John D. Groarke

Use of an admission early warning score to predict patient morbidity and mortality and treatment success

Background: Early warning scores (EWS) are used to identify physiological deterioration in patients. Studies to date have primarily focused on the correlation between trends in serially recorded EWS of inpatients and clinical outcomes. This study examined the predictive value of an EWS calculated immediately on presentation to hospital for acute medical patients. Method: A prospective study of 225 consecutive medical admissions. Pulse, systolic blood pressure, respiratory rate, oxygen saturation and neurological status were used to calculate an EWS. Patients were divided into four score categories based on their EWS. The primary endpoints examined were intensive care unit (ICU)/coronary care unit (CCU) admission, death, cardiac arrest and length of hospital stay. Results: For each rise in score category there was an increased risk of admission to ICU (odds ratio (OR) 3.35, CI 1.52 to 7.40, p = 0.003), admission to CCU (OR 1.82, CI 1.07 to 3.09, p = 0.027), death (OR 2.19, CI 1.41 to 3.39, p = 0.000) and reaching the combined endpoint of CCU/ICU admission or death (OR 2.19, CI 1.41 to 3.39, p = 0.000). The higher the score the longer the length of hospital admission (p = 0.04). A decrease in EWS between first presentation to hospital and transfer to the ward was associated with a decreased risk of reaching the combined endpoint of CCU or ICU admission or death (OR 2.56, CI 1.11 to 5.89, p = 0.028). Discussion: Higher admission EWS correlate with increased risk of CCU/ICU admission, death and longer hospital stays independent of patient age. An improvement in serial EWS within 4 h of presentation to hospital predicts improved clinical outcomes. The EWS is a potential triage tool in the emergency department for acute medical patients.

Cardiovascular complications of radiation therapy for thoracic malignancies: the role for non-invasive imaging for detection of cardiovascular disease

Radiation exposure to the thorax is associated with substantial risk for the subsequent development of cardiovascular disease. Thus, the increasing role of radiation therapy in the contemporary treatment of cancer, combined with improving survival rates of patients undergoing this therapy, contributes to a growing population at risk of cardiovascular morbidity and mortality. Associated cardiovascular injuries include pericardial disease, coronary artery disease, valvular disease, conduction disease, cardiomyopathy, and medium and large vessel vasculopathy-any of which can occur at varying intervals following irradiation. Higher radiation doses, younger age at the time of irradiation, longer intervals from the time of radiation, and coexisting cardiovascular risk factors all predispose to these injuries. The true incidence of radiation-related cardiovascular disease remains uncertain due to lack of large multicentre studies with a sufficient duration of cardiovascular follow-up. There are currently no consensus guidelines available to inform the optimal approach to cardiovascular surveillance of recipients of thoracic radiation. Therefore, we review the cardiovascular consequences of radiation therapy and focus on the potential role of non-invasive cardiovascular imaging in the assessment and management of radiation-related cardiovascular disease. In doing so, we highlight characteristics that can be used to identify individuals at risk for developing post-radiation cardiovascular disease and propose an imaging-based algorithm for their clinical surveillance.

Cancer-Drug Discovery and Cardiovascular Surveillance

The story of impressive evolution in treatment for chronic myeloid leukemia has taken an unexpected turn, as serious adverse cardiovascular events have occurred in patients treated with the tyrosine kinase inhibitors ponatinib and nilotinib.

