Modeling Precision Cardio-Oncology: Using Human-Induced Pluripotent Stem Cells for Risk Stratification and Prevention.

PURPOSE OF REVIEW: Cardiovascular toxicity is a leading cause of mortality among cancer survivors and has become increasingly prevalent due to improved cancer survival rates. In this review, we synthesize evidence illustrating how common cancer therapeutic agents, such as anthracyclines, human epidermal growth factors receptors (HER2) monoclonal antibodies, and tyrosine kinase inhibitors (TKIs), have been evaluated in cardiomyocytes (CMs) derived from human-induced pluripotent stem cells (hiPSCs) to understand the underlying mechanisms of cardiovascular toxicity. We place this in the context of precision cardio-oncology, an emerging concept for personalizing the prevention and management of cardiovascular toxicities from cancer therapies, accounting for each individual patient's unique factors. We outline steps that will need to be addressed by multidisciplinary teams of cardiologists and oncologists in partnership with regulators to implement future applications of hiPSCs in precision cardio-oncology. RECENT FINDINGS: Current prevention of cardiovascular toxicity involves routine screenings and management of modifiable risk factors for cancer patients, as well as the initiation of cardioprotective medications. Despite recent advancements in precision cardio-oncology, knowledge gaps remain and limit our ability to appropriately predict with precision which patients will develop cardiovascular toxicity. Investigations using patient-specific CMs facilitate pharmacological discovery, mechanistic toxicity studies, and the identification of cardioprotective pathways. Studies with hiPSCs demonstrate that patients with comorbidities have more frequent adverse responses, compared to their counterparts without cardiac disease. Further studies utilizing hiPSC modeling should be considered, to evaluate the impact and mitigation of known cardiovascular risk factors, including blood pressure, body mass index (BMI), smoking status, diabetes, and physical activity in their role in cardiovascular toxicity after cancer therapy. Future real-world applications will depend on understanding the current use of hiPSC modeling in order for oncologists and cardiologists together to inform their potential to improve our clinical collaborative practice in cardio-oncology. When applying such in vitro characterization, it is hypothesized that a safety score can be assigned to each individual to determine who has a greater probability of developing cardiovascular toxicity. Using hiPSCs to create personalized models and ultimately evaluate the cardiovascular toxicity of individuals' treatments may one day lead to more patient-specific treatment plans in precision cardio-oncology while reducing cardiovascular disease (CVD) morbidity and mortality.

Acute kidney injury in necrotizing enterocolitis predicts mortality.

BACKGROUND: Morbidity and mortality with necrotizing enterocolitis (NEC) remains a significant challenge. Acute kidney injury (AKI) has been shown to worsen survival in critically ill neonates. To our knowledge, this study is the first to evaluate the prevalence of AKI and its impact on outcomes in neonatal NEC. METHODS: We carried out a single-center retrospective chart review of all neonates treated for NEC between 2003 and 2015 (N = 181). AKI is defined as a rise in serum creatinine (SCr) from a previous trough according to neonatal modified KDIGO criteria (stage 1 = SCr rise 0.3 mg/dL or SCr 150 < 200%, stage 2 = SCr rise 200 < 300%, stage 3 = SCr rise ≥300%, SCr 2.5 mg/dL or dialysis). Primary outcome was in-hospital mortality and secondary outcomes were hospital length of stay (LOS) and need for and type of surgery. RESULTS: Acute kidney injury occurred in 98 neonates (54%), with 39 stage 1 (22%), 31 stage 2 (18%), and 28 stage 3 (16%), including 5 requiring dialysis. Non-AKI and AKI groups were not statistically different in age, weight, Bell's NEC criteria, and medication exposure (vasopressors, vancomycin, gentamicin, or diuretic). Neonates with AKI had higher mortality (44% vs 25.6%, p = 0.008) and a higher chance of death (HR 2.4, CI 1.2-4.8, p = 0.009), but the effect on LOS on survivors did not reach statistical significance (79 days, interquartile range [IQR] 30-104 vs 54 days, IQR 30-92, p = 0.09). Overall, 48 (27.9%) patients required surgical intervention. CONCLUSIONS: This study shows that AKI not only occurs in over half of patients with NEC, but that it is also associated with more than a two-fold higher mortality, highlighting the importance of early recognition and potentially early intervention for AKI.

Outcomes After Prolonged ICU Stays in Postoperative Cardiac Surgery Patients.

