Association of cardiac biomarkers with long-term cardiovascular events in a community cohort.

MATERIALS AND METHODS: The study assessed major adverse cardiac events (MACE) (myocardial infarction, coronary artery bypass graft, percutaneous intervention, stroke, and death. Cox proportional hazards models assessed apolipoprotein AI (ApoA1), apolipoprotein B (ApoB), ceramide score, cystatin C, galectin-3 (Gal3), LDL-C, Non-HDL-C, total cholesterol (TC), N-terminal B-type natriuretic peptide (NT proBNP), high-sensitivity cardiac troponin (HscTnI) and soluble interleukin 1 receptor-like 1. In adjusted models, Ceramide score was defined by from N-palmitoyl-sphingosine [Cer(16:0)], N-stearoyl-sphingosine [Cer(18:0)], N-nervonoyl-sphingosine [Cer(24:1)] and N-lignoceroyl-sphingosine [Cer(24:0)]. Multi-biomarker models were compared with C-statistics and Integrated Discrimination Index (IDI). RESULTS: A total of 1131 patients were included. Adjusted NT proBNP per 1 SD resulted in a 31% increased risk of MACE/death (HR = 1.31) and a 31% increased risk for stroke/MI (HR = 1.31). Adjusted Ceramide per 1 SD showed a 13% increased risk of MACE/death (HR = 1.13) and a 29% increased risk for stroke/MI (HR = 1.29). These markers added to clinical factors for both MACE/death (p = 0.003) and stroke/MI (p = 0.034). HscTnI was not a predictor of outcomes when added to the models. DISCUSSION: Ceramide score and NT proBNP improve the prediction of MACE and stroke/MI in a community primary prevention cohort.

In a community cohort, where a wide range of biomarkers were evaluated, Ceramide score provided additive value over traditional cardiac risk factors alone for predicting stroke/MI. NT ProBNP provided additive value in prediction of MACE/death. Other biomarkers failed to improve the discrimination of these models.

Inhibition of angiogenesis in the management of refractory gastrointestinal bleeding in patients with LVAD support.

BACKGROUND: Gastrointestinal bleeding (GIB) in patients with continuous flow left ventricular assist devices (CF-LVADs) is often related to GI angiodysplasia (GIAD). We previously reported data on VEGF inhibition with IV bevacizumab in the treatment of LVAD-associated GIAD bleeding, and now present follow-up data on patients treated with IV bevacizumab and/or low-dose oral pazopanib. METHODS: All consecutive adult patients with LVAD-associated GIB from GIAD treated with bevacizumab or pazopanib, from July 20, 2017 to June 22, 2022, were included in the analysis. Data on hospitalizations, GI endoscopic procedures, and blood transfusions were obtained from first admission for GIB up to a median of 35.7 months following treatment initiation (range 1.3-59.8 months). RESULTS: Eleven patients (91% male, mean 69.5 ± 8.9 years) were included. Eight patients (73%) received IV bevacizumab, two patients (18%) received oral pazopanib, and one patient (9%) received bevacizumab followed by pazopanib therapy. We observed a significantly decreased number of annualized hospitalizations for GIB (median difference - 2.87, p = 0.002), blood transfusions (median difference - 20.9, p = 0.01), and endoscopies (median difference - 6.95, p = 0.007) in patients pre- and post-anti-angiogenic therapy (bevacizumab and/or pazopanib). Similarly, a significant improvement in these clinical outcomes was noted in the bevacizumab group with decreased annualized hospitalizations (median difference - 2.75, p = 0.014), blood transfusions (median difference - 24.5, p = 0.047), and number of endoscopies (median differences -6.88, p = 0.006). CONCLUSION: Anti-angiogenic therapy with IV bevacizumab and/or low-dose oral pazopanib appears to provide benefits in patients with LVAD-associated GIB with reduced hospitalizations, blood transfusions, and need for GI endoscopic procedures.

Heart-After-Liver Transplantation Attenuates Rejection of Cardiac Allografts in Sensitized Patients.

