fontan circulation seen at our center between 2009 and 2022. Univariate comparisons were completed comparing those with and without LC. Results: A total of 314 Fontan patients were included with a mean age of 20.2±10.7 years. Of those patients, 83 (26.4%) had at least 1 LC, including ascites (21.4%), protein losing enteropathy (11.8%), and plastic bronchitis (2.9%). Patients with LC were older (23.5±12.6 versus 19.1±9.8 years, P =0.001) and had their Fontan operation at an older age (5.5 with LC versus 4.0 years without LC, P <0.001). The presence of LC was associated with renal dysfunction ( P =0.004), thromboembolism ( P =0.01), and arrhythmia ( P <0.001). LC were also associated with higher mean Fontan pressures on catheterization (14.7±3.8 with LC versus 12.8±3.7 mm Hg without LC, P =0.003). Fontan patients with LC had higher rates of transplantation (25.3% versus 2.2%, P <0.001) and death (18.1% with LC versus 4.3% without LC, P <0.001). Conclusions: Fontan‐related lymphatic complications develop in 1 out of 4 patients by 20 years of age, and they are associated with older age, renal dysfunction, thromboembolism, and arrhythmia. Patients with LC have higher rates of transplantation and death. Our findings indicate that elevated central venous pressure, rather than systolic cardiac or atrioventricular valve function, is associated with these complications.