Protective role of Nrf2 against ischemia reperfusion injury and cardiac allograft vasculopathy.

Ischemia-reperfusion injury (IRI) and cardiac allograft vasculopathy (CAV) remain unsolved complications post-heart transplant (Tx). The antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) has been suggested to inhibit reactive oxygen species-mediated NF-κB activation. We hypothesized that Nrf2 inhibits NF-κB activation post-Tx and suppresses IRI and the subsequent development of CAV. IRI and CAV were investigated in murine heterotopic Tx models, respectively. Nrf2 wild-type (WT) and KO mice were used as donors. Sulforaphane was used as an Nrf2 agonist. In saline-treated animals following 24 hours of reperfusion in isogenic grafts, Nrf2-KO showed significantly less SOD1/2 activity compared with WT. Nrf2-KO displayed significantly high total and phosphorylated p65 expressions and percentage of cells with nuclear p65. mRNA levels of NF-κB-mediated proinflammatory genes were also high. Graft dysfunction, apoptosis, and caspase-3 activity were significantly higher in Nrf2-KO. In the allograft studies, graft beating score was significantly weaker in Nrf2-KO compared with WT. Nrf2-KO also demonstrated significantly more coronary luminal narrowing. In WT animals, sulforaphane successfully augmented all the protective effects of Nrf2 with increase of SOD2 activity. Nrf2 inhibits NF-κB activation and protects against IRI via its antioxidant properties and suppresses the subsequent development of CAV.

Maximum Walking Speed at Discharge Could Be a Prognostic Factor for Vascular Events in Patients With Mild Stroke: A Cohort Study.

OBJECTIVE: To identify the prognostic value of physical activity-related factors as well as known vascular risk factors for vascular events in mild ischemic stroke (MIS). DESIGN: Single-center prospective cohort study. SETTING: University hospital. PARTICIPANTS: Consecutive patients (N=255) (175 men, median age 70.0y) with acute ischemic stroke and transient ischemic attack (TIA) with modified Rankin scale scores ranging from 0 to 2 were enrolled in this study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Enrolled patients were followed up for composite vascular events as primary outcomes up to 3 years postdischarge. Primary outcomes included stroke and cardiovascular death, hospitalization due to stroke or TIA recurrence, cardiovascular disease, and peripheral artery disease. During hospitalization, known vascular risk factors such as previous history of vascular events, stroke subtype, white matter lesions, and ankle-brachial index were assessed. Moreover, at the time of discharge, physical activity-related factors such as maximum walking speed (MWS), handgrip strength, knee extensor isometric muscle strength, anxiety, and depression were assessed as potential predictors. RESULTS: The Kaplan-Meier estimates of cumulative risk of composite vascular events at 1, 2, and 3 years were 9.6%, 14.4%, and 15.2%, respectively. After multivariate analysis, cerebral white matter lesions of periventricular hyperintensity (PVH) (grade=3; hazard ratio: 2.904; 95% confidence interval: 1.160 to 7.266; P=.023) and MWS (<1.45m/s; hazard ratio: 2.232; 95% confidence interval: 1.010 to 4.933; P=.047) were identified as significant independent predictors of composite vascular events. CONCLUSIONS: The results of this study indicate that MWS could be an independent prognostic factor for composite vascular events in MIS.

Development of a Self-Efficacy Questionnaire for Walking in Patients with Mild Ischemic Stroke.

PURPOSE: This study aimed to develop a self-efficacy questionnaire, which particularly focuses on walking in patients with mild ischemic stroke and transient ischemic attack. METHODS: We enrolled patients with acute ischemic stroke and transient ischemic attack who scored 0-2 on the modified Rankin Scale. The process of development of questionnaire on self-efficacy for walking with 7 items (SEW-7) was composed of 3 steps: (1) item generation; (2) item reduction; and (3) testing the final version. The measurement properties were assessed according to the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. RESULTS: A total of 168 patients (mean age 69.4 ± 10.1 years) were enrolled for testing the questionnaire on SEW-7. The total score of the SEW-7 ranged from 7 to 35 points. Internal consistency was acceptable with the Cronbach's alpha coefficient of .93. Test-retest reliability was good with intraclass correlation coefficient of .83 (95% confidence interval: .67-.91). The smallest detectable changes at individual and group levels were 8.0 and 1.5, respectively. The results of principal component analysis showed a single factor explaining 71.8% of the total variance. The SEW-7 questionnaire showed moderate to strong correlation with physical activity parameters (step counts: r = .596, P < .001; physical activity-related energy expenditure: r = .615, P < .001; low-intensity physical activity: r = .449, P < .001; moderate- to vigorous-intensity physical activity: r = .581, P < .001). CONCLUSIONS: We propose a simple self-report questionnaire for walking, with 7 items. The SEW-7 has adequate measurement properties and may serve as a time-saving tool for promoting physical activity in mild ischemic stroke patients.