BACKGROUND: In patients undergoing heart transplantation, significant allosensitization limits access to organs, resulting in longer wait times and high waitlist mortality. Current desensitization strategies are limited in enabling successful transplantation. OBJECTIVES: The purpose of this study was to describe the cumulative experience of combined heart-liver transplantation using a novel heart-after-liver transplant (HALT) protocol resulting in profound immunologic protection. METHODS: Reported are the results of a clinical protocol that was instituted to transplant highly sensitized patients requiring combined heart and liver transplantation at a single institution. Patients were dual-organ listed with perceived elevated risk of rejection or markedly prolonged waitlist time due to high levels of allo-antibodies. Detailed immunological data and long-term patient and graft outcomes were obtained. RESULTS: A total of 7 patients (age 43 ± 7 years, 86% women) with high allosensitization (median calculated panel reactive antibody = 77%) underwent HALT. All had significant, unacceptable donor specific antibodies (DSA) (>4,000 mean fluorescence antibody). Prospective pre-operative flow cytometric T-cell crossmatch was positive in all, and B-cell crossmatch was positive in 5 of 7. After HALT, retrospective crossmatch (B- and T-cell) became negative in all. DSA fell dramatically; at last follow-up, all pre-formed or de novo DSA levels were insignificant at <2,000 mean fluorescence antibody. No patients experienced >1R rejection over a median follow-up of 48 months (interquartile range: 25 to 68 months). There was 1 death due to metastatic cancer and no significant graft dysfunction. CONCLUSIONS: A heart-after-liver transplantation protocol enables successful transplantation via near-elimination of DSA and is effective in preventing adverse immunological outcomes in highly sensitized patients listed for combined heart-liver transplantation.

Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial.

BACKGROUND: Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting. METHODS: This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm. RESULTS: With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI > 30 kg/m2 (vs < 25 mg/kg2, OR 2.21 [95% CI 1.40-3.49]), cumulative dose of doxorubicin ≥240 mg/m2 (OR 1.36 [95% CI 1.01-1.82]) and of epirubicin≥ 480 mg/m2 (OR 2.33 [95% CI 1.55-3.51]). CONCLUSIONS: Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D.

Soluble Neprilysin in the General Population: Clinical Determinants and Its Relationship to Cardiovascular Disease.

Background Neprilysin is a metalloprotease involved in proteolysis of numerous peptides, including natriuretic peptides, and is of prognostic and therapeutic importance in heart failure with reduced ejection fraction. No studies have investigated circulating neprilysin in the community, its clinical correlates, or its relationship to cardiovascular disease in the general population. Methods and Results Plasma neprilysin was measured in 1536 participants from Olmsted County, Minnesota, using a commercially available sandwich ELISA assay. Clinical and echocardiographic correlates and subsequent outcomes were determined. Soluble neprilysin is non-normally distributed in the community (median: 3.9 ng/mL; interquartile range: 1.0-43.0 ng/mL). There was no relationship between plasma neprilysin and age (Spearman correlation: -0.04, P=0.16); body mass index (Spearman correlation: -0.04, P=0.16); glomerular filtration rate (Spearman correlation: -0.007, P=0.8); or A-, B-, or C-type natriuretic peptides (Spearman correlation: 0.03, P=0.22; -0.001, P=0.96; 0.01, P=0.67, respectively). Among tertiles of neprilysin, the lowest tertile group had the highest prevalence of smokers (P<0.001), hypertension (P=0.04), dyslipidemia (P=0.03), and diastolic dysfunction (P=0.02). Soluble neprilysin was not prospectively associated with death or heart failure over a median of 10.7 years. Conclusions In a large community-based cohort, for the first time, we described the distribution of circulating neprilysin in the general community. We observed that neprilysin does not correlate with natriuretic peptide levels and is not independently associated with adverse outcomes. The novel associations observed between low soluble neprilysin levels and an adverse cardiometabolic and smoking profile requires further investigation.

Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib-induced cardiotoxicity in patients with HER2-positive early-stage breast cancer: a NeoALTTO sub-study (BIG 1-06).

