Mookadam, Farouk

Abstract Background: Proteasome inhibition with carfilzomib (CFZ) has shown to be effective therapy in relapsed refractory multiple myeloma (MM).1 Cardiac toxicity induced by CFZ has been reported in a small subset of patients treated in phase 3 clinical trials, including congestive heart failure (CHF) in approximately 2-5% of patients. The natural history or reversibility of cardiac dysfunction with CFZ has not been fully reported. The myocardium constantly contracts in adults and thus, adequate protein metabolism may be essential; and hence, effective proteasome degradation may pose a risk for contractility. Methods and results: We identified 12 patients, who received CFZ at Mayo Clinic in Arizona, and had a drop in ejection fraction (EF) attributable to the use of CFZ. Medical records were reviewed for baseline cardiovascular (CV) risk factors, CV disease reversibility and mortality resulting from CFZ induced cardiac dysfunction. Patients who had a drop in EF attributed to other causes, were not included in this count. The median age at the time of initiation of therapy with CFZ was 62.5 years (range, 55-70 years), median body mass index was 27.65 (range, 21 - 40), with 4 (33%) patients being obese and 6 (50%) in the overweight range. Two (17%) patients had history of coronary artery disease while 9 (75%) had hypertension, and were on medical treatment prior to CFZ initiation. Six (46%) patients had a previous history of CHF. Two of these had symptomatic systolic dysfunction, however at the time of CFZ initiation, EF had improved. The other 4 with prior CHF had sub-normal EFs noted on echocardiograms done prior to initiation of CFZ (median EF of these 4 was 49%). Overall, baseline EF was available for 10 out of these 12 patients and median EF at baseline was 55% (range, 45 - 67%). Other risk factors predisposing to cardiac dysfunction were smoking in 1 patient and history of radiation to the chest in 2 (17%) patients. No patient had received cardiotoxic dose of anthracyclines prior to starting CFZ. Myeloma therapies: All patients had received multiple lines of therapy for MM (median 4, range, 2-7). Ten (83%) patients had previous received bortezomib and 10 (83%) had received autologous stem cell transplant. Cardiac events and CFZ use: Median duration of CFZ therapy received prior to documented systolic dysfunction was 4 months (range, 0.5 - 20 months), with 3 episodes happening with less than one month of total CFZ therapy. Five out of the 12 (42%) patients had previously discontinued CFZ for other reasons when the systolic dysfunction was noted. However they were included since CHF occurred shortly after treatment (median of 2 months, range, 0.5 - 3). The median drop in EF was 22% (range, 9 - 45%). Recovery/ outcomes: Follow-up echocardiograms were available in 8 patients and all of these showed some improvement in EF (table 1). Median improvement in EF noted by the time of last follow up was 16% (range, 7-30%). Median best EF noted after the initial drop was 48% (range, 35 - 67%). Two patients never discontinued CFZ and EF improved spontaneously, to 67% and 64% respectively, after an initial drop. Another patient was rechallenged with CFZ due to progression of MM, 8 months after initial discontinuation, and did not have recurrence of systolic dysfunction. No patients succumbed to CHF. Six (50%) out of these 12 patients had died by the time of last follow-up. Cause of death was progressive MM in 4 (67%) and sepsis secondary to immunosuppression resulting from chemotherapy in 2 (33%). Conclusions: Our data, although with limited number of patients, suggests using caution when treating patients who have underlying cardiac risk factors with CFZ. Nevertheless, the cardiotoxicity was mostly reversible, with the minimal EF after recovery of 35%. In the setting of a life threatening malignancy, the impact and reversibility of cardiotoxicity needs to be understood so as not to prevent the utilization of otherwise effective therapy such as CFZ. Larger studies are needed to confirm these findings. References: 1. Stewart et al. Carfilzomib, Lenalidomide and Dexamethasone for relapsed multiple myeloma. NEJM 2015;372:142-52. Disclosures Mikhael: Celgene: Research Funding; Abbvie: Research Funding; Sanofi: Research Funding; Onyx: Research Funding. Reeder:Novartis, Millennium, BMS and Celgene: Research Funding. Bergsagel:Amgen, BMS, Novartis, Incyte: Consultancy; Novartis: Research Funding. Fonseca:Millennium, a Takeda Company: Consultancy; Sanofi: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Millennium, a Takeda Company: Consultancy; Novartis: Consultancy; AMGEN: Consultancy; Janssen: Consultancy; Janssen: Consultancy; BMS: Consultancy; Millennium, a Takeda Company: Consultancy; Bayer: Consultancy; Millennium, a Takeda Company: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Celgene: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Celgene: Consultancy; BMS: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; AMGEN: Consultancy.