Tricuspid Valve Annular Dilation as a Predictor of Right Ventricular Failure After Implantation of a Left Ventricular Assist Device.

BACKGROUND: Tricuspid annular (TA) dilation has been suggested as a more reliable marker of concomitant advanced right ventricular failure (RVF) than severity of tricuspid regurgitation (TR). Our objective was to examine the impact of TA dilation on occurrence of RVF and in-hospital mortality following left ventricular assist device (LVAD) implant. METHODS: Consecutive patients undergoing implantation of a continuous-flow LVAD implant were grouped according to the presence or absence of preoperative dilated TA. Clinical characteristics, hemodynamics, and short-term postoperative outcomes were compared between groups. RVF was defined as unplanned right ventricular assist device (RVAD) or postoperative use of inotropes for >14 days. Linear and logistic regressions were used to explore associations of TA with occurrence of RVF and duration of inotrope use. RESULTS: We included 69 patients who had continuous-flow LVAD implanted between 2006 and 2013 (50 ± 13 years old; 69% males; 37% ischemic etiology; 69% bridge-to-transplant LVAD; 18% INTERMACS 1-2; 48% with significant TR). RVF occurred in nine cases, and overall in-hospital mortality rate was 14%. Tricuspid valve repair was performed in ten cases. Dilated TA (OR 4.86; 95% CI 1.05-22.33; p = 0.04) was associated with RVF. In an adjusted multivariable analysis, indexed TA was an independent predictor of increased days of inotrope use (0.8-day increase in inotrope use for every 1 mm/m2 increase; p = 0.04). CONCLUSION: In this cohort, TA dilation was a predictor of RVF after LVAD implant. The potential benefit of concomitant TVR in selected patients with a dilated TA undergoing LVAD implantation remains to be determined.

Time to revisit role of transcatheter balloon aortic valvuloplasty: a bridge-therapy to subsequent treatment case report.

Recently there has been a noticeable resurgence in the usage of percutaneous balloon aortic valvuloplasty (BAV) by the development of less invasive endovascular therapies including transcatheter aortic valve implantation (TAVI). We performed BAV in a 91-year-old man with end-stage severe symptomatic aortic stenosis (AS) and an impending abdominal aortic aneurysm (AAA) rupture who had been refused surgical treatment because of the comorbidities with stage V chronic kidney disease (CKD) and severe left ventricular dysfunction. Improvement in hemodynamics and kidney function was observed after BAV. Subsequently, we performed endovascular aneurysm repair (EVAR) successfully for AAA using iodinated contrast. No deterioration of kidney function was confirmed after the procedure. The patient was discharged without any adverse events. At present, the possibilities of TAVI or surgical aortic valve replacement (s-AVR) are under consideration as the definitive therapy for the upcoming aortic valve restenosis. In conclusion, this inoperable patient with multiple comorbidities was successfully treated, at lower risk, by catheter-based two-stage therapy.

Long-term efficacy of nusinersen and its evaluation in adolescent and adult patients with spinal muscular atrophy types 1 and 2.

