Kenneth Knecht - Academia.edu (original) (raw)

Papers by Kenneth Knecht

Journal of Heart and Lung Transplantation, Apr 1, 2015

Although used routinely the pleiotropic benefits of statins remain understudied in children after... more Although used routinely the pleiotropic benefits of statins remain understudied in children after heart transplantation. We hypothesized that statin therapy would reduce the incidence of rejection, cardiac allograft vasculopathy (CAV) and post-transplant lymphoproliferative disease (PTLD). Methods: This was a retrospective review of 1,020 pediatric (age 5-18 years) heart transplant recipients in the multicentre Pediatric Heart Transplant Study registry from 2001-2012. Data were missing for 56 patients. Patients with previous PTLD, undergoing re-transplantation, survival < 1 year or with missing data regarding statin use were excluded from the analysis. Early statin use was defined as initiation prior to 1 year post-transplant. The effects of statins beyond the first year were estimated by Kaplan-Meier and Cox regression multivariate analysis for freedom from PTLD, rejection requiring treatment, any severity of CAV, and survival. Results: Statin-treated children (average age at transplant 13.2 ± 3.3 years) had significantly earlier rejection (HR 1.44, 95% CI 1.11-1.85, p= 0.0056) compared to untreated children (transplanted at 12 ± 3.6 years) after the first year post-transplant (see Figure-unadjusted freedom from rejection) after adjusting for conventional risk factors for rejection. Freedom from PTLD and CAV and overall survival up to 6 years post-transplant were not affected by statin use (multivariable analyses not performed), however, the number of events was small. Conclusion: In our cohort, early statin therapy did not confer an early survival benefit and was not associated with delayed onset of rejection, PTLD or CAV. Only a third of the cohort were started on a statin within 1 year of transplant. These statin-treated patients may be a pre-selected, high-risk rejection subgroup. Additional studies are needed to better define treated patients and their outcome from statin use.

Journal of Heart and Lung Transplantation, Apr 1, 2016

BACKGROUND: Although used routinely, the pleiotropic benefits of statins remain understudied in c... more BACKGROUND: Although used routinely, the pleiotropic benefits of statins remain understudied in children after heart transplantation. We hypothesized that statin therapy would reduce the incidence of rejection, cardiac allograft vasculopathy (CAV) and post-transplant lymphoproliferative disease (PTLD). METHODS: This study was a retrospective review of 964 pediatric (ages 5 to 18 years) heart transplant recipients in the multicenter Pediatric Heart Transplant Study registry from 2001 to 2012. Patients were excluded if they were undergoing re-transplantation, survived o1 year post-transplant, or had missing data regarding statin use. The effects of statins beyond the first year were estimated by Kaplan-Meier and Cox regression multivariable analysis for freedom from PTLD, rejection requiring treatment, any severity of CAV, and survival. RESULTS: Statin use was variable among participating centers with only 30% to 35% of patients Z10 years of age started on a statin at o1 year post-transplant. After the first year post-transplant, statintreated children (average age at transplant 13.24 Ϯ 3.29 years) had significantly earlier rejection (HR 1.42, 95% CI 1.11 to 1.82, p ¼ 0.006) compared with untreated children (transplanted at 12 Ϯ 3.64 years) after adjusting for conventional risk factors for rejection. Freedom from PTLD, CAV and overall survival up to 5 years post-transplant were not affected by statin use, although the number of events was small. CONCLUSIONS: Statin therapy did not confer a survival benefit and was not associated with delayed onset of PTLD or CAV. Early (o1 year post-transplant) statin therapy was associated with increased later frequency of rejection. These findings suggest that a prospective trial evaluating statin therapy in pediatric heart transplant recipients is warranted.

