Shivank Madan

Blood Pressure and Adverse Events During Continuous Flow Left Ventricular Assist Device Support

Background—Adverse events (AEs), such as intracranial hemorrhage, thromboembolic event, and progressive aortic insufficiency, create substantial morbidity and mortality during continuous flow left ventricular assist device support yet their relation to blood pressure control is underexplored. Methods and Results—A multicenter retrospective review of patients supported for at least 30 days and ⩽18 months by a continuous flow left ventricular assist device from June 2006 to December 2013 was conducted. All outpatient Doppler blood pressure (DOPBP) recordings were averaged up to the time of intracranial hemorrhage, thromboembolic event, or progressive aortic insufficiency. DOPBP was analyzed as a categorical variable grouped as high (>90 mm Hg; n=40), intermediate (80–90 mm Hg; n=52), and controlled (<80 mm Hg; n=31). Cumulative survival free from an AE was calculated using Kaplan–Meier curves and Cox hazard ratios were derived. Patients in the high DOPBP group had worse baseline renal function, lower angiotensin-converting enzyme inhibitor or angiotensin receptor blocker usage during continuous flow left ventricular assist device support, and a more prevalent history of hypertension. Twelve (30%) patients in the high DOPBP group had an AE, in comparison with 7 (13%) patients in the intermediate DOPBP group and only 1 (3%) in the controlled DOPBP group. The likelihood of an AE increased in patients with a high DOPBP (adjusted hazard ratios [95% confidence interval], 16.4 [1.8–147.3]; P=0.012 versus controlled and 2.6 [0.93–7.4]; P=0.068 versus intermediate). Overall, a similar association was noted for the risk of intracranial hemorrhage (P=0.015) and progressive aortic insufficiency (P=0.078) but not for thromboembolic event (P=0.638). Patients with an AE had a higher DOPBP (90±10 mm Hg) in comparison with those without an AE (85±10 mm Hg; P=0.05). Conclusions—In a population at risk, higher DOPBP during continuous flow left ventricular assist device support was significantly associated with a composite of AEs.

Frailty Assessment in Advanced Heart Failure

BACKGROUND Several studies have recently demonstrated the value of frailty assessment in a general heart failure (HF) population; however, it is unknown whether these findings are also applicable in advanced HF. We investigated the utility of frailty assessment and its prognostic value in elderly patients with advanced HF. METHODS Forty consecutive elderly subjects aged ≥65 years, with left ventricular ejection fraction ≤35%, New York Heart Association class III or IV, and a 6-minute walk test <300 m were enrolled from the HF clinic at Montefiore Medical Center between October 2012 and July 2013. Subjects were assessed for frailty with the Fried Frailty Index, consisting of 5 components: hand grip strength, 15-foot walk time, weight loss, physical activity, and exhaustion. All subjects were prospectively followed for death or hospitalization. RESULTS At baseline, the mean age of the cohort was 74.9 ± 6.5 years, 58% female, left ventricular ejection fraction 25.6 ± 6.4%, 6-minute walk test 195.8 ± 74.3 m and length of follow-up 454 ± 186 days. Thirty-five percent were prefrail and 65% were frail. Frailty status was associated with the combined primary endpoint of mortality and all-cause hospitalization (hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.15-3.25, P = .013). On individual analysis, frailty was associated with all-cause hospitalizations (HR 1.92, 95% CI 1.12-3.27, P = .017) and non-HF hospitalizations (HR 3.31, 95% CI 1.14- 9.6, P = .028), but was not associated with HF hospitalizations alone (HR 1.31, 95% CI 0.68-2.49, P = .380). CONCLUSIONS Frailty assessment in patients with advanced HF is feasible and provides prognostic value. These findings warrant validation in a larger cohort.

Nonalcoholic fatty liver disease and carotid artery atherosclerosis in children and adults: a meta-analysis.