BACKGROUNDS: The efficacy of nusinersen and its evaluation in patients with spinal muscular atrophy (SMA) has been established in clinical trials only for pediatric patients, not for adolescent and adult patients who developed SMA in infancy or early childhood. We report a long-term follow-up in adolescent and adult patients with SMA types 1 and 2. METHODS: Nusinersen-treated patients with SMA types 1 and 2 between 2017 and 2022 were retrospectively reviewed. We compared baseline motor function tests with those after the final treatment. Physical and occupational therapists performed Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Hammersmith Functional Motor Scale-Expanded (HFMSE), and Revised Upper Limb Module (RULM). The Landau and Galant reflexes were not performed in CHOP-INTEND. Meaningful improvement was defined as CHOP-INTEND, 4; HFSME, 3; and RULM, 2. RESULTS: Seven patients with SMA (type 1, 1; type 2, 6) with a median age of 23 (range, 12-40)years were treated with nusinersen for 3.55 (1.78-4.53)years. Improvement was detected in CHOP-INTEND (pre, 5 [0-31]; post, 21 [0-39]; difference, 5 [0-26]; p = 0.100) without significance, although not in HFMSE (pre, 0 [0-3]; post, 0 [0-5]; difference, 0 [0-2]; p = 0.346) and RULM (pre, 1 [0-20]; post, 3 [0-21]; difference, 1 [0-2]; p = 0.089). Owing to prolonged treatment intervals with the COVID-19 pandemic, RULM worsened in two patients. CONCLUSION: Nusinersen was effective in long-term follow-up. Only CHOP-INTEND showed meaningful improvement. The interval between doses of nusinersen should not be prolonged even with the COVID-19 pandemic.

Hybrid repair of a Kommerell diverticulum associated with a right aortic arch and a left descending aorta.

This report describes the first successful case of a hybrid endovascular approach for management of aneurysmal Kommerell diverticulum arising from the left descending aorta in a right aortic arch. This patient also had dilatation of the ascending aorta and a small aortic arch aneurysm. This three-step procedure consisted of (1) ascending aorta replacement with total debranching using a handmade quarto-branched composite graft; (2) endovascular exclusion of Kommerell diverticulum and the aortic arch aneurysm by covering the whole aortic arch; and (3) coil embolization against the root of the left subclavian artery. The patient had no complications at 16 months after completion.

Human Embryonic Stem Cell-Derived Cardiomyocytes Regenerate the Infarcted Pig Heart but Induce Ventricular Tachyarrhythmias.

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) show considerable promise for regenerating injured hearts, and we therefore tested their capacity to stably engraft in a translationally relevant preclinical model, the infarcted pig heart. Transplantation of immature hESC-CMs resulted in substantial myocardial implants within the infarct scar that matured over time, formed vascular networks with the host, and evoked minimal cellular rejection. While arrhythmias were rare in infarcted pigs receiving vehicle alone, hESC-CM recipients experienced frequent monomorphic ventricular tachycardia before reverting back to normal sinus rhythm by 4 weeks post transplantation. Electroanatomical mapping and pacing studies implicated focal mechanisms, rather than macro-reentry, for these graft-related tachyarrhythmias as evidenced by an abnormal centrifugal pattern with earliest electrical activation in histologically confirmed graft tissue. These findings demonstrate the suitability of the pig model for the preclinical development of a hESC-based cardiac therapy and provide new insights into the mechanistic basis of electrical instability following hESC-CM transplantation.

High-risk cardiac surgery as an alternative to transplant or mechanical support in patients with end-stage heart failure.

OBJECTIVE: Although the results of cardiac surgery in patients with poor left ventricular function have been widely published, the outcomes in patients with end-stage heart failure who meet criteria for advanced therapies are not well investigated. As access to transplantation and ventricular assist device therapy remains limited, we explored the possibility of conventional surgery as an alternative option for highly selected patients with end-stage heart failure. METHODS: We identified patients with left ventricular ejection fraction <20% and VO2 max <14 mL/min/m2, who were initially referred for advanced therapies but were instead offered a conventional procedure from 2002 to 2012. We examined the short- and midterm outcomes and compared survival with that after our advanced therapies in the same era. RESULTS: A total of 133 patients were identified; 68 were deemed to be transplant-eligible, whereas 65 were transplant-ineligible. Seventy-nine percent were in New York Heart Association class III/IV. In-hospital mortality was 12%. Actuarial survival at 5 and 10 years was 72% ± 4% and 39% ± 8%, respectively. Nonischemic etiology was identified as a predictor of late mortality. In the propensity-adjusted model, our transplant-eligible patients had comparable long-term survival to our transplantation patients (HR 1.48 [95% confidence interval, 0.66-3.2], P = .34), whereas the survival in our transplant-ineligible subset was comparable to the survival after our left ventricular assist device therapy (HR 0.49 [95% confidence interval, 0.16-1.50], P = .21). CONCLUSIONS: Despite high perioperative risk, the midterm survival after conventional surgery in patients eligible for advanced therapies seems to be acceptable and may be an alternative option for highly selected patients with end-stage heart failure.

Predictive impact of daily physical activity on new vascular events in patients with mild ischemic stroke.

