Takotsubo Cardiomyopathy During Anti-HER2 Therapy for Metastatic Breast Cancer.

Human epidermal growth factor receptor 2 (HER2)-targeted antibodies, including pertuzumab and trastuzumab, improve overall survival and progression-free survival among women with HER2-positive metastatic breast cancer, but grade ≥3 cardiotoxicity occurs in approximately 8% of cases. Here we report a case of Takotsubo cardiomyopathy associated with the use of dual anti-HER2 therapy in a 63-year-old woman who presented to the emergency department with an 8- to 10-hour history of progressive dyspnea after completing her third cycle of pertuzumab plus trastuzumab in addition to nab-paclitaxel chemotherapy. To our knowledge, this patient represents the first reported case of Takotsubo cardiomyopathy associated with pertuzumab plus trastuzumab combination therapy in the literature.

The anticoagulation choices of internal medicine residents for stroke prevention in non-valvular atrial fibrillation.

PURPOSE OF THE STUDY: To explore the oral anticoagulation (OAC) prescribing choices of Canadian internal medicine residents, at different training levels, in comparison with the Canadian Cardiovascular Society (CCS) guidelines for non-valvular atrial fibrillation (NVAF). STUDY DESIGN: Cross-sectional, web-based survey, involving clinical scenarios designed to favour the use of non-vitamin K antagonists (NOACs) as per the 2014 CCS NVAF guidelines. Additional questions were also designed to determine resident attitudes towards OAC prescribing. RESULTS: A total of 518 internal medicine responses were analysed, with 196 postgraduate year (PGY)-1s, 169 PGY-2s and 153 PGY-3s. The majority of residents (81%) reported feeling comfortable choosing OAC, with 95% having started OAC in the past 3 months. In the initial clinical scenario involving an uncomplicated patient with a CHADS2 score of 3, warfarin was favoured over any of the NOACs by PGY-1s (81.6% vs 73.9%), but NOACs were favoured by PGY-3s (88.3% vs 83.7%). This was the only scenario where OAC choices varied by PGY year, as each of the subsequent clinical scenarios residents generally favoured warfarin over NOACs irrespective of level of training. The majority of residents stated that they would no longer prescribe warfarin once NOAC reversal agents are available, and residents felt risk of adverse events was the most important factor when choosing OAC. CONCLUSIONS: Canadian internal medicine residents favoured warfarin over NOACs for patients with NVAF, which is in discordance with the evidence-based CCS guidelines. This finding persisted throughout the 3 years of core internal medicine training.

Utility of the LACE index at the bedside in predicting 30-day readmission or death in patients hospitalized with heart failure.

UNLABELLED: The Length of stay, Acuity, Comorbidities, Emergency department visits in prior 6 months (LACE) index threshold of 10 predicts readmission or death in general medical patients in administrative databases. We assessed whether the unadjusted LACE index, computed at the bedside, can predict 30-day outcomes in patients hospitalized for heart failure. METHODS: We used logistic regression with LACE as the continuous predictor and 30-day readmissions and 30-day readmission or death as outcomes. We determined a suitable LACE threshold using logistic regression and the closest-to-(0,1) criterion for dichotomized LACE scores. We assessed model discrimination with C statistics and 95% CI. RESULTS: Of 378 patients, a majority (91%) had LACE scores ≥10. Incremental LACE scores increased the odds of 30-day readmissions (odds ratio [OR] 1.13, 95% CI 1.02-1.24) and 30-day readmissions or death (OR 1.11, 95% CI 1.01-1.22). C statistics for 30-day readmissions (0.59, 95% CI 0.52-0.65) and 30-day readmission or death (0.57, 95% CI 0.51-0.64) were nonsignificantly lower than the Centers for Medicare/Medicaid Services-endorsed readmission risk score (0.61, 95% CI 0.55-0.67 and 0.62, 95% CI 0.55-0.68, respectively). LACE ≥13 predicted 30-day readmissions (OR 1.91, 95% CI 1.17-3.09) and 30-day readmission or death (OR 1.59, 95% CI 1.00-2.54), and met the closest-to-(0,1) criterion for optimal threshold. CONCLUSIONS: LACE calculated at the bedside predicts 30-day clinical outcomes in hospitalized heart failure patients. While there is a continuum of risk, a threshold of ≥13 is more suitable than ≥10 to identify high-risk patients. Given its modest discrimination, however, we do not recommend its preferential use over validated risk prediction tools such as readmission risk score.