American Journal of Cardiology, Apr 1, 2009

Korotkoff sounds (KSs) are the clinical norm for noninvasively estimating systemic arterial blood... more Korotkoff sounds (KSs) are the clinical norm for noninvasively estimating systemic arterial blood pressure (BP) in children and adults. Their existence and reliability in children &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;3 years old was unknown. This study addressed the presence and accuracy of KSs in children &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;3 years. Measurements of the first KS (K1), K4, and K5 (the commonly used sounds) were compared with invasive measurements of systolic and diastolic BP in &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =3 inflations/subject. Subjects were prospectively divided by age &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1 (n = 20), 1 to 12 (n = 29), and 13 to 36 months (n = 17). KSs were audible with low frequency in subjects &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1 month old and they were excluded from further analysis. In 143 inflations, K1 was audible in 125, K4 in 104, and K5 in 114; the frequency of audible KSs increased with subject age. Reliability of KSs as a surrogate for measured systolic and diastolic BP was assessed using paired t tests. K1 was not significantly different for the entire group or any subgroup. K4 was significantly different in all age groups. K5 was significantly different in only subjects &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;6 months. In conclusion, K1, K4, and K5 are routinely audible and K1 and K5 provide a reliable estimate of systolic and diastolic BP in children age 1 to 36 months.

Journal of Heart and Lung Transplantation, Apr 1, 2019

Pediatric Transplantation, Jan 18, 2022

Background: We aimed to evaluate right ventricular (RV) function longitudinally using tissue Dopp... more Background: We aimed to evaluate right ventricular (RV) function longitudinally using tissue Doppler imaging (TDI) echocardiography in preterm infants. Methods: We selected 101 very-low-birth-weight (VLBW) infants for the study. Echocardiographic examinations including TDI were performed serially within 7 days of life. Pulsed-Doppler TDI waveforms were recorded at the tricuspid valve annulus, and peak systolic velocities (Sa), early diastolic velocities (Ea), and late diastolic velocities (Aa) were measured. Results: Sa, Ea and Aa were all reduced significantly from 3 h to 12 h, and then increased gradually thereafter. These three velocities also increased with gestational age in the early neonatal period. The ratio of Ea to Aa (Ea/Aa) did not change significantly within the first week of life. The ratio of E to Ea (E/Ea) in VLBW infants also seemed to remain stable from birth to day 7. The values of Sa appeared to be associated with cardiac output in the early neonatal period. Both Sa and Aa in intubated infants were significantly higher than in non-intubated infants. Conclusion: RV TDI velocities of preterm infants in the early neonatal period are influenced by gestational age, postnatal age, and respiratory status, although the RV E/Ea ratio appears to be almost stable throughout the neonatal period. Our findings may provide some basis for assessment of RV function in critically ill preterm infants.

Journal of Heart and Lung Transplantation, Apr 1, 2017

length of stay, and incidence of mechanical circulatory support or transplant during admission. T... more length of stay, and incidence of mechanical circulatory support or transplant during admission. The most common incorrect diagnostic label given to 'missed' patients were bacterial infection (treated with unnecessary antibiotics) in 21.7% (23/106) and viral syndrome in 14.2% (15/106) patients. On examining associated process breakdowns involved, 48.1% (50/106) had an absence of documentation of differential diagnoses, 85.8% (91/106) did not have CHF documented as a differential diagnosis; in 76.4% (81/106) cases there was absence of any diagnostic tests ordered for further workup, and in 58.5% (62/106) abnormal physical exam or testing was not appropriately followed up. Conclusion: Almost 50% of children with new diagnoses of acute CHF are missed at initial presentation, many of which are labelled as bacterial infections. A lower incidence of renal dysfunction might suggest that these cases were less critically ill, but their outcomes and utilization were similar to the correctly diagnosed cases. Because clear red flags were missed and many patients received unnecessary antibiotics, strategies to improve recognition of acute CHF are needed.

Journal of Heart and Lung Transplantation, Dec 1, 2021

Su-Gang Gong, Jing He and Ping Yuan helped conduct the study and analyze the data. Prof Jin-Ming ... more Su-Gang Gong, Jing He and Ping Yuan helped conduct the study and analyze the data. Prof Jin-Ming Liu contributed to the experimental design, writing and revision of the manuscript. All authors had full access to all study data and had final responsibility for the decision to submit the article for publication. All have reviewed the manuscript and approved the final version for submission.

