Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines.

Primary mitochondrial disease describes a diverse group of neuro-metabolic disorders characterised by impaired oxidative phosphorylation. Diagnosis is challenging; >350 genes, both nuclear and mitochondrial DNA (mtDNA) encoded, are known to cause mitochondrial disease, leading to all possible inheritance patterns and further complicated by heteroplasmy of the multicopy mitochondrial genome. Technological advances, particularly next-generation sequencing, have driven a shift in diagnostic practice from 'biopsy first' to genome-wide analyses of blood and/or urine DNA. This has led to the need for a reference framework for laboratories involved in mitochondrial genetic testing to facilitate a consistent high-quality service. In the United Kingdom, consensus guidelines have been prepared by a working group of Clinical Scientists from the NHS Highly Specialised Service followed by national laboratory consultation. These guidelines summarise current recommended technologies and methodologies for the analysis of mtDNA and nuclear-encoded genes in patients with suspected mitochondrial disease. Genetic testing strategies for diagnosis, family testing and reproductive options including prenatal diagnosis are outlined. Importantly, recommendations for the minimum levels of mtDNA testing for the most common referral reasons are included, as well as guidance on appropriate referrals and information on the minimal appropriate gene content of panels when analysing nuclear mitochondrial genes. Finally, variant interpretation and recommendations for reporting of results are discussed, focussing particularly on the challenges of interpreting and reporting mtDNA variants.

Pathogenic SLC25A26 variants impair SAH transport activity causing mitochondrial disease.

The SLC25A26 gene encodes a mitochondrial inner membrane carrier that transports S-adenosylmethionine (SAM) into the mitochondrial matrix in exchange for S-adenosylhomocysteine (SAH). SAM is the predominant methyl-group donor for most cellular methylation processes, of which SAH is produced as a by-product. Pathogenic, biallelic SLC25A26 variants are a recognized cause of mitochondrial disease in children, with a severe neonatal onset caused by decreased SAM transport activity. Here, we describe two, unrelated adult cases, one of whom presented with recurrent episodes of severe abdominal pain and metabolic decompensation with lactic acidosis. Both patients had exercise intolerance and mitochondrial myopathy associated with biallelic variants in SLC25A26, which led to marked respiratory chain deficiencies and mitochondrial histopathological abnormalities in skeletal muscle that are comparable to those previously described in early-onset cases. We demonstrate using both mouse and fruit fly models that impairment of SAH, rather than SAM, transport across the mitochondrial membrane is likely the cause of this milder, late-onset phenotype. Our findings associate a novel pathomechanism with a known disease-causing protein and highlight the quests of precision medicine in optimizing diagnosis, therapeutic intervention and prognosis.

Identifying opportunities to advance health equity in interventional cardiology: Structural heart disease.

Health care practices are influenced by variety of factors. These factors that include social determinants, race and ethnicity, and gender not only affect access to health care but can also affect quality of care and patient outcomes. These are a source of health care disparities. This article acknowledges that these disparities exist in getting optimal care in structural heart disease, reviews the literature and proposes steps that can help reduce these disparities on personal and committee levels.

Outcomes in Multivessel Coronary Disease Stratified by The Society of Thoracic Surgeons Risk.

BACKGROUND: Surgical risk stratified outcomes after contemporary revascularization strategies have not been well described. We report these outcomes in patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) for multivessel coronary disease. METHODS: A total of 5836 patients with multivessel disease who underwent CABG (n = 4420) or PCI (n = 1416) were included in this retrospective observational analysis. Data were stratified based on The Society of Thoracic Surgeons risk score. A score less than 4% was considered low risk and a score greater than or equal to 4% was considered intermediate-high risk. Outcomes included mortality, inpatient readmissions, and repeat revascularizations. RESULTS: In the CABG population, 3863 (87.3%) were low risk and 557 (12.6%) were intermediate-high risk. The 5-year mortality for the low-risk cohort was 10.9% (95% confidence interval [CI], 9.83%-12.05%), and for the intermediate-high-risk cohort it was 40.1% (95% CI, 35.76%-44.54%). Among those undergoing PCI, 1163 (82.1%) were low risk, while 249 (17.6%) were intermediate-high risk. The 5-year mortality for the low-risk cohort was 21.6% (95% CI, 19.10%-24.26%), and for the intermediate-high-risk cohort it was 61.8% (95% CI, 54.72%-68.70%). CONCLUSIONS: This study reports outcomes stratified by surgical risk after PCI or CABG in patients with multivessel coronary disease. These data can help guide the revascularization strategy choice for individual patients.