Human severe sepsis cytokine mixture increases ß2-integrin-dependent polymorphonuclear leukocyte adhesion to cerebral microvascular endothelial cells in vitro.

INTRODUCTION: Sepsis-associated encephalopathy (SAE) is a state of acute brain dysfunction in response to a systemic infection. We propose that systemic inflammation during sepsis causes increased adhesion of leukocytes to the brain microvasculature, resulting in blood-brain barrier dysfunction. Thus, our objectives were to measure inflammatory analytes in plasma of severe sepsis patients to create an experimental cytokine mixture (CM), and to use this CM to investigate the activation and interactions of polymorphonuclear leukocytes (PMN) and human cerebrovascular endothelial cells (hCMEC/D3) in vitro. METHODS: The concentrations of 41 inflammatory analytes were quantified in plasma obtained from 20 severe sepsis patients and 20 age- and sex-matched healthy controls employing an antibody microarray. Two CMs were prepared to mimic severe sepsis (SSCM) and control (CCM), and these CMs were then used for PMN and hCMEC/D3 stimulation in vitro. PMN adhesion to hCMEC/D3 was assessed under conditions of flow (shear stress 0.7 dyn/cm(2)). RESULTS: Eight inflammatory analytes elevated in plasma obtained from severe sepsis patients were used to prepare SSCM and CCM. Stimulation of PMN with SSCM led to a marked increase in PMN adhesion to hCMEC/D3, as compared to CCM. PMN adhesion was abolished with neutralizing antibodies to either ß2 (CD18), αL/ß2 (CD11α/CD18; LFA-1) or αM/ß2 (CD11ß/CD18; Mac-1) integrins. In addition, immune-neutralization of the endothelial (hCMEC/D3) cell adhesion molecule, ICAM-1 (CD54) also suppressed PMN adhesion. CONCLUSIONS: Human SSCM up-regulates PMN pro-adhesive phenotype and promotes PMN adhesion to cerebrovascular endothelial cells through a ß2-integrin-ICAM-1-dependent mechanism. PMN adhesion to the brain microvasculature may contribute to SAE.

Left atrial volume and function measured by cardiac magnetic resonance imaging as predictors of shocks and mortality in patients with implantable cardioverter-defibrillators.

Left atrial (LA) volume and function (LA ejection fraction, LAEF) have demonstrated prognostic value in various cardiovascular diseases. We investigated the incremental value of LA volume and LAEF as measured by cardiovascular magnetic resonance imaging (CMR) for prediction of appropriate implantable cardioverter defibrillator (ICD) shock or all-cause mortality, in patients with ICD. We conducted a retrospective, multi-centre observational cohort study of patients who underwent CMR prior to primary or secondary prevention ICD implantation. A single, blinded reader measured maximum LA volume index (maxLAVi), minimum LA volume index (minLAVi), and LAEF. The primary outcome was a composite of independently adjudicated appropriate ICD shock or all-cause death. A total of 392 patients were enrolled. During a median follow-up time of 61 months, 140 (35.7%) experienced an appropriate ICD shock or died. Higher maxLAVi and minLAVi, and lower LAEF were associated with greater risk of appropriate ICD shock or death in univariate analysis. However, in multivariable analysis, LAEF (HR 0.92 per 10% higher, 95% CI 0.81-1.04, p = 0.17) and maxLAVi (HR 1.02 per 10 ml/m2 higher, 95% CI 0.93-1.12, p = 0.72) were not independent predictors of the primary outcome. In conclusion, LA volume and function measured by CMR were univariate but not independent predictors of appropriate ICD shocks or mortality. These findings do not support the routine assessment of LA volume and function to refine risk stratification to guide ICD implant. Larger studies with longer follow-up are required to further delineate the clinical implications of LA size and function.