BACKGROUND: Biomarkers of cardiac damages, such as troponin T (TnT) and the amino-terminal fragment of brain natriuretic peptide (NT-proBNP), may be useful as early predictors of cardiac dysfunction. The role of these biomarkers in patients receiving lapatinib and/or trastuzumab before anthracyclines is unknown. This study explores TnT and NT-proBNP as predictors of early cardiac toxicity in neoadjuvant breast cancer patients. METHODS: This sub-study of the NEOALTTO trial tested if changes in the levels of TnT and NT-proBNP occurred after 2 weeks of anti-HER2 therapy (lapatinib, trastuzumab or their combination) alone and/or after 18 weeks of anti-HER2 therapy plus weekly paclitaxel. RESULTS: 173 and 172 were tested at all three timepoints for NT-proBNP and TnT, respectively. The incidence of biomarker elevation was overall low at all timepoints for all the three treatment arms. A total of 13 CEs in 11 patients occurred. Biomarker elevations in patients with CEs were very rare; only one patient with subsequent CE had a NT-proBNP elevation at baseline and at week 2. CONCLUSION: These results suggest that TnT and proBNP may not be useful as early predictors of cardiac toxicity in anthracycline-naïve patients receiving trastuzumab and/or lapatinib.

Long term outcomes of cardiac transplant for immunoglobulin light chain amyloidosis: The Mayo Clinic experience.

AIM: To determine the outcome of orthotopic heart transplantation (OHT) in immunoglobulin light chain (AL) amyloidosis. METHODS: The medical records of patients with AL who underwent orthotopic heart transplantation at the Mayo Clinic in Rochester Minnesota from 1992 to 2011 were reviewed. Patients met at least one of the following at: New York Heart Association class IV heart failure, ventricular thickness > 15 mm, ejection fraction < 40%. Selection guidelines for heart transplant included age < 60 years, absence of multiple myeloma and significant extra-cardiac organ involvement. Baseline characteristics including age, gender, organ involvement, and New York Heart Association functional class were recorded. Laboratory data, waiting time until heart transplant, and type of treatment of the underlying plasma cell disorder were recorded. Survival from the time of OHT was calculated using Kaplan-Meier survival curves. Survival of patients undergoing OHT for AL was compared to that of non-amyloid patients undergoing OHT during the same time period. RESULTS: Twenty-three patients (median age 53 years) with AL received OHT. There were no deaths in the immediate perioperative period. Twenty patients have died post OHT. For the entire cohort, the median overall survival was 3.5 years (95%CI: 1.2, 8.2 years). The 1-year survival post OHT was 77%, the 2-year survival 65%, and the 5-year survival 43%. The 5-year survival for non-amyloid patients undergoing OHT during the same era was 85%. Progressive amyloidosis contributed to death in twelve patients. Of those without evidence of progressive amyloidosis, the cause of death included complications of autologous hematopoietic stem cell transplantation for 3 patients, post-transplant lymphoproliferative disorder for 2 patients; and for the remaining one death was related to each of the following causes: acute rejection; cardiac vasculopathy; metastatic melanoma; myelodysplastic syndrome; and unknown. Eight patients had rejection at a median of 1.8 mo post OHT (range 0.4 to 4.9 mo); only one patient died of rejection. Median survival of seven patients who achieved a complete hematologic response to either chemotherapy or autologous hematopoietic stem cell transplantation was 10.8 years. CONCLUSION: Our data demonstrate that long term survival after heart transplant is feasible in AL patients with limited extra-cardiac involvement who achieve complete hematologic response.

Early trends in N-terminal pro-brain natriuretic peptide values after left ventricular assist device implantation for chronic heart failure.

Left ventricular assist devices (LVADs) acutely decrease left ventricular wall stress. Thus, early postoperative levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) should decrease. This study investigated postoperative changes in NT-proBNP levels, the parameters related to changes, and the possible association with complications by performing a retrospective analysis of changes in daily NT-proBNP (pg/ml) levels from admission to discharge both before and after LVAD implantation in a tertiary referral center. For 72 patients implanted with HeartMate II LVADs, baseline NT-proBNP levels were elevated at 3,943 ng/ml (interquartile range 1,956 to 12,964). Preoperative stabilization led to marked decreases in NT-proBNP. Levels peaked 3 days after surgery and subsequently decreased. Patients with complicated postoperative courses had higher early postoperative elevations. By discharge, NT-proBNP decreased markedly but was still 2.83 (1.60 to 5.76) times the age-based upper limit of normal. The 26% reduction in NT-proBNP between admission and discharge was due mostly to the preoperative reductions and not those induced by the LVAD itself. The decrease was not associated with decreases in LV volume. In conclusion, preoperative treatment reduces NT-proBNP values. The magnitude of early postoperative changes is related to the clinical course. Levels at discharge remain markedly elevated and similar to values after preoperative stabilization despite presumptive acute LV unloading.