Antiphospholipid syndrome (APS) is an autoimmune disorder that has a strong propensity for a hypercoagulable state and is known to be associated with venous and arterial thromboembolism. We describe an uncommon case of APS in the setting of non-Hodgkin’s lymphoma, with thromboembolism, and a rare complication after an uncommon etiology of myocardial infarction. This case highlights the importance of early and appropriate type of anticoagulation to reduce the morbidity and mortality in patients with APS.

ABSTRACT Purpose We assessed resting central/peripheral blood pressure (BP), postexercise BP, and hemodynamic responses (stroke volume, cardiac output, and systemic vascular resistance) after acute exercise and 2 wk of aerobic training in lean and centrally obese men matched for BP. Methods Eight lean (body mass index < 25 kg·m −2 , visceral fat = 279 ± 224 cm 3 ) and eight centrally obese (body mass index > 30 kg·m −2 , visceral fat = 1471 ± 374 cm 3 ) men performed six training sessions (3 d·wk −1 for 40 min at 65%–70% HR max ). Resting BP and hemodynamic measurements were obtained at baseline, after exercise for 60 min, and at 24 h and 48 h after the last training session. Results Postexercise brachial and central systolic BP (SBP) and mean arterial BP decreased 3–4 mm Hg below resting in lean ( P < 0.001) and increased by 3 mm Hg in obese ( P < 0.02). Posttraining resting brachial/central SBP were reduced by 3–4 mm Hg only in lean men ( P < 0.05). Pretraining postexercise hypotension was significantly correlated with the training-induced change in resting brachial SBP at 48 h ( r = 0.58, P = 0.02), but not at 24 h ( r = 0.38, P = 0.15). Similar correlations were observed between acute reductions in central SBP and central SBP at 24 h ( r = 0.43, P = 0.09) and 48 h ( r = 0.54, P = 0.03) posttraining. Conclusions In contrast to the consistent results for lean men, postexercise hypotension was not observed in centrally obese men, and resting SBP was not reduced after a short aerobic training program. Considerable individual variation in postexercise BP response among obese men may have implications for design of exercise interventions to lower BP in these individuals.

Abstract Aims High-intensity interval training (HIIT) improves peak oxygen uptake and left ventricular diastology in patients with heart failure with preserved ejection fraction (HFpEF). However, its effects on myocardial strain in HFpEF remain unknown. We explored the effects of HIIT and moderate-intensity aerobic continuous training (MI-ACT) on left and right ventricular strain parameters in patients with HFpEF. Furthermore, we explored their relationship with peak oxygen uptake (VO2peak). Methods and results Fifteen patients with HFpEF (age = 70 ± 8.3 years) were randomized to either: (i) HIIT (4 × 4 min, 85–90% peak heart rate, interspersed with 3 min of active recovery; n = 9) or (ii) MI-ACT (30 min at 70% peak heart rate; n = 6). Patients were trained 3 days/week for 4 weeks and underwent VO2peak testing and 2D echocardiography at baseline and after completion of the 12 sessions of supervised exercise training. Left ventricular (LV) and right ventricular (RV) average global peak systolic longitudinal strain (GLS) and peak systolic longitudinal strain rate (GSR) were quantified. Paired t-tests were used to examine within-group differences and unpaired t-tests used for between-group differences (α = 0.05). Right ventricular average global peak systolic longitudinal strain improved significantly in the HIIT group after training (pre = −18.4 ± 3.2%, post = −21.4 ± 1.7%; P = 0.02) while RV-GSR, LV-GLS, and LV-GSR did not (P &gt; 0.2). No significant improvements were observed following MI-ACT. No significant between-group differences were observed for any strain measure. ΔLV-GLS and ΔRV-GLS were modestly correlated with ΔVO2peak (r = −0.48 and r = −0.45; P = 0.1, respectively). Conclusions In patients with HFpEF, 4 weeks of HIIT significantly improved RV-GLS.