Vision and driving: Canada.

Supported by the findings of a major review of vision standards for driving in Canada, the Canadian Ophthalmological Society's Committee on Vision Standards for Driving issued a series of recommendations in 2000 to the Canadian Medical Association. Many of these recommendations, including changes in visual acuity and visual field standards and consideration for exceptional cases, have been implemented across Canada. Canadian courts have stated that it is important to provide on-road assessments for visually impaired individuals who wish to continue driving. Most Canadian provinces and territories will allow visually impaired drivers a license if they pass the test. However, these on-road assessments use scarce resources and may be expensive for the driver. Limited licensure is a widespread practice, but whether it effectively protects drivers is not established. Except for Alberta, Quebec, and Nova Scotia, all Canadian provinces and territories have legislated mandatory reporting of visually impaired drivers by vision care providers.

It's Never Too Late: Spotting Congenital Absence of the Pericardium in an Older Adult.

A 75-year-old male with a cardiopulmonary history presented with chest pain and dyspnea. He was hypertensive. An electrocardiogram showed paced rhythm. A high-sensitivity test showed his troponin T level was minimally elevated. Coronary angiography results were unremarkable. Chest radiography revealed an elevated cardiac apex, previously attributed to cardiomegaly. Echocardiography revealed a teardrop shaped heart in a nonstandard apical window. Computed tomography confirmed congenital absence of the left pericardium. Challenges of recognizing a rare condition are highlighted. Congenital absence of the pericardium, an often benign but rarely catastrophic condition, can masquerade for decades before diagnosis, underlining the importance of clinical vigilance in evaluating common cardiac complaints.

Un homme de 75 ans qui avait des antécédents cardiopulmonaires a éprouvé une douleur thoracique et accusé une dyspnée. Il souffrait d'hypertension. Un électrocardiogramme a montré un rythme électro-entraîné. Le dosage de la troponine T hautement sensible a révélé des concentrations minimalement élevées. Les résultats de l'angiographie coronarienne étaient normaux. La radiographie pulmonaire a révélé un apex du cœur élevé, antérieurement attribué à la cardiomégalie. L'échocardiographie a révélé un cœur en forme de larme dans une fenêtre apicale non standard. La tomodensitométrie a permis de confirmer l'absence congénitale du péricarde gauche. Nous présentons les enjeux liés à l'identification d'une maladie rare. Puisque l'absence congénitale du péricarde, une anomalie souvent bénigne, mais rarement catastrophique, peut demeurer dissimulée durant des décennies avant le diagnostic, nous soulignons l'importance de la vigilance clinique dans l'évaluation des symptômes cardiaques courants.

How do family medicine residents choose an anticoagulation regimen for patients with nonvalvular atrial fibrillation?