Novel method for transaxillary Impella 5.0 implantation in patients with tortuous arterial anatomy.

A novel method of transaxillary Impella 5.0 implantation utilizing a vascular sheath can overcome difficult arterial anatomy and provide mechanical support for patients in critical cardiogenic shock.

Relationship between predicting bleeding complication in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score and mortality among patients with atrial fibrillation undergoing percutaneous coronary intervention.

BACKGROUND: The predicting bleeding complication in patients undergoing stent implantation and subsequent dual antiplatelet therapy, PRECISE-DAPT (P-DAPT) score has been validated in large cohorts as an effective tool in predicting bleeding complication after dual antiplatelet therapy (DAPT) as well as in predicting in-hospital mortality. The implication of using this score to predict outcomes, including mortality in patients with atrial fibrillation (AF) undergoing PCI is unknown. OBJECTIVE: Role of P-DAPT score to study clinical outcomes, including mortality, hospitalization, and major bleeding, particularly among patients with AF. METHODS: This is a retrospective observational study of 18,850 consecutive patients who underwent percutaneous coronary intervention (PCI) across a large multihospital healthcare system from 2010 to 2019. Patients were stratified into four groups depending on the presence or absence of AF and P-DAPT score, with score ≥ 25 defined as high risk. The primary outcome was all-cause mortality. The secondary outcomes evaluated were hospitalization and major bleeding. RESULTS: In the unadjusted analyses, a P-DAPT score ≥ 25, in both AF and non-AF population, was associated with increased mortality, hospitalization, and bleeding. After adjusting for baseline covariates, no significant differences in major bleeding risk were found across the four groups. However, a P-DAPT score of ≥25 in AF patients was associated with a higher risk for hospitalizations related to cardiovascular causes (HR: 2.15 95% CI 2.00-2.3, p < .0001). Among AF patients, P-DAPT score ≥ 25 was found to be strongly associated with mortality (HR 3.5; 95% CI 2.95-4.25, p < .0001) as compared with AF patients with score < 25 (HR 1.18, 95% CI 0.88-1.54, p = .26). CONCLUSION: In this large cohort of patients undergoing PCI, the P-DAPT score can help to identify patients at high risk for long-term mortality, particularly among those with atrial fibrillation.

The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency.

PURPOSE: Mitochondrial DNA (mtDNA) depletion syndrome (MDDS) encompasses a group of genetic disorders of mtDNA maintenance. Mutation of RRM2B is an uncommon cause of infantile-onset encephalomyopathic MDDS. Here we describe the natural history of this disease. METHODS: Multinational series of new genetically confirmed cases from six pediatric centers. RESULTS: Nine new cases of infantile-onset RRM2B deficiency, and 22 previously published cases comprised a total cohort of 31 patients. Infants presented at a mean of 1.95 months with truncal hypotonia, generalized weakness, and faltering growth. Seizures evolved in 39% at a mean of 3.1 months. Non-neurological manifestations included respiratory distress/failure (58%), renal tubulopathy (55%), sensorineural hearing loss (36%), gastrointestinal disturbance (32%), eye abnormalities (13%), and anemia (13%). Laboratory features included elevated lactate (blood, cerebrospinal fluid (CSF), urine, magnetic resonance (MR), spectroscopy), ragged-red and cytochrome c oxidase-deficient fibers, lipid myopathy, and multiple oxidative phosphorylation enzyme deficiencies in skeletal muscle. Eight new RRM2B variants were identified. Patients with biallelic truncating variants had the worst survival. Overall survival was 29% at 6 months and 16% at 1 year. CONCLUSIONS: Infantile-onset MDDS due to RRM2B deficiency is a severe disorder with characteristic clinical features and extremely poor prognosis. Presently management is supportive as there is no effective treatment. Novel treatments are urgently needed.