The Incidence, Pattern, and Prognostic value of Left Ventricular Myocardial Scar by Late Gadolinium Enhancement in Patients with Atrial Fibrillation

OBJECTIVES This study sought to identify the frequency, pattern, and prognostic significance of left ventricular (LV) late gadolinium enhancement (LGE) in patients with atrial fibrillation (AF). BACKGROUND There are limited data on the presence, pattern, and prognostic significance of LV myocardial fibrosis in patients with AF. LGE during cardiac magnetic resonance imaging is a marker for myocardial fibrosis. METHODS A group of 664 consecutive patients without known prior myocardial infarction who were referred for radiofrequency ablation of AF were studied. Cardiac magnetic resonance imaging was requested to assess pulmonary venous anatomy. RESULTS Overall, 73% were men, with a mean age of 56 years and a mean LV ejection fraction of 56 ± 10%. LV LGE was found in 88 patients (13%). The endpoint was all-cause mortality, and in this cohort, 68 deaths were observed over a median follow-up period of 42 months. On univariate analysis, age (hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 1.03 to 1.08; chi-square likelihood ratio [LRχ(2)]: 15.2; p = 0.0001), diabetes (HR: 2.39; 95% CI: 1.41 to 4.09; LRχ(2): 10.3; p = 0.001), a history of heart failure (HR: 1.78; 95% CI: 1.09 to 2.91; LRχ(2): 5.37; p = 0.02), left atrial dimension (HR: 1.04; 95% CI: 1.01 to 1.08; LRχ(2): 6.47; p = 0.01), presence of LGE (HR: 5.08; 95% CI: 3.08 to 8.36; LRχ(2): 28.8; p < 0.0001), and LGE extent (HR: 1.15; 95% CI: 1.10 to 1.21; LRχ(2): 35.6; p < 0.0001) provided the strongest associations with mortality. The mortality rate was 8.1% per patient-year in patients with LGE compared with 2.3% patients without LGE. In the best overall multivariate model for mortality, age and the extent of LGE were independent predictors of mortality. Indeed, each 1% increase in the extent of LGE was associated with a 15% increased risk for death. CONCLUSIONS In patients with AF, LV LGE is a frequent finding and is a powerful predictor of mortality.

Recognizing and managing left ventricular dysfunction associated with therapeutic inhibition of the vascular endothelial growth factor signaling pathway.

Opinion statementTherapeutic inhibition of the vascular endothelial growth factor (VEGF) signaling pathway (VSP) is increasingly employed in the contemporary treatment of many cancer types. VSP inhibitors include the anti-VEGF monoclonal antibody (bevacizumab), soluble VEGF receptors (VEGF Trap), and small molecule tyrosine kinase inhibitors (TKIs) targeting the intracellular kinase domain of VEGF receptors. These agents are associated with cardiovascular toxicities such as hypertension, thrombosis, myocardial ischemia, and left ventricular (LV) dysfunction. Data on VSP inhibitor-associated LV dysfunction are largely limited to retrospective studies. Prospective studies are needed to establish the clinical significance of VSP inhibitor-associated LV dysfunction in the general population. Pre-clinical models of VSP inhibitor-associated LV dysfunction have identified mechanisms of cardiotoxicity and may improve our understanding of the pathophysiology underlying other cardiomyopathies. This review provides an overview of LV dysfunction that can occur in patients treated with VSP inhibitors. Potential strategies for clinical detection and management of this cardiotoxicity are explored, while acknowledging that currently available data specific to VSP-inhibitor LV dysfunction are limited. Avenues for future research are suggested.

Heart Failure and Midrange Ejection Fraction Implications of Recovered Ejection Fraction for Exercise Tolerance and Outcomes

