Ryan T. Kipp

Chemical inhibition of the TFIIH-associated kinase Cdk7/Kin28 does not impair global mRNA synthesis

The process of gene transcription requires the recruitment of a hypophosphorylated form of RNA polymerase II (Pol II) to a gene promoter. The TFIIH-associated kinase Cdk7/Kin28 hyperphosphorylates the promoter-bound polymerase; this event is thought to play a crucial role in transcription initiation and promoter clearance. Studies using temperature-sensitive mutants of Kin28 have provided the most compelling evidence for an essential role of its kinase activity in global mRNA synthesis. In contrast, using a small molecule inhibitor that specifically inhibits Kin28 in vivo, we find that the kinase activity is not essential for global transcription. Unlike the temperature-sensitive alleles, the small-molecule inhibitor does not perturb protein–protein interactions nor does it provoke the disassociation of TFIIH from gene promoters. These results lead us to conclude that other functions of TFIIH, rather than the kinase activity, are critical for global gene transcription.

Patient preferences for coronary artery bypass graft surgery or percutaneous intervention in multivessel coronary artery disease.

Objectives: Determine if patients prefer multivessel percutaneous coronary intervention (mv‐PCI) over coronary artery bypass graft surgery (CABG) for treatment of symptomatic multivessel coronary artery disease (mv‐CAD) despite high 1‐year risk. Background: Patient risk perception and preference for CABG or mv‐PCI to treat medically refractory mv‐CAD are poorly understood. We hypothesize that patients prefer mv‐PCI instead of CABG even when quoted high mv‐PCI risk. Methods: 585 patients and 31 physicians were presented standardized questionnaires with a hypothetical scenario describing chest pain and medically refractory mv‐CAD. CABG or mv‐PCI was presented as treatment options. Risk scenarios included variable 1‐year risks of death, stroke, and repeat procedures for mv‐PCI and fixed risks for CABG. Participants indicated their preference of revascularization method based on the presented risks. We calculated the odds that patients or physicians would favor mv‐PCI over CABG across a range of quoted risks of death, stroke, and repeat procedures. Results: For nearly all quoted risks, patients preferred mv‐PCI over CABG, even when the risk of death was double the risk with CABG or the risk of repeat procedures was more than three times that for CABG (P < 0.0001). Compared to patients, physicians chose mv‐PCI less often than CABG as the risk of death and repeat procedures increased (P < 0.001 and P = 0.004, respectively). Conclusion: Patients favor mv‐PCI over CABG to treat mv‐CAD, even if 1‐year risks of death and repeat procedures far exceed risk with CABG. Physicians are more influenced by actual risk and prefer mv‐PCI less than patients despite similarly quoted 1‐year risks.

Machine Learning Algorithm Predicts Cardiac Resynchronization Therapy Outcomes: Lessons From the COMPANION Trial

Background: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in heart failure patients with reduced left ventricular function and intraventricular conduction delay. However, individual outcomes vary significantly. This study sought to use a machine learning algorithm to develop a model to predict outcomes after CRT. Methods and Results: Models were developed with machine learning algorithms to predict all-cause mortality or heart failure hospitalization at 12 months post-CRT in the COMPANION trial (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure). The best performing model was developed with the random forest algorithm. The ability of this model to predict all-cause mortality or heart failure hospitalization and all-cause mortality alone was compared with discrimination obtained using a combination of bundle branch block morphology and QRS duration. In the 595 patients with CRT-defibrillator in the COMPANION trial, 105 deaths occurred (median follow-up, 15.7 months). The survival difference across subgroups differentiated by bundle branch block morphology and QRS duration did not reach significance (P=0.08). The random forest model produced quartiles of patients with an 8-fold difference in survival between those with the highest and lowest predicted probability for events (hazard ratio, 7.96; P<0.0001). The model also discriminated the risk of the composite end point of all-cause mortality or heart failure hospitalization better than subgroups based on bundle branch block morphology and QRS duration. Conclusions: In the COMPANION trial, a machine learning algorithm produced a model that predicted clinical outcomes after CRT. Applied before device implant, this model may better differentiate outcomes over current clinical discriminators and improve shared decision-making with patients.

Injectable loop recorder implantation in an ambulatory setting by advanced practice providers: Analysis of outcomes

Implantable loop recorder (ILR) insertion has historically been performed in a surgical environment such as the electrophysiology (EP) lab. The newest generation loop recorder (Medtronic Reveal LINQ™, Minneapolis, MN, USA) is injectable with potential for implantation in a non‐EP lab setting by advanced practice providers (APPs) facilitating improved workflow and resource utilization. We report the safety and efficacy of injectable ILR placement in the ambulatory care setting by APPs.