ObjectivesThe tricuspid annular plane systolic excursion (TAPSE) is a validated measure of right ventricular function; however, the apical echocardiographic window varies and has limitations in intensive care unit (ICU) patients receiving mechanical ventilation or those with underlying disease and air entrapment. We aimed to evaluate the subcostal echocardiographic assessment of tricuspid annular kick (SEATAK) as an alternative to TAPSE in critically ill patients.MethodsTo measure SEATAK, we obtained the subcostal inferior vena cava view and used M‐mode to measure excursion of the tricuspid annulus (kick). Analysis was performed with JMP for Bland‐Altman and Spearman correlations.ResultsWe evaluated 45 patients, 26 (57.8%) of whom were women, with a mean age of 60.8 years. We were not able to obtain the apical view to measure TAPSE in 8.9% of the patients. In contrast, SEATAK was measured in all patients. The mean SEATAK and TAPSE were 1.62 cm and 1.93 cm, respectively, with a mean pairwise difference of −0.26 cm (95% CI: −0.19 to −0.35), with the SEATAK value being lower than TAPSE. The overall correlation was strong and significant (ρ = .86, P=.03). The graphical correlation was maintained between TAPSE and SEATAK and the degree of RVF.ConclusionIn patients presenting with RVF in the ICU (or in situations where the apical echocardiographic view is suboptimal for tricuspid annular assessment), SEATAK can be an alternative to TAPSE. Further research is needed to validate and determine the sensitivity and specificity of SEATAK for RVF prognostication.

BackgroundTrastuzumab has substantially improved overall survival and reduced the risk of disease recurrence in patients with human epidermal growth factor receptor type II (HER‐II)–positive breast cancer. However, this benefit may be at the increased risk of cardiotoxicity. We aimed to explore the early subclinical left and right ventricular as well as atrial dysfunction, in trastuzumab‐treated patients with HER‐II–positive breast cancer, using velocity vector imaging.MethodsEchocardiography images were acquired in 50 patients with HER‐II–positive breast cancer undergoing trastuzumab therapy. All patients had baseline and 3–6 months and 12–15 months of follow‐up echocardiograms after initiation of trastuzumab therapy. Subendocardial borders of all the cardiac chambers were traced from the apical views to obtain volumetric and deformation indices.ResultsMean age was 60 ± 13 years. Left ventricular (LV) ejection fraction as well as conventional indices of right ventricular (RV) function did not change with trastuzumab. The RV peak systolic global longitudinal strain (GLε) significantly decreased (−24.53 ± 6.03 vs. −21.28 ± 5.11 vs. −21.84 ± 5.15, baseline vs. first and second follow‐ups, P = 0.01). LV peak systolic GLε was reduced by 1.19 at early follow‐up (P < 0.05). Left atrial reservoir and booster pump functions as well as right atrial reservoir function were reduced through follow‐up as well.ConclusionsThe RV exhibited greater change in strain after trastuzumab treatment when compared to the LV. Atria function was reduced by trastuzumab as well. The repercussion of these findings and their potential implication will warrant further study.

Aim The benefit of preventive percutaneous coronary intervention (PCI) in ST elevation myocardial infarction (STEMI) has been shown in randomised trials. However, all the randomised trials are underpowered to detect benefit in cardiac death. We aim to systematically review evidence on the cardiac mortality benefit of preventive PCI in patients presenting with acute STEMI in randomised patient populations. Methods PubMed, Scopus, Cochrane and clinicaltrials.gov databases were searched for studies published until 30 September 2013. The studies were limited to randomised clinical trials. Independent observers abstracted the data on outcomes, characteristics and qualities of studies included. Fixed effect model was employed for meta-analysis. Heterogeneity of studies included was analysed using I2 statistics. Results In three randomised clinical trials published, involving 748 patients with acute STEMI and multivessel disease, 416 patients were randomised to preventive PCI and 332 to culprit-only PCI. Patients undergoing preventive PCI had significant lower risk of cardiovascular deaths (pooled OR 0.39, 95% CI 0.18 to 0.83, p=0.01, I2=0%), repeat revascularisation (pooled OR 0.28, 95% CI 0.18 to 0.44, p=0.00001, I2=0%) and non-fatal myocardial infarction (pooled OR 0.38, 95% CI 0.20 to 0.75, p=0.005, I2=0%) compared with culprit-only revascularisation. Conclusions In patients presenting with acute STEMI and significant multivessel coronary artery disease, based on our data, preventive PCI is associated with lower risk of cardiovascular mortality compared with primary PCI of only the culprit artery. This finding needs to be confirmed in larger adequately powered randomised clinical trials.