Background— Evidence-based therapies for heart failure (HF) differ significantly according to left ventricular ejection fraction (LVEF). However, few data are available on the phenotype and prognosis of patients with HF with midrange LVEF of 40% to 55%, and the impact of recovered systolic function on the clinical features, functional capacity, and outcomes of this population is not known. Methods and Results— We studied 944 patients with HF who underwent clinically indicated cardiopulmonary exercise testing. The study population was categorized according to LVEF as follows: HF with reduced LVEF (HFrEF; LVEF 55%; n=47). HF with midrange ejection fraction and no recovered ejection fraction and HF with recovered midrange ejection fraction had similar clinical characteristics, which were intermediate between those of HFrEF and HFpEF, and comparable values of predicted peak oxygen consumption and minute-ventilation/carbon dioxide production slope, which were better than HFrEF and similar to HFpEF. After a median of 4.4 (2.9–5.7) years, there were 253 composite events (death, left ventricular assistant device implantation, or transplantation). In multivariable Cox-regression analysis, HF with recovered midrange ejection fraction had lower risk of composite events than HFrEF (hazard ratio, 0.25; 95% confidence interval, 0.13–0.47) and HF with midrange ejection fraction and no recovered ejection fraction (hazard ratio, 0.31; 95% confidence interval, 0.15–0.67), and similar prognosis when compared with HFpEF. In contrast, HF with midrange ejection fraction and no recovered ejection fraction tended to show intermediate risk of outcomes in comparison with HFpEF and HFrEF, albeit not reaching statistical significance in fully adjusted analyses. Conclusions— Patients with HF with midrange LVEF demonstrate a distinct clinical profile from HFpEF and HFrEF patients, with objective measures of functional capacity similar to HFpEF. Within the midrange LVEF HF population, recovered systolic function is a marker of more favorable prognosis.Background—Evidence-based therapies for heart failure (HF) differ significantly according to left ventricular ejection fraction (LVEF). However, few data are available on the phenotype and prognosis of patients with HF with midrange LVEF of 40% to 55%, and the impact of recovered systolic function on the clinical features, functional capacity, and outcomes of this population is not known. Methods and Results—We studied 944 patients with HF who underwent clinically indicated cardiopulmonary exercise testing. The study population was categorized according to LVEF as follows: HF with reduced LVEF (HFrEF; LVEF<40%; n=620); HF with midrange ejection fraction and no recovered ejection fraction (LVEF was consistent between 40% and 55%; n=107); HF with recovered midrange ejection fraction (LVEF, 40%–55% but previous LVEF<40%; n=170); and HF with preserved LVEF (HFpEF; LVEF>55%; n=47). HF with midrange ejection fraction and no recovered ejection fraction and HF with recovered midrange ejection fraction had similar clinical characteristics, which were intermediate between those of HFrEF and HFpEF, and comparable values of predicted peak oxygen consumption and minute-ventilation/carbon dioxide production slope, which were better than HFrEF and similar to HFpEF. After a median of 4.4 (2.9–5.7) years, there were 253 composite events (death, left ventricular assistant device implantation, or transplantation). In multivariable Cox-regression analysis, HF with recovered midrange ejection fraction had lower risk of composite events than HFrEF (hazard ratio, 0.25; 95% confidence interval, 0.13–0.47) and HF with midrange ejection fraction and no recovered ejection fraction (hazard ratio, 0.31; 95% confidence interval, 0.15–0.67), and similar prognosis when compared with HFpEF. In contrast, HF with midrange ejection fraction and no recovered ejection fraction tended to show intermediate risk of outcomes in comparison with HFpEF and HFrEF, albeit not reaching statistical significance in fully adjusted analyses. Conclusions—Patients with HF with midrange LVEF demonstrate a distinct clinical profile from HFpEF and HFrEF patients, with objective measures of functional capacity similar to HFpEF. Within the midrange LVEF HF population, recovered systolic function is a marker of more favorable prognosis.