Surgical versus percutaneous multivessel coronary revascularization in patients with chronic kidney disease.

OBJECTIVES: This study compared contemporary outcomes following surgical versus percutaneous coronary revascularization for multivessel coronary artery disease (MVCAD) in patients with chronic kidney disease. METHODS: Patients with MVCAD and a reduced glomerular filtration rate (<60 ml/min) undergoing coronary bypass surgery (CABG) or percutaneous coronary intervention (PCI) at a single institution between 2010 and 2017 were included. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE) defined as a composite outcome of death, stroke, myocardial infarction or repeat revascularization. Multivariable Cox regression models were used for risk-adjustment and propensity matching was also performed. RESULTS: A total of 1853 patients were included in the study (1269 CABG, 584 PCI). CABG was associated with greater 5-year freedom from MACCE (70.1% vs 47.3%, P < 0.0001), a finding that persisted after risk-adjustment. The rates of early and late mortality and readmission were also lower with CABG as were individual rates of myocardial infarction and repeat revascularization. A propensity-matched analysis generated 704 well-matched patients (352 in each arm) with similar results, including greater 5-year freedom from MACCE (72.8% vs 45.8%, P < 0.0001), improved 5-year survival (73.9% vs 52.3%, P < 0.0001), lower readmission (cause-specific hazard ratio 0.68, 95% confidence interval 0.58-0.80; P < 0.0001), lower individual rates of myocardial infarction (2.6% vs 9.7%, P < 0.0001) and repeat revascularization (1.1% vs 7.4%, P < 0.0001). CONCLUSIONS: CABG is associated with a lower MACCE rate than that of PCI in patients with MVCAD and chronic kidney disease. Multidisciplinary discussions regarding the optimal revascularization strategy are important in MVCAD, particularly in more complex scenarios such as chronic kidney disease.

Impact of Chronic Kidney Disease and Anemia on Outcomes After Percutaneous Coronary Revascularization.

Few studies have evaluated outcomes after percutaneous coronary intervention (PCI) in patients with both anemia (hemoglobin < 12 g/dl in women; <13 in men) and chronic kidney disease (CKD, estimated glomerular filtration rate < 60 ml/min/1.73 m2). Patients with coronary artery disease who underwent PCI in our health system from 2010 to 2018 were included (n = 10,756), excluding those with ST-elevation myocardial infarction or shock. We evaluated the individual and combined effects of anemia and CKD on outcomes. Five-year mortality was highest in the cohort with both anemia and CKD and lowest in those with neither. After multivariate analysis, with the group with neither anemia nor CKD as a reference, the adjusted hazard ratio for mortality was 1.68 (95% confidence interval [CI] 1.45 to 1.95, p <0.001) for those with anemia alone, 1.33 (95% CI 1.15 to 1.53, p <0.001) for those with CKD alone, and 2.83 (95% CI 2.49 to 3.22, p <0.001) for those with both anemia and CKD. With respect to readmission and reintervention, similar tends were observed, with patients with both CKD and anemia having the highest risk for these outcomes. In conclusion, the combined effects of anemia and CKD on outcomes post-PCI appear to be worse than either of their effects individually.

Coronary Bypass Versus Percutaneous Revascularization in Multivessel Coronary Artery Disease.