RC0639: phase II study of paclitaxel, trastuzumab, and lapatinib as adjuvant therapy for early stage HER2-positive breast cancer.

Lapatinib adds to the efficacy of trastuzumab in preclinical models and also in the neo-adjuvant setting. This study assesses the safety and feasibility of adding lapatinib to paclitaxel and trastuzumab (THL) as part of the adjuvant therapy for HER2-positive breast cancer (HER2+ BC). In this single-arm phase II study, patients with stages I-III HER2+ BC received standard anthracycline-based chemotherapy followed by weekly taxane, with concurrent standard trastuzumab, plus daily lapatinib for a total of 12 months. The primary endpoint was symptomatic congestive heart failure, secondary endpoints included overall safety. A total of 109 eligible patients were enrolled. Median follow-up is 4.3 years. No patients experienced congestive heart failure while on treatment. Mean left ventricular ejection fraction at baseline and at the end of THL were 63.6 % (N = 109, SD = 5.7) and 59.8 % (N = 98, SD = 8.1), respectively [mean change -3.95 % (N = 98, SD = 8.3), p < 0.001]. One hundred and two patients initiated post-AC treatment; of them, 31 % experienced grade 3 (no G4) diarrhea with lapatinib at 750 mg/day. The addition of lapatinib to paclitaxel and trastuzumab following AC does not add cardiac toxicity. Lapatinib dose of 750 mg/day in combination with standard chemotherapy plus trastuzumab has acceptable overall tolerability.

Use of B-type natriuretic peptide as a screening tool for left ventricular diastolic dysfunction in rheumatoid arthritis patients without clinical cardiovascular disease.

OBJECTIVE: Patients with rheumatoid arthritis (RA) are at an increased risk for heart failure and left ventricular diastolic dysfunction (LVDD). B-type natriuretic peptide (BNP) may be useful to screen for LVDD in the general population. We compared the effectiveness of BNP as a screening tool for LVDD in RA and non-RA subjects without cardiovascular disease (CVD). METHODS: Study subjects were recruited from population-based samples with and without RA, excluding subjects with CVD. LVDD was assessed by 2-dimensional and Doppler echocardiography and categorized as none, mild, moderate/severe, or indeterminate. Linear regression and proportional odds models evaluated the association between LVDD and BNP, adjusting for age, sex, and body mass index. RESULTS: Among 231 RA and 1,730 non-RA subjects without CVD, BNP was significantly higher in subjects with moderate/severe LVDD compared to those with no or mild LVDD (P = 0.02 for RA and P < 0.001 for non-RA subjects). More RA subjects had elevated BNP than non-RA subjects (16% versus 9%; P < 0.001). Positive predictive value (25% in RA and 18% in non-RA subjects) and sensitivity (40% in RA and 26% in non-RA subjects) were similarly low in both cohorts, but specificity was significantly lower in RA than in non-RA subjects (89% versus 94%; P = 0.02). CONCLUSION: While RA subjects were more likely to have elevated BNP, few RA patients with elevated BNP actually have LVDD. Also, normal BNP levels are less likely to rule out LVDD in RA than in non-RA subjects. Therefore, BNP may be less effective for screening in RA subjects compared to the general population.

Increased serum N-terminal pro-B-type natriuretic peptide levels in patients with medial arterial calcification and poorly compressible leg arteries.