Aim To examine the choices Canadian family medicine residents make for oral anticoagulation (OAC) for patients with nonvalvular atrial fibrillation (AF). BACKGROUND: AF increases the risk of strokes. An important consideration in AF management is risk stratification for stroke and prescription of appropriate OAC. Family physicians provide the vast majority of OAC prescriptions. METHODS: We administered a survey to residents in multiple Canadian family medicine training programmes. Questions explored the experiences and attitudes towards risk stratification and choices of OAC when presented with standardized clinical scenarios. In each scenario, a novel oral anticoagulant (NOAC) would be the preferred treatment according to the contemporary Canadian and European guidelines. Findings A total of 247 residents participated in the survey. Most used the congestive heart failure, hypertension, age ≥ 75, diabetes mellitus, stroke or TIA (2 points) (81%) and congestive heart failure, hypertension, age ≥ 75 (2 points) or age 65-74 (1 point), diabetes mellitus, stroke or TIA, vascular disease including peripheral arterial disease, myocardial infarction, or aortic plaque, sex (female) (67%) risk stratification schemes while the preferred bleeding risk stratification scheme was hypertension, abnormal liver or renal function, stroke, bleeding, labile international normalized ratio, elderly (age ≥ 65), drugs or alcohol (84%). In the clinical scenarios, residents generally preferred warfarin in favour of NOACs, independent of training level. Residents ranked the risk of adverse events and the cost to the patient as their most and least important consideration when prescribing OAC, respectively. Therefore in patients with nonvalvular AF, Canadian family medicine residents prefer warfarin in comparison with NOACs despite the latest Canadian and European guideline recommendations. This knowledge gap may be enhanced by multiple factors, including a sometimes magnified fear of adverse events and a rapidly changing landscape in stroke prophylaxis.

Resident Physicians Choices of Anticoagulation for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation.

Atrial fibrillation (AF) is a common cardiac arrhythmia and is associated with an increased risk of ischemic stroke. The aim of this study was to identify practice patterns of Canadian resident physicians pertaining to stroke prevention in nonvalvular AF according to the Canadian Cardiovascular Society guidelines. A Web-based survey consisting of 16 multiple-choice questions was distributed to 11 academic centres. Questions involved identification of risks of stroke, bleeding, and selection of appropriate therapy in clinical scenarios that involve a patient with AF with a Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack (CHADS2) score of 3 and no absolute contraindications to anticoagulation. There were 1014 total respondents, of whom 570 were internal, 247 family, 137 emergency medicine, and 60 adult cardiology residents. For a patient with a new diagnosis of AF, warfarin was chosen by 80.3%, novel oral anticoagulants (NOACs) by 60.3%, and acetylsalicylic acid (ASA) by 7.2% of residents. To a patient with a history of gastrointestinal bleed during ASA treatment, warfarin was recommended by 75.1%, NOACs by 36.1%, ASA by 12.1%, and 4% were unsure. For a patient with a history of an intracranial bleed, warfarin was recommended by 38.8%, NOACs by 23%, ASA by 24.8%, and 18.2% were unsure. For a patient taking warfarin who had a labile international normalized ratio, 89% would switch to a NOAC and 29.5% would continue warfarin. This study revealed that, across a wide sampling of disciplines and centres, resident physician choices of anticoagulation in nonvalvular AF differ significantly from contemporary Canadian Cardiovascular Society guidelines.

Factors Associated with Low Flow in Aortic Valve Stenosis.

BACKGROUND: Low-flow low-gradient aortic stenosis (AS) is a predictor of worse outcome compared with normal-flow AS. Although depressed left ventricular ejection fraction (LVEF) is associated with low flow, there is less evidence to support the role of other indices of cardiac structure and function. METHODS: Clinical and echocardiographic data from patients with native AS and valve areas ≤ 1.0 cm(2) were retrospectively analyzed to identify characteristics that are associated with low-flow low-gradient AS. RESULTS: In total, 941 patients were included. On multivariate analysis, factors independently associated with low flow (stroke volume index < 35 mL/m(2)) included worse right ventricular systolic function, atrial fibrillation, lower LVEF, and higher left ventricular mass, with moderate or severe mitral regurgitation independently associated with low flow in the 694 patients (74%) with preserved LVEFs. CONCLUSIONS: Right ventricular dysfunction and atrial fibrillation are independently associated with low-flow low-gradient AS, while moderate or severe MR is independently associated with low flow in patients with preserved LVEF. These associations with low flow in AS are clinically important to recognize, to avoid underestimation of AS severity.