Long-term morbidity and mortality after implantable cardioverter-defibrillator implantation with procedural complication: A report from the National Cardiovascular Data Registry

BACKGROUND Long-term outcomes and predictors of mortality after implantable cardioverter-defibrillator (ICD) implantation related complication are unclear. OBJECTIVE The purpose of this study was to determine the risk of mortality and hospitalization after complication during ICD implantation and identify predictors of adverse outcomes. METHODS We performed a retrospective registry study of Medicare beneficiaries who were first-time ICD recipients enrolled in the National Cardiovascular Data Registry ICD Registry between January 2006 and March 2010. Mortality and hospitalization rates were examined using Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression analysis. Covariates associated with mortality 3 years after ICD implantation complication were investigated. RESULTS The study cohort comprised 136,143 Medicare beneficiaries. Complications during the index hospitalization occurred in 7046 patients (5.18%), and complications within 90 days of device implantation occurred in 10,005 patients (7.34%). In adjusted analyses, complications within 90 days of implantation were associated with an increased risk of all-cause mortality at 1 year (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.05-1.20; P = .006) and 3 years (HR 1.09; 95% CI 1.05-1.13; P <.0001). These results were consistent for a combined endpoint of all-cause mortality or hospitalization. Patient, device, and hospital characteristics associated with 3-year mortality were similar between those with and those without complications. CONCLUSION Among Medicare beneficiaries, the occurrence of complications within 90 days of ICD implantation was associated with increased risk of all-cause mortality and all-cause mortality or hospitalization at 1 and 3 years. Patient, procedure, and hospital characteristics associated with mortality at 3 years after implantation were similar regardless of whether acute procedural complication occurred.

P‐Wave Amplitude and PR Changes in Patients With Inappropriate Sinus Tachycardia: Findings Supportive of a Central Mechanism

Background The mechanism of inappropriate sinus tachycardia (IST) remains incompletely understood. Methods and Results We prospectively compared 3 patient groups: 11 patients with IST (IST Group), 9 control patients administered isoproterenol (Isuprel Group), and 15 patients with cristae terminalis atrial tachycardia (AT Group). P‐wave amplitude in lead II and PR interval were measured at a lower and higher heart rate (HR1 and HR2, respectively). P‐wave amplitude increased significantly with the increase in HR in the IST Group (0.16±0.07 mV at HR1=97±12 beats per minute versus 0.21±0.08 mV at HR2=135±21 beats per minute, P=0.001). The average increase in P‐wave amplitude in the IST Group was similar to the Isuprel Group (P=0.26). PR interval significantly shortened with the increases in HR in the IST Group (146±15 ms at HR1 versus 128±16 ms at HR2, P<0.001). A similar decrease in the PR interval was noted in the Isuprel Group (P=0.6). In contrast, patients in the atrial tachycardia Group experienced PR lengthening during atrial tachycardia when compared with baseline normal sinus rhythm (153±25 ms at HR1=78±17 beats per minute versus 179±29 ms at HR2=140±28 beats per minute, P<0.01). Conclusions We have shown that HR increases in patients with IST were associated with an increase in P‐wave amplitude in lead II and PR shortening similar to what is seen in healthy controls following isoproterenol infusion. The increase in P‐wave amplitude and absence of PR lengthening in IST support an extrinsic mechanism consistent with a state of sympatho‐excitation with cephalic shift in sinus node activation and enhanced atrioventricular nodal conduction.

Concealed Accessory Pathways with a Single Ventricular and Two Discrete Atrial Insertion Sites.

Atrioventricular reciprocating tachycardia (AVRT) utilizing a concealed accessory pathway is common. It is well appreciated that some patients may have multiple accessory pathways with separate atrial and ventricular insertion sites.

Percutaneous Mechanical Assist for Severe Cardiogenic Shock Due to Acute Right Ventricular Failure

Acute right ventricular failure can lead to severe cardiogenic shock and death. Recovery may be achieved with early supportive measures. In many patients, intravenous fluid and inotropic resuscitation is inadequate to improve cardiac output. In these cases, percutaneous mechanical assist may provide a non‐surgical bridge to recovery. Herein, we describe a case series of patients with severe, refractory cardiogenic shock due to acute right ventricular failure who received a continuous flow percutaneous ventricular device primarily utilizing the right internal jugular vein for out flow cannula placement.