OBJECTIVE: To determine whether serum levels of N-terminal (NT) pro-B-type natriuretic peptide (pro-BNP) are higher in patients with poorly compressible arteries (PCA) than in patients with peripheral artery disease (PAD) and control subjects without PCA or PAD. METHODS AND RESULTS: Medial arterial calcification in the lower extremities results in PCA and may be associated with increased arterial stiffness and hemodynamic/myocardial stress. PCA was defined as having an ankle-brachial index >1.4 or an ankle blood pressure >255 mm Hg, whereas PAD was defined as having an ankle-brachial index ≤0.9. Study participants with PCA (n=100; aged 71±10 years; 70% men) and age- and sex-matched patients with PAD (n=300) were recruited from the noninvasive vascular laboratory. Age- and sex-matched controls (n=300) were identified from a community-based cohort and had no history of PAD. NT pro-BNP levels were approximately 2.5-fold higher in patients with PCA than in patients with PAD and approximately 4-fold higher than in age- and sex-matched controls. In multivariable regression analyses that adjusted for age, sex, smoking, hypertension, history of coronary heart disease/stroke, systolic blood pressure, and serum creatinine, NT pro-BNP levels remained significantly higher in patients with PCA than in patients with PAD and controls (P<0.001). CONCLUSIONS: Patients with medial arterial calcification and PCA have higher serum levels of NT pro-BNP than patients with PAD and controls, which is suggestive of an adverse hemodynamic milieu and increased risk for adverse cardiovascular outcomes.

Increased prevalence of diastolic dysfunction in rheumatoid arthritis.

OBJECTIVE: To compare the prevalence of left ventricular (LV) diastolic dysfunction in subjects with and without rheumatoid arthritis (RA), among those with no history of heart failure (HF), and to determine risk factors for diastolic dysfunction in RA. METHODS: A cross-sectional, community-based study comparing cohorts of adults with and without RA and without a history of HF was carried out. Standard two-dimensional/Doppler echocardiography was performed in all participants. Diastolic dysfunction was defined as impaired relaxation (with or without increased filling pressures) or advanced reduction in compliance or reversible or fixed restrictive filling. RESULTS: The study included 244 subjects with RA and 1448 non-RA subjects. Mean age was 60.5 years in the RA cohort (71% female) and 64.9 years (50% female) in the non-RA cohort. The vast majority (>98%) of both cohorts had preserved ejection fraction (EF> or =50%). Diastolic dysfunction was more common in subjects with RA at 31% compared with 26% (age and sex adjusted) in non-RA subjects (OR=1.6; 95% CI 1.2 to 2.4). Patients with RA had significantly lower LV mass, higher pulmonary arterial pressure and higher left atrial volume index than non-RA subjects. RA duration and interleukin 6 (IL-6) level were independently associated with diastolic dysfunction in RA even after adjustment for cardiovascular risk factors. CONCLUSION: Subjects with RA have a higher prevalence of diastolic dysfunction than those without RA. RA duration and IL-6 are independently associated with diastolic dysfunction, suggesting the impact of chronic autoimmune inflammation on myocardial function in RA. Clinical implications of these findings require further investigation.

Combined heart and liver transplantation: a single-center experience.

BACKGROUND: Simultaneous combined orthotopic heart and liver transplantation (CHLTx) remains a lifesaving procedure for the patients suffering from coincident end-stage heart and liver disease and several metabolic disorders. We analyze the long-term outcome of the patients undergoing CHLTx. METHODS: Between January 1992 and May 2007, 15 CHLTx were attempted at the Mayo Clinic including two combined heart, liver, and kidney transplantations and one combined heart, lung, and liver transplantations. Pretransplant cardiac diagnoses were familial amyloidosis (11), hemochromatosis (1), restrictive cardiomyopathy and cardiac cirrhosis (1), previously operated congenital heart disease and cardiac cirrhosis (1), and primary pulmonary hypertension with primary biliary cirrhosis (1). RESULTS: Heart and liver transplantation were performed as a single combined procedure in 13 (93%) hemodynamically stable patients, and there was no perioperative mortality. Survival rates for the CHLTx recipients at 1 year, 5 years, and 10 years were 100%, 75%, and 60%, respectively, and did not differ from survival after isolated heart transplantation (93%, 83%, and 65%, respectively, P=0.39). Freedom from cardiac allograft rejection (ISHLT > or =grade 2) for CHLTx was 83% at 1 month, did not change with time, and was lower than after isolated heart transplantation (P=0.02). At the mean follow-up of 61.6+/-53.6 months, normal left ventricular ejection fraction and good liver allograft function were demonstrated. Three patients developed end-stage renal failure secondary to calcineurin nephrotoxicity. CONCLUSION: Simultaneous heart and liver transplantation is feasible and achieved excellent results for selected patients.