BACKGROUND: This study focused on contemporary outcomes after coronary artery bypass graft (CABG) surgery versus percutaneous coronary intervention (PCI) in patients with multivessel coronary artery disease (MVCAD). METHODS: This was a propensity-matched retrospective, observational analysis. Patients with MVCAD who underwent CABG or PCI between 2010 and 2018 and for whom data were available through the National Cardiovascular Data Registry or The Society of Thoracic Surgeons Adult Cardiac Surgery Database were included. The primary outcome was overall survival. Secondary outcomes included freedom from inpatient readmission and freedom from repeat revascularization. RESULTS: Of the initial 6,163 patients with MVCAD, the propensity-matched cohort included 844 in each group. The estimated 1-year mortality was 11.5% and 7.2% (p < 0.001) in the PCI and CABG groups, respectively, with an overall hazard ratio for mortality of PCI versus CABG of 1.64 (95% confidence interval [CI], 1.29 to 2.10; p < 0.001). The overall hazard ratio for readmission for PCI versus CABG was 1.42 (95% CI, 1.23 to 1.64; p < 0.001). The overall hazard ratio for repeat revascularization for PCI versus CABG was 4.06 (95% CI, 2.39 to 6.91; p < 0.001). Overall major adverse cardiovascular events and individual outcomes of mortality, readmission, and repeat revascularization all favored CABG across virtually all major clinical subgroups. CONCLUSIONS: This contemporary propensity-matched analysis of patients undergoing coronary revascularization for MVCAD demonstrates a significant mortality benefit with CABG over PCI, and this benefit is consistent across virtually all major patient subgroups. Futures studies are needed reflecting routine practice to assess how best to approach shared decision making and informed consent when it comes to revascularization decisions in any patient with MVCAD.

Clinicopathologic and molecular spectrum of RNASEH1-related mitochondrial disease.

OBJECTIVE: Pathologic ribonuclease H1 (RNase H1) causes aberrant mitochondrial DNA (mtDNA) segregation and is associated with multiple mtDNA deletions. We aimed to determine the prevalence of RNase H1 gene (RNASEH1) mutations among patients with mitochondrial disease and establish clinically meaningful genotype-phenotype correlations. METHODS: RNASEH1 was analyzed in patients with (1) multiple deletions/depletion of muscle mtDNA and (2) mendelian progressive external ophthalmoplegia (PEO) with neuropathologic evidence of mitochondrial dysfunction, but no detectable multiple deletions/depletion of muscle mtDNA. Clinicopathologic and molecular evaluation of the newly identified and previously reported patients harboring RNASEH1 mutations was subsequently undertaken. RESULTS: Pathogenic c.424G>A p.Val142Ile RNASEH1 mutations were detected in 3 pedigrees among the 74 probands screened. Given that all 3 families had Indian ancestry, RNASEH1 genetic analysis was undertaken in 50 additional Indian probands with variable clinical presentations associated with multiple mtDNA deletions, but no further RNASEH1 mutations were confirmed. RNASEH1-related mitochondrial disease was characterized by PEO (100%), cerebellar ataxia (57%), and dysphagia (50%). The ataxia neuropathy spectrum phenotype was observed in 1 patient. Although the c.424G>A p.Val142Ile mutation underpins all reported RNASEH1-related mitochondrial disease, haplotype analysis suggested an independent origin, rather than a founder event, for the variant in our families. CONCLUSIONS: In our cohort, RNASEH1 mutations represent the fourth most common cause of adult mendelian PEO associated with multiple mtDNA deletions, following mutations in POLG, RRM2B, and TWNK. RNASEH1 genetic analysis should also be considered in all patients with POLG-negative ataxia neuropathy spectrum. The pathophysiologic mechanisms by which the c.424G>A p.Val142Ile mutation impairs human RNase H1 warrant further investigation.

Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene.

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are severe autosomal recessive disorders associated with decreased mtDNA copy number in clinically affected tissues. The hepatocerebral form (mtDNA depletion in liver and brain) has been associated with mutations in the POLG, PEO1 (Twinkle), DGUOK and MPV17 genes, the latter encoding a mitochondrial inner membrane protein of unknown function. The aims of this study were to clarify further the clinical, biochemical, cellular and molecular genetic features associated with MDS due to MPV17 gene mutations. We identified 12 pathogenic mutations in the MPV17 gene, of which 11 are novel, in 17 patients from 12 families. All patients manifested liver disease. Poor feeding, hypoglycaemia, raised serum lactate, hypotonia and faltering growth were common presenting features. mtDNA depletion in liver was demonstrated in all seven cases where liver tissue was available. Mosaic mtDNA depletion was found in primary fibroblasts by PicoGreen staining. These results confirm that MPV17 mutations are an important cause of hepatocerebral mtDNA depletion syndrome, and provide the first demonstration of mosaic mtDNA depletion in human MPV17 mutant fibroblast cultures. We found that a severe clinical phenotype was associated with profound tissue-specific mtDNA depletion in liver, and, in some cases, mosaic mtDNA depletion in fibroblasts.