Background: Prolonged postoperative intensive care unit (ICU) stays are common after cardiac surgery and are associated with poor outcomes. There are few studies evaluating how risk factors associated with mortality may change during prolonged ICU stays or how mortality may vary with length of stay. We evaluated operative and long-term mortality in post-cardiac surgery patients after prolonged ICU stays at 7, 14, 21, and 28 days and factors associated with mortality. Methods: We included University of Michigan Medical Center cardiac surgery patients with ≥ 7 postoperative days in the ICU. We determined factors associated with hospital mortality at 7, 14, 21, and 28 days of ICU stay using logistic regression, and among hospital survivors, we determined the factors associated with long-term mortality using Cox regression. Results: Of 8309 ICU admissions from cardiac surgery, 1174 (14%) had ICU stays > 7 days. Operative mortality was 11%, 18%, 22%, and 35% for the 7-, 14-, 21-, and 28-day groups, respectively. Mechanical ventilation on the day of assessment was associated with increased odds ratios of operative mortality in all models. Of the 1049 (89%) hospital survivors, 420 (40%) died by late follow-up. Median (IQR) Cox model survival was 10.7 (0.7) years. Longer ICU stays, postoperative pneumonia, and elevated discharge blood urea nitrogen were associated with increased hazard of dying; whereas higher discharge platelet count and cardiac transplant were protective. Conclusions: Both operative and late mortality increased as the duration of a ICU stay increased after cardiac surgery.

A virtual-hybrid approach to launching a cardio-oncology clinic during a pandemic.

BACKGROUND: As cardiovascular disease is a leading cause of death in cancer survivors, the new subspecialty of Cardio-Oncology has emerged to address prevention, monitoring, and management of cardiovascular toxicities to cancer therapies. During the coronavirus disease of 2019 (COVID-19) pandemic, we developed a Virtual-Hybrid Approach to build a de novo Cardio-Oncology Clinic. METHODS: We conceptualized a Virtual-Hybrid Approach including three arms: information seeking in locations with existing Cardio-Oncology clinics, information gathering at the location for a new clinic, and information sharing to report clinic-building outcomes. A retrospective review of outcomes included collection and synthesis of data from our first 3 months (at pandemic peak) on types of appointments, cancers, drugs, and cardiotoxicities. Data were presented using descriptive statistics. RESULTS: A de-novo Cardio-Oncology clinic was developed structured from the ground up to integrate virtual and in-person care in a hybrid and innovative model, using the three arms of the Virtual-Hybrid Approach. First, we garnered in-person and virtual preparation through hands-on experiences, training, and discussions in existing Cardio-Oncology Clinics and conferences. Next, we gleaned information through virtual inquiry and niche-building. With partners throughout the institution, a virtual referral process was established for outpatient referrals and inpatient e-consult referrals to actualize a hybrid care spectrum for our patients administered by a multidisciplinary hybrid care team of clinicians, ancillary support staff, and clinical pharmacists. Among the multi-subspecialty clinic sessions, approximately 50% were in Cardio-Oncology, 20% in Preventive Cardiology, and 30% in General Cardiology. In the hybrid model, the Heart & Vascular Center had started to re-open, allowing for 65% of our visits to be in person. In additional analyses, the most frequent cardiovascular diagnosis was cardiomyopathy (34%), the most common cancer drug leading to referral was trastuzumab (29%), and the most prevalent cancer type was breast cancer (42%). CONCLUSION: This Virtual-Hybrid Approach and retrospective review provides guidance and information regarding initiating a brand-new Cardio-Oncology Clinic during the pandemic for cancer patients/survivors. This report also furnishes virtual resources for patients, virtual tools for oncologists, cardiologists, and administrators tasked with starting new clinics during the pandemic, and innovative future directions for this digital pandemic to post-pandemic era.

Influence of concurrent chronic kidney disease on intraoperative parathyroid hormone monitoring during parathyroidectomy for primary hyperparathyroidism.

BACKGROUND: The influence of chronic kidney disease on intraoperative parathyroid hormone monitoring during parathyroidectomy for primary hyperparathyroidism has not been well-established. We hypothesize that chronic kidney disease influences intraoperative parathyroid hormone degradation kinetics during parathyroidectomy. METHODS: This is a single institution retrospective cohort study of consecutive patients with primary hyperparathyroidism underdoing parathyroidectomy. Patients were stratified according to normal kidney function (glomerular filtration rates ≥60 mL/min/1.73 m2 or presence of chronic kidney disease (glomerular filtration rates 15 - 60 mL/min/1.73 m2). Demographics, laboratory data, operative findings, and intraoperative parathyroid hormone data were compared between groups. RESULTS: Of the 964 study patients, 235 had chronic kidney disease (24.4%), while 729 (75.6%) had normal kidney function. The chronic kidney disease population had a greater median preoperative serum parathyroid hormone (PTH) (125 vs 114 pg/mL; P < .001), but similar median intraoperative parathyroid hormone levels (chronic kidney disease versus normal): baseline (190 vs 189; P=.232), 5 minutes (51 vs 47; P = .667), 10 minutes (37 vs 35; P=.626), and at 15 minutes postexcision (28 vs 27; P=.539). There was no significant difference in the kinetics of the intraoperative parathyroid hormone degradation slope from the baseline to the 15-minute postexcision levels comparing chronic kidney disease with normal kidney function (-21.02 vs -20.83; P=.957). Patients with chronic kidney disease had 15-minute postexcision intraoperative parathyroid hormone levels within the normal range (12 - 65 pg/mL) as frequently as patients with normal kidney function (81% vs 82%; P=.906) and had similar rates of persistent disease (3.4% vs 3.4%; P=.985). CONCLUSION: Patients with chronic kidney disease undergoing parathyroidectomy for primary hyperparathyroidism have similar intraoperative parathyroid hormone degradation kinetics, and the intraoperative parathyroid hormone criteria used to predict cure should be similar to those with normal kidney function.