Acute cellular rejection and the subsequent development of allograft vasculopathy after cardiac transplantation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is primarily immune-mediated. We investigated the role of cellular rejection in CAV development. METHODS: The study comprised 252 cardiac transplant recipients (mean age, 49.02 +/- 17.05 years; mean follow-up, 7.61 +/- 4.49 years). Total rejection score (TRS) based on the 2004 International Society of Heart and Lung Transplantation R grading system (0R = 0, 1R = 1, 2R = 2, 3R = 3) and any rejection score (ARS; calculated as 0R = 0, 1R = 1, 2R = 1; 3R = 1, or the number of rejections of any grade) were normalized for the total number of biopsy specimens. CAV was defined as coronary stenosis of 40% or more and/or distal pruning of secondary side branches. Thirty-two patients had undergone 3-dimensional intravascular ultrasound (IVUS) at baseline and with virtual histology (VH) IVUS at 24 months. RESULTS: In univariate analysis, 6-month TRS (hazard ratio [HR], 1.9; 95% confidence interval [CI], 0.99-3.90, p = 0.05) and ARS (HR, 2.22; 95% CI, 1.01-4.95; p = 0.047) were associated with increased risk of CAV. In multivariate analysis, 6-month TRS (HR, 2.84; 95% CI, 1.44-6.91, p = 0.02) was significantly associated with increased risk of CAV onset. The 12- and 24-month rejection scores were not risk factors for the onset of CAV. By Kaplan-Meier analysis, 6-month TRS exceeding 0.3 was associated with a significantly shorter time to CAV onset (p = 0.018). There was direct correlation (r = 0.44, p = 0.012) between TRS at 6 months and the percentage of necrotic core demonstrated by VH-IVUS at 24 months. CONCLUSION: Recurrent cellular rejection has a cumulative effect on the onset of CAV. The mechanism may be due to increased inflammation resulting in increased plaque burden suggesting a relationship between the immune basis of cellular rejection and CAV.

Autologous stem cell transplant after heart transplant for light chain (Al) amyloid cardiomyopathy.

BACKGROUND: Historically, patients with AL amyloidosis and overt congestive heart failure have had an ominous prognosis with median survival of approximately 6 months. METHODS: Between 1994 and 2005, 11 patients underwent sequential orthotopic heart transplantation (HT) followed by autologous peripheral blood stem cell transplantation (SCT) for treatment of AL amyloidosis. Patients were accepted for this approach if they had heart-dominant AL with minimal/no other organ impairment and no evidence of multiple myeloma. Conditioning chemotherapy consisted of melphalan 200 mg/m(2) (6 patients) or melphalan 140 mg/m(2) (5 patients). RESULTS: Two patients died of complications from the SCT (18% transplant-related mortality). Nine patients survived both the HT and the SCT. Three patients subsequently died from progressive amyloidosis at 66, 56.7 and 55 months after SCT. The 1- and 5-year survival for HT was 82% and 65%. The median survival was 76 months from HT and 57 months from SCT. CONCLUSIONS: These data suggest that aggressive treatment of the underlying plasma cell clone after HT may improve long-term outcomes in patients with cardiac amyloid. HT followed by SCT is feasible and offers the possibility of remission for carefully selected patients with cardiac amyloidosis.

Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial.

PURPOSE: To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial. PATIENTS AND METHODS: Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months. RESULTS: Of 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%. CONCLUSION: The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC.

Impaired functional status and echocardiographic abnormalities signifying global dysfunction enhance the prognostic significance of previously unrecognized myocardial infarction detected by electrocardiography.