Prospective study of POLG mutations presenting in children with intractable epilepsy: prevalence and clinical features.

PURPOSE: To assess the frequency and clinical features of childhood-onset intractable epilepsy caused by the most common mutations in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma. METHODS: Children presenting with nonsyndromic intractable epilepsy of unknown etiology but without documented liver dysfunction at presentation were eligible for this prospective, population-based study. Blood samples were analyzed for the three most common POLG mutations. If any of the three tested mutations were found, all the exons and the exon-intron boundaries of the POLG gene were sequenced. In addition, we retrospectively reviewed the notes of patients presenting with intractable epilepsy in which we had found POLG mutations. All available clinical data were collected by questionnaire and by reviewing the medical records. KEY FINDINGS: We analyzed 213 blood DNA samples from patients fulfilling the inclusion criteria of the prospective study. Among these, five patients (2.3%) were found with one of the three common POLG mutations as homozygous or compound heterozygous states. In addition, three patients were retrospectively identified. Seven of the eight patients had either raised cerebrospinal fluid (CSF) lactate (n = 3) or brain magnetic resonance imaging (MRI) changes (n = 4) at presentation with intractable epilepsy. Three patients later developed liver dysfunction, progressing to fatal liver failure in two without previous treatment with sodium valproate (VPA). Furthermore, it is worth mentioning that one patient presented first with an autism spectrum disorder before seizures emerged. SIGNIFICANCE: Mutations in POLG are an important cause of early and juvenile onset nonsyndromic intractable epilepsy with highly variable associated manifestations including autistic features. This study emphasizes that genetic testing for POLG mutations in patients with nonsyndromic intractable epilepsies is very important for clinical diagnostics, genetic counseling, and treatment decisions because of the increased risk for VPA-induced liver failure in patients with POLG mutations. We recommend POLG gene testing for patients with intractable seizures and at least one elevated CSF lactate or suggestive brain MRI changes (predominantly abnormal T2 -weighted thalamic signal) with or without status epilepticus, epilepsia partialis continua, or liver manifestations typical for Alpers disease, especially when the disease course is progressive.

Distal myopathy with cachexia: an unrecognised phenotype caused by dominantly-inherited mitochondrial polymerase γ mutations.

BACKGROUND: The myopathy associated with mutations in the nuclear-encoded mitochondrial DNA maintenance gene POLG, coding for the catalytic subunit of DNA polymerase, is typically proximal with early ophthalmoplegia. RESULTS: We report two unrelated patients in whom a distal, mainly upper limb, myopathy was the predominant and early clinical feature. One patient also suffered with marked cachexia. DNA genomic sequence analysis identified novel dominant heterozygous missense POLG mutations (Leu896Arg and Tyr951His) located within the conserved catalytic polymerase domain of the protein in both cases. CONCLUSIONS: Distal upper limb myopathy/cachexia is not previously described with dominant POLG mutations and our observations further highlight the diverse clinical spectrum of POLG-related mitochondrial disorders. These data indicate that dominant POLG mutations should be considered in the differential diagnosis of distal upper limb predominant myopathy.

Benefit of long-term dual anti-platelet therapy in patients treated with drug-eluting stents: from the NHLBI dynamic registry.