Observational studies suggest that nonalcoholic fatty liver disease (NAFLD) is associated with increased carotid intimal medial thickness (C-IMT) and carotid plaques in both children and adults. We carried out a meta-analysis to evaluate the relationship between NAFLD and carotid atherosclerosis measured as C-IMT and carotid plaque prevalence. Medline (Ovid), PubMed, Web of Science, and CINAHL databases were searched from 1946 to September 2014, complemented with a manual review of references of the published articles for studies that compared C-IMT or carotid plaque prevalence in adults and children. Results were pooled using both fixed and random effects models. Of the studies identified, 20 were suitable for testing the effect of NAFLD on C-IMT in adults, 13 for testing the effect of NAFLD on carotid plaque prevalence in adults, and five for testing the effect of NAFLD on C-IMT in the pediatric population. The pooled data from 20 studies (19 274 adult participants: NAFLD=8652, controls=10 622) showed significantly increased C-IMT in patients with NAFLD, compared with controls without NAFLD, according to both fixed [standardized mean difference (SMD)=0.251, 95% confidence interval (CI): 0.220–0.282, P<0.001] and random effects models (SMD=0.944, 95% CI: 0.728–1.160, P<0.001). NAFLD was also found to be associated with a higher carotid artery plaque prevalence when compared with controls, according to both fixed (OR=1.273, 95% CI=1.162–1.394, P<0.001) and random effects models (OR=1.769, 95% CI: 1.213–2.581, P=0.003), on pooling of 13 studies (14 445 adult participants: NAFLD=5399 and controls=9046). Analysis of pooled data from five studies in the pediatric population (1121 pediatric participants: NAFLD=312 and controls=809) also found NAFLD to be associated with significantly increased C-IMT according to fixed (SMD=0.995, 95% CI: 0.840–1.150, P<0.001) and random effects models (1.083, 95% CI: 0.457–1.709, P=0.001). NAFLD is associated with increased C-IMT in both children and adults, and with increased carotid plaque prevalence in adults. Individuals identified with carotid disease should be evaluated for NAFLD and vice versa.

Nonalcoholic Fatty Liver Disease and Mean Platelet Volume: A Systemic Review and Meta-analysis.

Background: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity, metabolic syndrome, and cardiovascular disease. Increased mean platelet volume (MPV), a marker of platelet activity, is associated with acute myocardial infarction, stroke, thrombosis, and increased mortality after myocardial infarction. The purpose of this study was to perform a meta-analysis to investigate the relationship between NAFLD and MPV. Methodology: A systematic search of MEDLINE (Ovid), PubMed, and CINAHL databases from 1950 to May 2014, complemented with manual review of references of published articles for studies comparing MPV in patients with and without NAFLD was done. Results were pooled using both fixed and random effects model. Results: Our analysis from pooling of data from 8 observational studies including 1428 subjects (NAFLD=842 and non-NAFLD=586) showed that MPV was significantly higher in patients with NAFLD than those without. The standardized mean difference in MPV between NAFLD and controls was 0.457 (95% confidence interval: 0.348-0.565, P<0.001) using fixed and 0.612 (95% confidence interval: 0.286-0.938, P<0.001) using random effects model. Conclusions: This study suggests that MPV is significantly higher in patients with NAFLD, indicating the presence of increased platelet activity in such patients. Future research is needed to investigate whether this increased MPV is associated with increased cardiovascular disease in patients with NAFLD.

Antiplatelet Therapy and Adverse Hematologic Events During Heart Mate II Support

Background—Hematologic adverse events are common during continuous flow left ventricular assist device support; yet, their relation to antiplatelet therapy, including aspirin (ASA) dosing, is uncertain. Methods and Results—A single-center retrospective review of all patients supported by a continuous flow left ventricular assist device (Heart Mate II) from June 2006 to November 2014 was conducted. Patients were categorized into 3 groups: (1) ASA 81 mg+dipyridamole 75 mg daily (n=26) with a target international normalized ratio (INR) of 2 to 3 from June 2006 to August 2009; (2) ASA 81 mg daily (n=18) from September 2009 to August 2011 with a target INR of 1.5 to 2; and (3) ASA 325 mg daily from September 2011 to November 2014 with a target INR of 2 to 3 (n=70). Hemorrhagic and thrombotic outcomes were retrieved ⩽365 days after implantation. Cumulative survival free from adverse events was calculated using Kaplan–Meier curves and Cox proportional hazard ratios were generated. Hemorrhagic events occurred in 6 patients on ASA 81 mg+dipyridamole (26%; 0.42 events per patient year; mean INR at event, 2.2), 4 patients on ASA 81 mg (22%; 0.38 events per patient year; mean INR at event, 2.0), and in 38 patients on ASA 325 mg (54%; 1.4 events per patient year; mean INR at event, 2.2); P=0.004. Patients on ASA 325 mg had a higher adjusted hazard ratio of 2.9 (95% confidence interval, 1.2–7.0 versus ASA 81 mg+dipyridamole; P=0.02) and 3.4 (95% confidence interval, 1.2–9.5 versus ASA 81 mg; P=0.02) for hemorrhagic events. Thrombotic events rates were not different between groups. Conclusions—High-dose ASA in Heart Mate II patients treated concomitantly with warfarin is associated with an increased hazard of bleeding but does not reduce thrombotic events.