$Research paper thumbnail of Relationship between donor fraction cell‐free DNA and clinical rejection in heart transplantation$

Pediatric Transplantation, 2022

BACKGROUND Clinical rejection (CR) defined as decision to treat clinically suspected rejection wi... more BACKGROUND Clinical rejection (CR) defined as decision to treat clinically suspected rejection with change in immunotherapy based on clinical presentation with or without diagnostic biopsy findings is an important part of care in heart transplantation. We sought to assess the utility of donor fraction cell-free DNA (DF cfDNA) in CR and the utility of serial DF cfDNA in CR patients in predicting outcomes of clinical interest. METHODS Patients with heart transplantation were enrolled in two sequential, multi-center, prospective observational studies. Blood samples were collected for surveillance or clinical events. Clinicians were blinded to the results of DF cfDNA. RESULTS A total of 835 samples from 269 subjects (57% pediatric) were included for this analysis, including 28 samples associated with CR were analyzed. Median DF cfDNA was 0.43 (IQR 0.15, 1.36)% for CR and 0.10 (IQR 0.07, 0.16)% for healthy controls (p < .0001). At cutoff value of 0.13%, the area under curve (AUC) was 0.82, sensitivity of 0.86, specificity of 0.67, and negative predictive value of 0.99. There was serial decline in DF cfDNA post-therapy, however, those with cardiovascular events (cardiac arrest, need for mechanical support or death) showed significantly higher levels of DF cfDNA on Day 0 (2.11 vs 0.31%) and Day 14 (0.51 vs 0.22%) compared to those who did not have such an event (p < .0001). CONCLUSION DF cfDNA has excellent agreement with clinical rejection and, importantly, serial measurement of DF cfDNA predict clinically significant outcomes post treatment for rejection in these patients.

The Journal of Heart and Lung Transplantation, 2018

examined the impact of dnDSA on HTx outcomes and developed a novel risk prediction model for seve... more examined the impact of dnDSA on HTx outcomes and developed a novel risk prediction model for severe acute cellular and antibody mediated rejection (ACR & AMR). Methods: Consecutive adult patients who underwent HTx between 2009 and 2013 with routine serial monitoring for dnDSA were included. Freedom from rejection based on 1546 endomyocardial biopsies was analyzed. Time-dependent Cox-proportional hazard modeling was used for multivariable analyses and for development of the risk prediction model. Results: Amongst 86 HTx recipients, 29 (33.7%) developed dnDSA. Timedependent multivariable analysis revealed class I dnDSA to be independently associated with AMR (HR= 27.8, p< 0.001), and class II dnDSA with severe ACR (HR= 3.42, p= 0.011). In the rejection risk prediction model, appropriate constants were chosen based on a) the conditional period during which no AMR or severe ACR occured but dnDSA developed as well as b) the time t at which the probability of rejection was estimated. Slopes are the coefficients for different variables derived from the time-dependent Cox modeling. Risk prediction equation and sample result for different patient characteristics who do not have rejection or development of de-novo donor specific antibodies within first 30 days after heart transplantation were shown in figure 1. Conclusion: Routine monitoring for dnDSA after HTx is important to identify patients who are at increased risk of AMR and severe ACR. Use of an innovative rejection risk calculator incorporating the presence of dnDSA is proposed to individualize immunosuppression in an effort to improve clinical outcomes of HTx recipients.

Improved Survival While Waiting in Pediatric Patients Listed For Cardiac Transplantation. Backgro... more Improved Survival While Waiting in Pediatric Patients Listed For Cardiac Transplantation. Background: Although survival after transplantation (HTx) in children has improved, wait list mortality continues to have a significant effect on overall survival. The potential impact of improved management of patients listed for HTx, specifically recent availability (after 2004) of pediatric ventricular assist devices (VAD), has not been examined. Purpose: To determine the effect of changes in pre-transplant management and era of listing on survival of pediatric patients listed for HTx. We also sought to determine risk factors for death and transplantation. Methods: We performed a retrospective study of patients listed for (HTx) (<18 years old) between January 1993 and December 2009 at a large pediatric heart transplant center. Survival was determined using Kaplan Meier and parametric survival analysis as well as non-parametric (Fine Gray) and parametric competing outcomes modeling. Risk f...