BACKGROUND: The relationship between electrocardiographic unrecognized myocardial infarction (UMI), abnormal functional status, echocardiographic abnormalities, and mortality has not been evaluated. METHODS: A population-based random sample of 2042 Olmsted County residents, age > or = 45 years, was studied by self-administered questionnaire, chart review, ECG and echocardiogram, and 5 year follow-up for all-cause mortality. UMI (n = 81) was diagnosed if ECG-MI criteria were met without previous documented myocardial infarction. Functional Status was assessed by the Goldman Specific Activity Scale. RESULTS: UMI subjects had an increased prevalence of abnormal functional status compared to no MI controls (22% vs 11%, P < 0.05). This association was independent of sex, obesity, smoking, diabetes, and pulmonary disease. It became insignificant after stratifying for echocardiographic abnormalities. Compared to no MI controls, UMI subjects with impaired functional status had a higher mortality hazard ratio (HR 7.2; P<0.0001) than those without impaired functional status (HR 2.7; P = 0.02). In UMI subjects with impaired functional status and any echocardiographic abnormality signifying global ventricular dysfunction (systolic or diastolic dysfunction, left atrial or left ventricular enlargement), the mortality risk was even higher (HR 9.5; P<0.001) and persisted in multivariate analyses. This increased mortality risk was unaffected by adjustment for regional wall motion abnormalities. CONCLUSIONS: The assessment of impaired functional status and echocardiographic abnormalities improves the prognostic significance of UMI. Even in the absence of regional wall motion abnormalities, structural abnormalities of global dysfunction may play a role in mediating the increased mortality associated with UMI.

Outcome of patients with low ejection fraction undergoing coronary artery bypass grafting: renal function and mortality after 3.8 years.

BACKGROUND: There are few data regarding medium-term outcome of coronary artery bypass grafting (CABG) in patients with severe left ventricular (LV) systolic dysfunction, particularly in the modern era, and even less assessing preoperative factors that might identify patients at highest risk. METHODS AND RESULTS: Three hundred seventy-nine consecutive patients with LV ejection fraction < or = 35%, who underwent isolated first CABG between 1995 and 1999 were studied. Potential preoperative and perioperative predictors of outcome were recorded and patients followed-up for a median of 3.8 years. The primary study end-point was all-cause mortality. The 30-day, 1-year, and 3-year survival rates were 94.5%, 88%, and 81%, respectively. The independent predictors of mortality were preoperative estimated glomerular filtration rate (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.97 to 0.99 per mL/min/1.73 m2; P<0.001) and age (HR, 1.03; 95% CI, 1.01 to 1.06 per year; P=0.005). CONCLUSIONS: Patients with significant LV systolic dysfunction undergoing isolated CABG using contemporary techniques have a good medium-term survival. Renal dysfunction is the strongest independent predictor of mortality.

The case for selective re-issuance of medical certificates to allow pilots who have received a heart transplant to resume flying.

BACKGROUND: Cardiac transplant recipients have been regarded as not medically fit to fly an airplane. Recently, the Federal Aviation Administration decided to re-examine this policy and, in response, this study was undertaken to determine the risk of death from any cause and sudden-onset death in heart transplant recipients during the 12 months after an annual evaluation. METHODS: Of 6,510 patients undergoing primary orthotopic cardiac transplantation enrolled in the Cardiac Transplant Research Database (CTRD), 4,978 patients survived for at least 1 year and formed the basis of this study. Risk factors for death from any causes and sudden-onset death (a composite of causes of death that could conceivably result in a pilot's incapacitation) were determined during the 12-month period after an anniversary evaluation. Patients were re-entered into the analysis at each evaluation, resulting in a total of 23,575 anniversary evaluations. RESULTS: The presence of coronary allograft vasculopathy (CAV), left ventricular systolic dysfunction, history of rejection, malignancy, infection and pre-transplant insulin-dependent diabetes were associated with an increased risk of death from any cause and sudden-onset death during the 12-month period after an evaluation. Based on the absence of these risk factors, a group of heart transplant recipients could be defined with a 12-month risk of death from any cause of 1.0% and of sudden-onset death of 0.3% (which is identical to the mortality rate of a matched population from the U.S. life-table). CONCLUSION: Using these identified risk factors, a group of heart transplant recipients can be defined that are potentially medically certifiable to fly without compromising aviation safety.