Donor Troponin and Survival after Cardiac Transplantation: An Analysis of the United Network of Organ Sharing Registry

Background— Despite a limited supply of organs, only 1 in 3 potential donor hearts is accepted for transplantation. Elevated donor troponin levels have generally been considered a contraindication to heart transplantation; however, the data supporting this practice are limited. Methods and Results— We identified 10 943 adult (≥18 years) heart transplant recipients in the United Network of Organ Sharing (UNOS) database with preserved donor left ventricular ejection fraction (≥50%) and where peak donor troponin I values were available. When analyzed as a continuous variable, there was no association between peak donor troponin levels and recipient mortality up to 1 year follow-up in unadjusted (hazards ratio, 0.999; 95% confidence interval, 0.997–1.002; P =0.856) and adjusted Cox models (hazards ratio, 1.000; 95% confidence interval, 0.997–1.002; P =0.950). Next, we divided the entire cohort into 3 groups based on donor troponin I values: 10 ng/mL (n=361). Using unadjusted and adjusted Cox models and Kaplan–Meier analysis, there was no significant difference in recipient mortality at 30 days, 1 year, 3 years, or 5 years between the 3 groups. Similarly, cardiac allograft vasculopathy up to 5 years and primary graft failure up to 30 days of follow-up post transplant did not differ between the 3 donor troponin groups. The median length of hospital stay post transplant was also similar across groups. Conclusions— Elevated donor troponin I levels in the setting of preserved left ventricular ejection fraction were not associated with intermediate-term mortality, cardiac allograft vasculopathy, or primary graft failure rates in hearts accepted for transplantation. This finding could help expand the donor pool.Background—Despite a limited supply of organs, only 1 in 3 potential donor hearts is accepted for transplantation. Elevated donor troponin levels have generally been considered a contraindication to heart transplantation; however, the data supporting this practice are limited. Methods and Results—We identified 10 943 adult (≥18 years) heart transplant recipients in the United Network of Organ Sharing (UNOS) database with preserved donor left ventricular ejection fraction (≥50%) and where peak donor troponin I values were available. When analyzed as a continuous variable, there was no association between peak donor troponin levels and recipient mortality up to 1 year follow-up in unadjusted (hazards ratio, 0.999; 95% confidence interval, 0.997–1.002; P=0.856) and adjusted Cox models (hazards ratio, 1.000; 95% confidence interval, 0.997–1.002; P=0.950). Next, we divided the entire cohort into 3 groups based on donor troponin I values: <1 ng/mL (n=7812), 1 to 10 ng/mL (n=2770), and >10 ng/mL (n=361). Using unadjusted and adjusted Cox models and Kaplan–Meier analysis, there was no significant difference in recipient mortality at 30 days, 1 year, 3 years, or 5 years between the 3 groups. Similarly, cardiac allograft vasculopathy up to 5 years and primary graft failure up to 30 days of follow-up post transplant did not differ between the 3 donor troponin groups. The median length of hospital stay post transplant was also similar across groups. Conclusions—Elevated donor troponin I levels in the setting of preserved left ventricular ejection fraction were not associated with intermediate-term mortality, cardiac allograft vasculopathy, or primary graft failure rates in hearts accepted for transplantation. This finding could help expand the donor pool.

Cessation of Continuous Flow Left Ventricular Assist Device–Related Gastrointestinal Bleeding After Heart Transplantation

Gastrointestinal bleeding (GIB) is a major complication of continuous flow left ventricular assist device (CF LVAD) therapy. The precise pathophysiology of CF LVAD–related bleeding remains poorly understood, and the effect of pump removal at the time of transplantation on actual bleeding frequency has not previously been studied. A single-center retrospective review was conducted on patients who received CF LVAD and subsequently developed GIB. Baseline demographics and markers of pulsatility (aortic valve opening and the HeartMate II [HM2] pulse index) were compared between those with and without GIB. In those patients who had GIB and proceeded to heart transplantation, the frequency and etiology of recurrent GIB post-transplant was assessed. A total of 88 GIBs occurred in 54 of 214 patients who received CF LVAD implantation (25%, 0.36 events per patient-year). Median time to first bleeding was 65 (interquartile range [IQR]: 37–229) days, and arteriovenous malformation (AVM) was the etiology in 36% of all episodes. On multivariate analysis, age (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 1.01–1.09; p = 0.006) and HM2 pulse index (OR: 0.57; 95% CI: 0.35–0.90; p = 0.017) were significantly associated with GIB. There were 28 patients who had at least one GIB event during LVAD support and proceeded to transplant. None of these patients had recurrent bleeding after heart transplantation. This is the first documentation that transplantation effectively eliminates CF LVAD–related GIB. Current guidelines recommending prioritization for transplant for patients who develop recurrent GIB after CF LVAD are justified.