Pediatric Transplantation, 2012

Acute rejection is a major morbidity in heart transplant recipients; diagnosis is difficult, and ... more Acute rejection is a major morbidity in heart transplant recipients; diagnosis is difficult, and rejection must often be treated reactively. Various serum biomarkers have been investigated for non-invasive monitoring of the cardiac allograft. NTproBNP is produced by the ventricular myocardium and may increase with evolving rejection allowing earlier diagnosis. Retrospective review of serum NTproBNP levels in pediatric heart transplant recipients has been carried out to evaluate the association with episodes of acute rejection. Repeated measures logistic regression was used to model associations for variables with first rejection and within an individual for change in NTproBNP and first rejection. Odds ratios for rejection risk given an increase in serum NTproBNP were calculated. Correlation of NTproBNP levels with renal function as estimated by modified Schwartz equation was performed to look for confounding. Higher serum NTproBNP level was associated with increased risk of rejection, but intersubject variability was wide. However, increase in an individual subject&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s serum level showed increased risk of rejection, greater with greater rise. Serum NTproBNP levels appear not greatly affected by renal function. NTproBNP shows promise in surveillance for pediatric heart transplant recipients. The greatest use appears to be in following trends for an individual instead of using an absolute value.

The Journal of Heart and Lung Transplantation, 2012

HLA antibodies were seen in 50% (8/16) of the neonatal group, none of the infant group, and 17% (... more HLA antibodies were seen in 50% (8/16) of the neonatal group, none of the infant group, and 17% (1/6) of controls; class II HLA antibodies were seen in 44% (7/16) of the neonatal group, none of the infant group, and 33% (2/6) of controls. While all subjects received fresh whole blood, the neonatal group had more fresh whole blood exposure (pϭ0.004). There was a trend toward a lower prevalence of sensitization with increasing time from last receipt of allograft or blood transfusion (pϭ0.06). Conclusions: Exposure to allograft at the Norwood procedure is associated with long-term sensitization in half of subjects, a response not seen after an isolated Glenn procedure. Sensitization was observed in those without prior allograft exposure, may decrease over time, and appears related in part to whole blood. These findings have implications for patients after congenital heart disease surgery if heart transplant is considered late in the clinical course.

The American Journal of Cardiology, 2009

Emerging Infectious Diseases, Dec 1, 2000

Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is fo... more Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above. All material published in Emerging Infectious Diseases is in the public domain and may be used and reprinted without special permission; proper citation, however, is required.

Journal of Heart and Lung Transplantation, Apr 1, 2013

Purpose Maintenance steroid (MS) use in pediatric heart transplantation (HT) is variable. Our pur... more Purpose Maintenance steroid (MS) use in pediatric heart transplantation (HT) is variable. Our purpose was to evaluate the impact of MS use on pediatric HT outcomes. Methods and Materials All patients Results A total of 1393 (64%) patients were MS+ and 785 (36%) were MS−. There were 315 MS- patients that had propensity matched MS+ controls. Kaplan Meier analysis showed no difference in graft loss ( Figure 1 ; p=0.9), graft loss due to rejection (p=0.09), or rejection (p=0.15). There was a higher incidence of RSHC in the MS- group (p=0.004), while there was a higher incidence of malignancy in the MS+ group (p=0.02). Conclusions The use of MS was not associated with enhanced graft survival after pediatric HT. MS+ patients had a higher incidence of malignancy and MS- patients had a higher incidence of RSHC. These risks should be taken into consideration when determining maintenance steroid use in institutional protocols as well as for individual patients.

Cardiology in The Young, Apr 27, 2023

Mid-aortic syndrome is a rare condition characterised by segmental narrowing of the thoracoabdomi... more Mid-aortic syndrome is a rare condition characterised by segmental narrowing of the thoracoabdominal aorta. Here, we demonstrate a case of mid-aortic syndrome in a 30-month-old female who was diagnosed via transesophageal echocardiography after presenting with dilated cardiomyopathy and severe heart failure requiring placement of a left ventricular assist device.