Efficacy of Hospital at Home in Patients with Heart Failure: A Systematic Review and Meta-Analysis.

BACKGROUND: Heart failure (HF) is the commonest cause of hospitalization in older adults. Compared to routine hospitalization (RH), hospital at home (HaH)--substitutive hospital-level care in the patient's home--improves outcomes and reduces costs in patients with general medical conditions. The efficacy of HaH in HF is unknown. METHODS AND RESULTS: We searched MEDLINE, Embase, CINAHL, and CENTRAL, for publications from January 1990 to October 2014. We included prospective studies comparing substitutive models of hospitalization to RH in HF. At least 2 reviewers independently selected studies, abstracted data, and assessed quality. We meta-analyzed results from 3 RCTs (n = 203) and narratively synthesized results from 3 observational studies (n = 329). Study quality was modest. In RCTs, HaH increased time to first readmission (mean difference (MD) 14.13 days [95% CI 10.36 to 17.91]), and improved health-related quality of life (HrQOL) at both, 6 months (standardized MD (SMD) -0.31 [-0.45 to -0.18]) and 12 months (SMD -0.17 [-0.31 to -0.02]). In RCTs, HaH demonstrated a trend to decreased readmissions (risk ratio (RR) 0.68 [0.42 to 1.09]), and had no effect on all-cause mortality (RR 0.94 [0.67 to 1.32]). HaH decreased costs of index hospitalization in all RCTs. HaH reduced readmissions and emergency department visits per patient in all 3 observational studies. CONCLUSIONS: In the context of a limited number of modest-quality studies, HaH appears to increase time to readmission, reduce index costs, and improve HrQOL among patients requiring hospital-level care for HF. Larger RCTs are necessary to assess the effect of HaH on readmissions, mortality, and long-term costs.

Impact of methanol intoxication on the human electrocardiogram.

BACKGROUND: Methanol is a common commercial compound that can lead to significant morbidity and mortality with high levels of exposure. The purpose of this study was to describe electrocardiographic (ECG) changes associated with methanol intoxication. METHODS: A retrospective chart review was conducted with data from Kingston General Hospital collected between 2006 and 2011. Patient data, including demographics, medications, and laboratory data were recorded. Twelve-lead ECGs were obtained and changes were noted in relation to timing and extent of methanol intoxication. RESULTS: Nine patients with a mean age of 45 years were analyzed. All patients ingested methanol orally and presented to hospital between < 1 to 25 h after ingestion. The mean plasma methanol concentration on admission was 49.8 mmol/L. A lower pH and higher plasma methanol concentration were associated with multiple ECG changes. On admission, ECG changes included sinus tachycardia (44%), PR prolongation (11%), QTc prolongation (22%) and non-specific T-wave changes (66%). One patient developed a type-1 Brugada ECG pattern. During their course in hospital, 7 patients required dialysis, 3 required mechanical ventilation, 3 developed visual impairment, and 1 died. All ECG changes normalized while in hospital. CONCLUSIONS: Methanol intoxication can lead to several ECG changes with sinus tachycardia and non-specific T-wave changes being the most common. These changes were more prominent in cases of severe acidosis.