BACKGROUND: Daily physical inactivity is associated with a substantially increased risk of cardiovascular events. However, the target level of daily physical activity remains unclear. AIM: We aimed to evaluate the impact of physical activity on long-term vascular events in patients with mild ischemic stroke. METHODS: We designed a single hospital-based prospective observational study and studied 166 ischemic stroke patients (mean age: 63.9 ± 9.2) who had a modified Rankin Scale 0-1. We measured the daily step count as a variable of the daily physical activity after three-months from the stroke onset. Other clinical characteristics including age, body mass index, blood pressure, blood laboratory tests, vascular function and medications were also assessed. The primary outcomes were hospitalization due to stroke recurrence, myocardial infarction, angina pectoris and peripheral artery disease. Survival curves were calculated by a Kaplan-Meier survival analysis, and the hazard ratios for recurrences were determined by univariate and multivariate Cox proportional hazards regression models. RESULTS: After a median follow-up periods of 1332 days, 34 vascular events (23 stroke recurrences, 11 coronary artery disease) and 7 drop-outs occurred, and the remaining patients were divided into two groups: the without recurrence group (n = 125) and the with recurrence group (n = 34). The daily step count was lower in the nonsurvivor group than in the survivor group. Univariate and multivariate Cox proportional hazards analyses revealed that the daily step counts was independent predictors of new vascular events. A daily step count cutoff value of 6025 steps per day was determined by analyzing the receiver-operating characteristics that showed a sensitivity of 69.4% and a specificity of 79.4%. The Kaplan-Meier survival curves after a log-rank test showed a significantly lower event rate in the more than 6025 steps per day group compared with the less than 6025 steps per day group (P = 0.0002). The positive and negative predictive values of less than 6025 steps were 38.0% and 91.6%, respectively. CONCLUSION: Our data indicate that daily physical activity evaluated by step counts may be useful for forecasting the prognosis in patients with mild ischemic stroke. Daily step counts of approximately 6000 steps per day may be an initial target level for reducing new vascular events.

Longitudinal assessment of inflammation in recipients of continuous-flow left ventricular assist devices.

BACKGROUND: The long-term effects of continuous-flow left ventricular assist device (CF-LVAD) support on trends of inflammatory markers over time are unknown. We examined the hypothesis that the levels of inflammatory markers in CF-LVAD recipients are higher than in healthy controls and that these levels increase over time with long-term CF-LVAD support. METHODS: We examined the levels of inflammatory markers longitudinally at baseline before CF-LVAD implantation and at 3, 6, and 9 months after implantation. We then compared the levels of inflammatory markers to those in a healthy control group. RESULTS: Compared with baseline values before CF-LVAD implantation, left ventricular end-diastolic diameter (LVEDd) and left ventricular end-systolic diameter (LVESd) decreased significantly at 3, 6, and 9 months after CF-LVAD implantation. Brain natriuretic peptide (BNP) levels dropped significantly after CF-LVAD implantation but did not normalize. Improvements in ejection fraction at 3, 6, and 9 months after CF-LVAD implantation did not reach significance. Monocyte chemoattractant protein-1, interferon γ-induced protein, and C-reactive protein levels were higher in the CF-LVAD recipients at each of the time points (baseline before CF-LVAD implantation and 3, 6, and 9 months after implantation) compared with levels in healthy controls. In CF-LVAD recipients, serum interleukin-8, tumour necrosis factor-α, and macrophage inflammatory protein-ß increased significantly at 9 months, and macrophage-derived chemokine increased at 6 months after CF-LVAD implantation compared with baseline. CONCLUSIONS: Despite improvements in LV dimensions and BNP levels, markers of inflammation remained higher in CF-LVAD recipients. High levels of inflammation in CF-LVAD recipients may result from heart failure preconditioning or the long-term device support, or both. Because inflammation may be detrimental to CF-LVAD recipients, future studies should determine whether inflammatory pathways are reversible.

Negative pressure therapy for post-sternotomy wound infections in young children.