Journal of Child and Adolescent Psychopharmacology, Mar 1, 2015

A recent article in your journal appropriately looks to examine the risk of adverse cardiovascula... more A recent article in your journal appropriately looks to examine the risk of adverse cardiovascular events in patients treated with stimulant medications (Søren et al.). However, the conclusions drawn from the findings may be erroneous, and require further clarification. The authors studied a large population-based cohort and looked for cardiovascular events in this population. Their findings would indicate that cardiovascular events are more common, approximately twofold, in children treated with these medications. If true, this alarming finding is of great importance and may lead to changes in the treatment of attention-deficit/hyperactivity disorder (ADHD). However, before any change in practice is made, clarification is needed. The majority of the cardiovascular events fall into broad categories (23% arrhythmia, 14% heart disease not otherwise specified [NOS], 40% cardiovascular disease NOS) requiring further definition. For example, ''arrhythmia'' may indicate sinus tachy-or bradycardia, sinus arrhythmia, or other benign diagnoses, which would not indicate alteration in treatment. Anything ''not otherwise specified'' raises similar concern, as this may run the gamut from palpitations without arrhythmia to noncardiac chest pain to hypo-or hypertension. The authors speculate on the physiologic etiology of their findings, but without fully defining these findings. That these authors' findings are significant is true, not in small part because they would be the first to document adverse cardiac affects in child and/or adolescent populations. Prior studies have failed to show similar events (Westover and Halm) or an increase in mortality (Mazza et al.). I concur with questions raised regarding the population-based clinical significance, given the low incidence even in this population. However, more importantly, I also question the individual clinical significance that hinges on these lacking definitions.

$Research paper thumbnail of Validation of donor fraction cell-free DNA with biopsy-proven cardiac allograft rejection in children and adults$

The Journal of Thoracic and Cardiovascular Surgery

The Journal of Heart and Lung Transplantation, 2021

Purpose There are limited data reporting outcomes of children with trisomy 21 undergoing heart tr... more Purpose There are limited data reporting outcomes of children with trisomy 21 undergoing heart transplantation (HTx). This project reports the waitlist and post-HTx outcomes of children with trisomy 21. Methods This is a retrospective cohort study of children with trisomy 21 listed for or who underwent HTx at 11 centers within North America and internationally. Demographic, medical, surgical, and post-HTx outcome data were collected and described. Results Twenty-one patients with trisomy 21 were listed for HTx from 1992 through 2019 (median age 8.5y, 43% male, 52% white). High-risk or failed repair of congenital heart disease was the indication for transplant in 16 (76%) patients with atrioventricular septal defect being the most common (N=12). Other diagnoses included dilated cardiomyopathy in 4 patients (secondary to anthracyclines in 2) and myocarditis in 1 patient. A total of 18 (86%) patients survived to transplant. Of this group, support at the time of transplant included inotropes (N=10, 56%), ventricular assist device (N=7, 39%), and mechanical ventilation (N=2, 11%). No patients required post-operative extracorporeal membrane oxygenation or dialysis. All centers reported the use of standard immunosuppression without alterations secondary to trisomy 21. All transplanted patients survived to hospital discharge with a median post-HTx length of stay of 19d. With a median follow-up of 2.9y, 16 (89%) patients were alive, 5 (28%) had rejection within the 1st year post-HTx, 2 (11%) developed post-transplant lymphoproliferative disorder (PTLD), and 7 (39%) were hospitalized for infection within the 1st year post-HTx. For the two post-HTx mortalities, the causes of death were 1) coronary allograft vasculopathy at 22y post-HTx and 2) multiple episodes of rejection and PTLD at 1.5y post-HTx (Figure). Conclusion Waitlist and intermediate post-HTx outcomes are acceptable in children with trisomy 21. The presence of trisomy 21 should not be an absolute contraindication to heart transplantation in the appropriate clinical setting.