The optimal duration of dual-antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is an important, unanswered question. This study was designed to evaluate the association of varying durations of DAPT on clinical outcomes after DES implantation for the treatment of coronary artery disease. Using the National Heart, Lung, and Blood Institute Dynamic Registry, patients enrolled in the last 2 waves after index percutaneous coronary intervention with DES and who were event free at the time of landmark analysis were included. Landmark analysis was performed 12 and 24 months after percutaneous coronary intervention, and patients were stratified according to continued use of DAPT or not. Subjects were evaluated for rates of death, myocardial infarction, and stent thrombosis at 4 years from their index procedures. The numbers of evaluable patients were 2,157 and 1,918 for the 12- and 24-month landmarks, respectively. In both landmark analyses, there was a significantly lower 4-year rate of death or myocardial infarction in the group that continued DAPT compared to the group that did not (12 months: 10.5% vs 14.5%, p = 0.01; 24 months: 5.7% vs 8.6%, p = 0.02). Beneficial differences in the group that continued on DAPT were preserved after multivariate and propensity adjustment. There were no significant differences in definite stent thrombosis in either landmark analysis. In conclusion, at 12 and 24 months after DES implantation, continued use of DAPT was associated with lower 4-year risk for death and myocardial infarction.

Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics.

Mutations in the nuclear-encoded mitochondrial maintenance gene RRM2B are an important cause of familial mitochondrial disease in both adults and children and represent the third most common cause of multiple mitochondrial DNA deletions in adults, following POLG [polymerase (DNA directed), gamma] and PEO1 (now called C10ORF2, encoding the Twinkle helicase) mutations. However, the clinico-pathological and molecular features of adults with RRM2B-related disease have not been clearly defined. In this multicentre study of 26 adult patients from 22 independent families, including five additional cases published in the literature, we show that extra-ocular neurological complications are common in adults with genetically confirmed RRM2B mutations. We also demonstrate a clear correlation between the clinical phenotype and the underlying genetic defect. Myopathy was a prominent manifestation, followed by bulbar dysfunction and fatigue. Sensorineural hearing loss and gastrointestinal disturbance were also important findings. Severe multisystem neurological disease was associated with recessively inherited compound heterozygous mutations with a mean age of disease onset at 7 years. Dominantly inherited heterozygous mutations were associated with a milder predominantly myopathic phenotype with a later mean age of disease onset at 46 years. Skeletal muscle biopsies revealed subsarcolemmal accumulation of mitochondria and/or cytochrome c oxidase-deficient fibres. Multiple mitochondrial DNA deletions were universally present in patients who underwent a muscle biopsy. We identified 18 different heterozygous RRM2B mutations within our cohort of patients, including five novel mutations that have not previously been reported. Despite marked clinical overlap between the mitochondrial maintenance genes, key clinical features such as bulbar dysfunction, hearing loss and gastrointestinal disturbance should help prioritize genetic testing towards RRM2B analysis, and sequencing of the gene may preclude performance of a muscle biopsy.

Anterior laxity, slippage, and recovery of function in the first year after tibialis allograft anterior cruciate ligament reconstruction.

BACKGROUND: The increase in anterior laxity and slippage is greater with metal interference screw fixation of a hamstring anterior cruciate ligament (ACL) graft than a bone-patellar tendon-bone graft. HYPOTHESIS: When slippage-resistant fixation is used with a soft tissue graft, early recovery of function does not result in a clinically important increase in anterior laxity and slippage STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Nineteen subjects were treated with a single-tunnel, single-looped, tibialis allograft with slippage-resistant, cortical fixation. An examiner, different from the treating surgeon, used stereophotogrammetric analysis to compute the increase in anterior laxity at a 150 N anterior force and slippage between the day of surgery and each monthly follow-up interval, and determined recovery of function and motion. RESULTS: Anterior laxity did not increase between the day of surgery and 1 year (P = .23). Total slippage plateaued after 1 month, but increased 1.5 mm between the day of surgery and 1 month (P < .05). Extension and flexion plateaued after 2 months (P < .0001 and P < .02, respectively); activity level (Tegner score) plateaued after 3 months (P < .05), function (Lysholm score) plateaued after 4 months (P < .002), and subjective satisfaction (International Knee Documentation Committee score) plateaued after 6 months (P < .02). CONCLUSION: Early recovery of function after ACL reconstruction with a soft tissue allograft did not result in a clinically important increase in anterior laxity and slippage at 1 year. We believe the avoidance of an increase in anterior laxity was related to the use of a transtibial technique designed to place the femoral and tibial tunnels without roof and posterior cruciate ligament impingement, the use of cortical fixation devices designed to resist slippage, the use of an aseptically harvested fresh-frozen tibialis allograft that was not irradiated or chemically processed, and the use of a self-administered rehabilitation program designed to encourage an early return of motion and function.