OBJECTIVES: Post-sternotomy wound infection remains a significant morbidity in congenital and paediatric cardiac surgery. However, the techniques used for this complication in children are not optimal in terms of mortality, morbidity and the use of medical resources. Negative pressure therapy is an effective modality in the treatment in adults, but reports of its use in children are limited. This study evaluated the use of negative pressure therapy in young children for post-sternotomy wound infections. METHODS: From October 2004 to June 2012, 15 consecutive cases of post-sternotomy wound infections in patients ≤6 years of age were managed with negative pressure therapy, and these patients were followed up for ≥12 months after wound closure. The median Aristotle comprehensive complexity score was 9.9 ± 4.0. The infection was identified at a median of 16 days after surgery, and the procedure was performed within 24 h of diagnosis. No additional surgical procedures were applied. RESULTS: No cases of hospital mortality or second surgery for infection control occurred. The median duration until wound closure was 25 days (range: 5-92 days). Further, no patient showed sternal instability at treatment termination. During the mean follow-up period of 45.8 ± 31.3 months after wound closure, no admission occurred for infection recurrence. According to a multivariable analysis, the infection depth and patient weight significantly lengthened treatment duration (P = 0.008 and 0.046, respectively). CONCLUSIONS: Negative pressure therapy is an effective treatment modality for wound infections in paediatric cardiac surgery and results in low morbidity, mortality and medical resource use.

Modified intraatrial translocation for prosthetic mitral valve endocarditis.

Despite prompt diagnosis and aggressive surgical treatment of prosthetic mitral valve endocarditis (PVE), morbidity and mortality remain high. Surgical strategies have mostly been limited to debridement and anatomic valve reinstallation. Alternative surgical techniques have been attempted sporadically against this mortal disease, either with protection by antibiotic sewing rings or by anatomic evacuation of infectious foci. These methods have not been performed concurrently, however, and their joint deployment might improve surgical outcome. We describe a surgical procedure of modified intraatrial translocation combined with sewing ring shielding, aimed at preventing the recurrence of severe methicillin-resistant staphylococci PVE in the mitral position.

Novel beating heart repair for anomalous origin of right coronary artery.

Anomalous origin of the right coronary artery (ARCA) from the left coronary sinus is a rare anatomic anomaly. It may cause myocardial ischemia and sudden death. Several treatments have been tried, including coronary bypass grafting, unroofing, and reimplantation. These techniques, however, have disadvantages such as postoperative flow competition, aortic insufficiency, or kinks and angulation of the coronary artery, respectively. To overcome these problems, we undertook a novel approach: beating heart repair. It does not require aortic cross-clamping, cardioplegic arrest, aortotomy, or manipulation of the aortic commissure. Beating heart repair is a simple and effective procedure, which adds an ideal treatment option for ARCA.

Hybrid repair of subclavian-axillary artery aneurysms and aortic arch aneurysm in a patient with Marfan syndrome.

A patient with Marfan syndrome who had previously undergone a Cabrol procedure and thoracoabdominal aortic replacement had enlarging, symptomatic aneurysms in the subclavian-axillary artery and aortic arch. Both vessels were replaced with prosthetic grafts. A thoracic endoprosthesis was inserted bridging the aortic arch graft and the previously implanted descending aorta graft. Another stent graft was placed, bridging the axillary artery and a branch of the aortic arch graft. All the stent graft landing zones were within grafts, avoiding contact between the endoprostheses and fragile aortic wall. The aneurysms were excluded from the circulation, and the patient had no serious complications.

Novel single-stage operation and inflow source: for thoracic aortic aneurysm and limb ischemia.

Patients with thoracic aortic aneurysms sometimes also have peripheral vascular disease. In such cases, staged operations are usually performed in order to avoid additional morbidity. We have achieved good long-term outcomes in 2 patients with use of a single-stage surgical technique. Our novel procedure uses a pre-sewn side branch with a Dacron graft as the inflow source for the aortofemoral bypass during thoracic aortic aneurysm repair. As of 25 and 52 months' follow-up, these grafts were patent in our 2 patients. We believe that this procedure is a safe and easy single-stage operation that achieves favorable patency. To our knowledge, this is the first report to document the use of a pre-sewn perfusion branch of a Dacron graft as an inflow source for aortofemoral bypass.

Repair of traumatic tricuspid insufficiency via minimally invasive port access.

We report on a successful tricuspid valve plasty using port-access minimally invasive cardiac surgery (MICS) for severe traumatic tricuspid insufficiency caused by blunt chest trauma suffered 15 years previously. A combination repair procedure, consisting of cleft closures, plication of the anteroseptal commissure, and ring annuloplasty, was necessary to achieve valve competence and proved possible via port access without difficulty. Port-access MICS is an alternative approach for tricuspid valve surgery.