Reverse atrial electrical remodelling induced by continuous positive airway pressure in patients with severe obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) is associated with cardiovascular morbidity and mortality, including atrial arrhythmias. Continuous positive airway pressure (CPAP) is the gold standard treatment for OSA; its impact on atrial electrical remodelling has not been fully investigated. Signal-averaged p-wave (SAPW) duration is an accepted marker for atrial electrical remodelling. OBJECTIVE: The objective of this study is to determine whether CPAP induces reverse atrial electrical remodelling in patients with severe OSA. METHODS: Consecutive patients attending the Sleep Disorder Clinic at Kingston General Hospital underwent full polysomnography. OSA-negative controls and severe OSA were defined as apnoea-hypopnea index (AHI) < 5 events/hour and AHI ≥ 30 events/hour, respectively. SAPW duration was determined at baseline and after 4-6 weeks of CPAP in severe OSA patients or without intervention controls. RESULTS: Nineteen severe OSA patients and 10 controls were included in the analysis. Mean AHI and minimum oxygen saturation were 41.4 ± 10.1 events/hour and 80.5 ± 6.5 % in severe OSA patients and 2.8 ± 1.2 events/hour and 91.4 ± 2.1 % in controls. At baseline, severe OSA patients had a greater SAPW duration than controls (131.9 ± 10.4 vs 122.8 ± 10.5 ms; p = 0.02). After CPAP, there was a significant reduction of SAPW duration in severe OSA patients (131.9 ± 10.4 to 126.2 ± 8.8 ms; p < 0.001), while SAPW duration did not change after 4-6 weeks in controls. CONCLUSION: CPAP induced reverse atrial electrical remodelling in patients with severe OSA as represented by a significant reduction in SAPW duration.

Failure to Treat Torsades de Pointes.

A healthy 22 year old male with no history of cardiac disease was admitted with severe community acquired pneumonia that was initially treated with moxifloxacin and azithromycin. At admission, he was found to be hypokalemic and hypomagnesemic. Two days after admission, he experienced several episodes of Torsades de Pointes (TdP). He was initially treated with isoproterenol. A temporary transvenous pacemaker was inserted and set at a rate of 100 bpm. After correction of electrolytes, withdrawal of QT-prolonging medications and ventricular pacing at the mentioned heart rate, another episode of TdP ensued.We report and discuss a case of recurrent TdP in spite of conventional acute management for this condition.

Tako-tsubo cardiomyopathy precipitated by alcohol withdrawal.

A 57 year-old woman with no history of cardiac disease presented to the emergency department with confusion and seizures secondary to alcohol withdrawal. Elevated troponin levels and an electrocardiogram demonstrating global T-wave inversions prompted coronary angiography, which revealed coronary vessels free of significant disease. An echocardiogram showed both hypokinesis of the left-ventricular mid-segments with apical involvement and a hyperkinetic base consistent with tako-tsubo cardiomyopathy (TCM). Several clinical conditions have been reported as triggers of TCM. We report a case of TCM in a post-menopausal woman that was precipitated by alcohol withdrawal.

Elevated plasma matrix metalloproteinases and their tissue inhibitors in patients with severe sepsis.

PURPOSE: Matrix metalloproteinases (MMPs) are essential for tissue remodeling. Our objectives were to determine (1) the concentrations of MMPs and their tissue inhibitors (TIMPs) in plasma obtained from patients with severe sepsis, (2) to correlate changes in MMP and TIMP levels with disease severity, and (3) to investigate recombinant activated protein C (rAPC) actions on plasma MMP2, 9 activities from severe sepsis patients. MATERIALS AND METHODS: Matrix metalloproteinase and TIMP levels were quantified in plasma from patients with severe sepsis using antibody microarrays and gelatin zymography. RESULTS: Plasma MMPs (3, 7, 8, 9) and TIMPs (1, 2, 4) on microarray were increased in severe sepsis on intensive care unit (ICU) day 1, with more than 3-fold increases in MMP3, MMP7, MMP8, MMP9, and TIMP4. Latent forms of MMP2, 9 on zymography were increased in plasma from patients with severe sepsis, whereas only half of severe sepsis patients showed active MMP9. Elevated MMP7 and MMP9 on ICU days 1 and 3 negatively correlated with multiple organ dysfunctions. The temporal activity patterns of MMP2, 9 during 21 ICU days were not altered in patients treated with rAPC or by the addition of exogenous rAPC to plasma. CONCLUSION: Most plasma MMPs and TIMPS were elevated in patients with severe sepsis, but only a limited subset of MMPs (7, 9) negatively correlated with disease severity. Recombinant activated protein C does not appear to directly alter MMP2, 9 activities.