Does graft construct lengthening at the fixations cause an increase in anterior laxity following anterior cruciate ligament reconstruction in vivo?

A millimeter-for-millimeter relation between an increase in length of an anterior cruciate ligament graft construct and an increase in anterior laxity has been demonstrated in multiple in vitro studies. Based on this relation, a 3 mm increase in length of the graft construct following surgery could manifest as a 3 mm increase in anterior laxity in vivo, which is considered clinically unstable. Hence, the two primary objectives were to determine whether the millimeter-for-millimeter relation exists in vivo for slippage-resistant fixation of a soft-tissue graft and, if it does not exist, then to what extent the increase in stiffness caused by biologic healing of the graft to the bone tunnel offsets the potential increase in anterior laxity resulting from lengthening at the sites of fixation. Sixteen subjects were treated with a fresh-frozen, nonirradiated, nonchemically processed tibialis allograft. Tantalum markers were injected into the graft, fixation devices, and bones. On the day of surgery and at 1, 2, 3, and 4 months, Roentgen stereophotogrammetric analysis was used to compute anterior laxity at 150 N of anterior force and the total slippage from both sites of fixation. A simple linear regression was performed to determine whether the millimeter-for-millimeter relation existed and a springs-in-series model of the graft construct was used to determine the extent to which the increase in stiffness caused by biological healing of the graft to the bone tunnel offset the increase in anterior laxity resulting from lengthening at the sites of fixation. There was no correlation between lengthening at the sites of fixation and the increase in anterior laxity at 1 month (R(2)=0.0, slope=0.2). Also, the increase in stiffness of the graft construct caused by biologic healing of the graft to the bone tunnel offset 0.7 mm of the 1.5 mm potential increase in anterior laxity resulting from lengthening at the sites of fixation. This relatively large offset of nearly 50% occurred because lengthening at the sites of fixation was small.

Paclitaxel-eluting versus sirolimus-eluting stents in diabetes mellitus: a report from the National Heart, Lung, and Blood Institute Dynamic Registry.

BACKGROUND: Diabetes is a powerful predictor of adverse events in patients undergoing percutaneous coronary intervention. Drug-eluting stents reduce restenosis rates compared with bare metal stents; however, controversy remains regarding which drug-eluting stents provides greater benefit in patients with diabetes. Accordingly, we compared the safety and efficacy of sirolimus-eluting stents (SES) with paclitaxel-eluting stents (PES) among diabetic patients in a contemporary registry. METHODS AND RESULTS: Using the National Heart, Lung, and Blood Institute Dynamic Registry, we evaluated 2-year outcomes of diabetic patients undergoing percutaneous coronary interventions with SES (n=677) and PES (n=328). Clinical and demographic characteristics, including age, body mass index, insulin use, left ventricular function, and aspirin/clopidogrel use postprocedure, did not differ significantly between the groups except that PES-treated patients had a greater frequency of hypertension and hyperlipidemia. At the 2-year follow-up, no significant differences were observed between PES and SES with regard to safety or efficacy end points. PES- and SES-treated patients had similar rates of death (10.7% versus 8.2%, P=0.20), death and myocardial infarction (14.9% versus 13.6%, P=0.55), repeat revascularization (14.8% versus 17.8%, P=0.36), and stent thrombosis (1.3% versus 1.3%, P=0.95). After adjustment, no significant differences between the 2 stent types in any outcome were observed. CONCLUSIONS: PES and SES are equally efficacious and have similar safety profiles in diabetic patients undergoing percutaneous coronary interventions in clinical practice.