Anthracycline Cardiotoxicity A New Paradigm for an Old Classic

Anthracyclines are potent anti-neoplastic agents with proven efficacy in the treatment of many pediatric and adult hematologic and solid organ cancers. Dose-dependent anthracycline induced cardiomyopathy is the most notorious and well-studied chemotherapy-induced cardiovascular toxicity that was first described in 1971 in 67 patients treated with adriamycin for a variety of tumors.1 The clinical significance of anthracycline cardiotoxicity is growing with increasing cancer survivorship and increasing use of anthracyclines in cohorts predisposed to adverse cardiac effects such as the elderly, those with cardiovascular comorbidities, and those receiving additional chemotherapies and/or thoracic irradiation. However, our current knowledge of anthracycline cardiotoxicity derives mainly from retrospective analyses of cancer patients with symptomatic heart failure during or after chemotherapy. This had led to wide variations in the estimated incidence and prognosis of anthracycline cardiotoxicity and has contributed to the lack of accepted guidelines for the surveillance and management of this potentially important complication of cancer therapy. For these reasons, the prospective study by Cardinale et al. in this issue of Circulation 2 evaluating the incidence of cardiotoxicity, its timing of occurrence, and its clinical response to medical therapy in a large population of anthracycline-treated adults is an important step towards resolving these uncertainties.

Timing and Causes of Readmission After Acute Heart Failure Hospitalization—Insights From the Heart Failure Network Trials

BACKGROUND Readmission or death after heart failure (HF) hospitalization is a consequential and closely scrutinized outcome, but risk factors may vary by population. We characterized the risk factors for post-discharge readmission/death in subjects treated for acute heart failure (AHF). METHODS AND RESULTS A post hoc analysis was performed on data from 744 subjects enrolled in 3 AHF trials conducted within the Heart Failure Network (HFN): Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE-AHF), Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), and Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF). All-cause readmission/death occurred in 26% and 38% of subjects within 30 and 60 days of discharge, respectively. Non-HF cardiovascular causes of readmission were more common in the ≤30-day timeframe than in the 31-60-day timeframe (23% vs 10%, P = .016). In a Cox proportional hazards model adjusting a priori for left ventricular ejection fraction <50% and trial, the risk factors for all-cause readmission/death included: elevated baseline blood urea nitrogen, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) non-use, lower baseline sodium, non-white race, elevated baseline bicarbonate, lower systolic blood pressure at discharge or day 7, depression, increased length of stay, and male sex. CONCLUSIONS In an AHF population with prominent congestion and prevalent renal dysfunction, early readmissions were more likely to be due to non-HF cardiovascular causes compared with later readmissions. The association between use of ACEI/ARB and lower all-cause readmission/death in Cox proportional hazards model suggests a role for these drugs to improve post-discharge outcomes in AHF.

Deficiencies in Patients’ Comprehension of Implantable Cardioverter Defibrillator Therapy

Background: Patients receive education before implantable cardioverter defibrillator (ICD) implantation. Patients’ understanding of ICD therapy requires investigation.

Identifying Early Changes in Myocardial Microstructure in Hypertensive Heart Disease

The transition from healthy myocardium to hypertensive heart disease is characterized by a series of poorly understood changes in myocardial tissue microstructure. Incremental alterations in the orientation and integrity of myocardial fibers can be assessed using advanced ultrasonic image analysis. We used a modified algorithm to investigate left ventricular myocardial microstructure based on analysis of the reflection intensity at the myocardial-pericardial interface on B-mode echocardiographic images. We evaluated the extent to which the novel algorithm can differentiate between normal myocardium and hypertensive heart disease in humans as well as in a mouse model of afterload resistance. The algorithm significantly differentiated between individuals with uncomplicated essential hypertension (N = 30) and healthy controls (N = 28), even after adjusting for age and sex (P = 0.025). There was a trend in higher relative wall thickness in hypertensive individuals compared to controls (P = 0.08), but no difference between groups in left ventricular mass (P = 0.98) or total wall thickness (P = 0.37). In mice, algorithm measurements (P = 0.026) compared with left ventricular mass (P = 0.053) more clearly differentiated between animal groups that underwent fixed aortic banding, temporary aortic banding, or sham procedure, on echocardiography at 7 weeks after surgery. Based on sonographic signal intensity analysis, a novel imaging algorithm provides an accessible, non-invasive measure that appears to differentiate normal left ventricular microstructure from myocardium exposed to chronic afterload stress. The algorithm may represent a particularly sensitive measure of the myocardial changes that occur early in the course of disease progression.