Association of centre volume and in-hospital mortality in heart failure hospitalisations

Background Centre volume is an important determinant of outcomes in patients requiring complex medical treatments or surgical procedures. Heart failure hospitalisation (HFH) has become an increasingly complex and resource intensive clinical event. We evaluated the effect of centre volume on mortality and costs in patients with HFH. Methods This was a retrospective registry-based analysis of adult patients discharged with a primary diagnosis of HF from hospitals across New York (NY) State over a 5-year period, between January 2009 and December 2013, using the Statewide Planning and Research Cooperative System inpatient discharge files. The primary outcome of interest was in-hospital mortality. All patients were followed from the day of admission to either in-hospital death or discharge alive. Results 300 972 HFHs from 198 facilities across NY State were included. Five-year centre volume was associated with a decrease in in-hospital mortality in unadjusted (HR=0.872, 95% CI 0.863 to 0.881, p<0.001) and adjusted Cox models (HR=0.869, 95% CI 0.859 to 0.879, p<0.001). After dividing the overall cohort into three groups based on 5-year centre volume, groups with medium and high volume centres had lower in-hospital mortality when compared with the group with low volume centres. The results were consistent in various subgroup analyses. Furthermore, hospitals in the higher centre volume groups had increased HFH costs across different severity of illness categories and involved increased use of cardiac procedures. Conclusions Higher centre volume was associated with lower HFH mortality but increased HFH costs and increased cardiac procedures in a cohort of Medicare and non-Medicare beneficiaries.

Sildenafil Is Associated With Reduced Device Thrombosis and Ischemic Stroke Despite Low-Level Hemolysis on Heart Mate II Support

Background Persistent low-level hemolysis (LLH) during continuous-flow mechanical circulatory support is associated with subsequent thrombosis. Free hemoglobin from ongoing hemolysis scavenges nitric oxide (NO) to create an NO deficiency which can augment platelet function leading to a prothrombotic state. The phosphodiesterase-5 inhibitor, sildenafil, potentiates NO signaling to inhibit platelet function. Accordingly, we investigated the association of sildenafil administration and thrombotic events in patients with LLH during Heart Mate II support. Methods and Results A single-center review of all patients implanted with a Heart Mate II who survived to discharge (n=144). LLH was defined by a discharge lactate dehydrogenase level of 400 to 700 U/L. Patients were categorized as (1) LLH not on sildenafil, (2) LLH on sildenafil, (3) no LLH not on sildenafil, and (4) no LLH on sildenafil. Age, sex, platelet count, and mean platelet volume were similar between groups. Seventeen patients had either device thrombosis or ischemic stroke. Presence of LLH was associated with a greater risk of thrombosis (adjusted hazard ratio, 15; 95% confidence interval, 4.5–50; P<0.001 versus no LLH, not on sildenafil). This risk was reduced in patients with LLH on sildenafil (adjusted hazard ratio, 1.7; 95% confidence interval, 0.2–16.1; P=0.61). Device thrombosis and ischemic stroke were associated with an increase in mean platelet volume (9.6±0.5 to 10.9±0.8 fL, P<0.001). Patients with LLH not on sildenafil had a greater increase in mean platelet volume in comparison to those with LLH on sildenafil (P<0.001). Conclusions Sildenafil is associated with reduced device thrombosis and ischemic stroke during ongoing LLH on Heart Mate II support.

Reply: Transient Wall Motion Abnormalities in Donor Hearts With Improved Left Ventricular Systolic Dysfunction: Takotsubo Revisited?

We thank Dr. Madias and Dr. El-Battrawy et al. for their thoughtful comments on our recently published study [(1)][1], which showed that donor hearts with left ventricular systolic dysfunction (LVSD) that are successfully resuscitated can be transplanted without increasing recipient mortality,