Cryoballoon antral pulmonary vein isolation vs contact force-sensing radiofrequency catheter ablation for pulmonary vein and posterior left atrial isolation in patients with persistent atrial fibrillation.

BACKGROUND: The role of cryoballoon ablation (CBA) for antral pulmonary vein isolation (APVI) has not been well established in persistent atrial fibrillation (PerAF). Isolation of the left atrial posterior wall (BOX) after APVI has been suggested to improve the efficacy of radiofrequency catheter ablation (RFA) in PerAF. OBJECTIVE: The purpose of this study was to compare characteristics and clinical outcomes of APVI by CBA vs APVI + BOX by contact force-guided RFA (CF-RFA) in patients with PerAF. METHODS: APVI was performed in 167 consecutive patients with PerAF (mean age 64 ± 9 years; left atrial diameter 46 ± 6 mm) using CBA (n = 90) or CF-RFA (n = 77). After APVI, a roofline was created in 33 of 90 patients (37%) in the CBA group and BOX was performed in all 77 patients in the CF-RFA group. RESULTS: During 21 ± 10 months of follow-up after a single ablation procedure, 37 of 90 patients (41%) in the CBA group (APVI) and 39 of 77 (51%) in the CF-RFA group (APVI + BOX) remained in sinus rhythm without antiarrhythmic drugs (AADs) (P = .22). During repeat ablation, APVI + BOX using CF-RFA was performed in 20 of 90 patients (22%) and in 18 of 77 patients (23%) who initially underwent CBA or CF-RFA, respectively. At 19 ± 10 months after repeat ablation, sinus rhythm was maintained in 55 of 90 patients (61%) and 52 of 77 patients (68%) in the CBA and CF-RFA groups without AADs, respectively (P = .39). CONCLUSION: In PerAF, an initial approach of APVI by CBA or APVI + BOX by CF-RFA has a similar efficacy of 40%-50% without AADs. After repeat ablation for APVI + BOX by CF-RFA in ∼25%, sinus rhythm is maintained in 60%-70% of patients without AADs.

Risk factors associated with lymphedema after lymph node dissection in melanoma patients.

BACKGROUND: Secondary lymphedema is a frequent complication after lymphadenectomy in melanoma patients, although few studies in melanoma adequately characterize risk factors for lymphedema, and of these, sample size is limited. This study aims to identify risk factors associated with the lymphedema after axillary lymph node dissection (ALND) and inguinal lymph node dissection (ILND) in a more robust cohort of melanoma patients. METHODS: We identified 269 ALND or ILND melanoma patients treated between 2008 and 2014. Demographic, clinical, and postoperative data were collected by review of the electronic medical record. Univariate and multivariate analysis were used to determine independent predictors of lymphedema. RESULTS: Fifty-six (20.8%) of the patients developed lymphedema after lymph node dissection with a median staging group of 3. ILND (odds ratio [OR] = 4.506, P < .001, 95% confidence interval [CI]: 2.289 to 8.869) and peripheral vascular disease (PVD; OR = 3.849, P = .020, 95% CI: 1.237 to 11.975) were significant predictors of lymphedema in multivariate analysis. Obese body mass index approached significance (OR = 1.802, P = .069, 95% CI: .955 to 3.399). CONCLUSIONS: PVD and ILND were the 2 factors associated with the highest risk of lymphedema in melanoma surgery with PVD increasing risk 2-fold in ILND patients and 3-fold in ALND patients. These findings may improve surgeon-patient communication of care goals and surgical risk assessment.

Association of genetic variation with gene expression and protein abundance within the natriuretic peptide pathway.

The natriuretic peptide (NP) system is a critical physiologic pathway in heart failure with wide individual variability in functioning. We investigated the genetic component by testing the association of single nucleotide polymorphisms (SNP) with RNA and protein expression. Samples of DNA, RNA, and tissue from human kidney (n = 103) underwent genotyping, RT-PCR, and protein quantitation (in lysates), for four candidate genes [NP receptor 1 (NPR1), NPR2, and NPR3 and membrane metalloendopeptidase]. The association of genetic variation with expression was tested using linear regression for individual SNPs, and a principal components (PC) method for overall gene variation. Eleven SNPs in NPR2 were significantly associated with protein expression (false discovery rate ≤0.05), but not RNA quantity. RNA and protein quantity correlated poorly with each other. The PC analysis showed only NPR2 as significant. Assessment of the clinical impact of NPR2 genetic variation is needed.