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BACKGROUND - The National Comprehensive Cancer Network and American Society of Clinical Oncology recommend consideration of the use of echocardiography 6 to 12 months after completion of anthracycline-based chemotherapy in at-risk populations. Assessment of BNP (B-type natriuretic peptide) has also been suggested by the American College of Cardiology/American Heart Association/Heart Failure Society of America for the identification of Stage A (at risk) heart failure patients. The real-world frequency of the use of these tests in patients after receipt of anthracycline therapy, however, has not been studied previously.
METHODS AND RESULTS - In this retrospective study, using administrative claims data from the OptumLabs Data Warehouse, we identified 31 447 breast cancer and lymphoma patients (age ≥18 years) who were treated with an anthracycline in the United States between January 1, 2008 and January 31, 2018. Continuous medical and pharmacy coverage was required for at least 6 months before the initial anthracycline dose and 12 months after the final dose. Only 36.1% of patients had any type of cardiac surveillance (echocardiography, BNP, or cardiac imaging) in the year following completion of anthracycline therapy (29.7% echocardiography). Surveillance rate increased from 37.5% in 2008 to 42.7% in 2018 (25.6% in 2008 to 40.5% echocardiography in 2018). Lymphoma patients had a lower likelihood of any surveillance compared with patients with breast cancer (odds ratio, 0.79 [95% CI, 0.74-0.85]; <0.001). Patients with preexisting diagnoses of coronary artery disease and arrhythmia had the highest likelihood of cardiac surveillance (odds ratio, 1.54 [95% CI, 1.39-1.69] and odds ratio, 1.42 [95% CI, 1.3-1.53]; <0.001 for both), although no single comorbidity was associated with a >50% rate of surveillance.
CONCLUSIONS - The majority of survivors of breast cancer and lymphoma who have received anthracycline-based chemotherapy do not undergo cardiac surveillance after treatment, including those with a history of cardiovascular comorbidities, such as heart failure.
Background Identification of occult diastolic dysfunction often requires invasive right heart catheterization with provocative maneuvers such as fluid challenge. Non-invasive predictors of occult diastolic dysfunction have not been identified. We hypothesized that echocardiographic measures of diastolic function are associated with occult diastolic dysfunction identified at catheterization. Methods and Results We retrospectively examined hemodynamic and echocardiographic data from consecutive patients referred for right heart catheterization with fluid challenge from 2009 to 2017. A replication cohort of 52 patients who prospectively underwent simultaneous echocardiography and right heart catheterization before and after fluid challenge at Monaldi Hospital, Naples, Italy. In the retrospective cohort of 126 patients (83% female, 56+14 years), 27/126 (21%) had occult diastolic dysfunction. After adjusting for tricuspid regurgitant velocity and left atrial volume index, E velocity (odds ratio 1.8, 95% CI 1.1-2.9, P=0.01) and E/e' (odds ratio 1.9, 95% CI 1.1-3, P=0.005) were associated with occult diastolic dysfunction with an optimal threshold of E/e' >8.6 for occult diastolic dysfunction (sensitivity 70%, specificity 64%). In the prospective cohort, 5/52 (10%) patients had diastolic dysfunction after fluid challenge. Resting E/e' (odds ratio 8.75, 95% CI 2.3-33, P=0.001) and E velocity (odds ratio 7.7, 95% CI 2-29, P=0.003) remained associated with occult diastolic dysfunction with optimal threshold of E/e' >8 (sensitivity 73%, specificity 90%). Conclusions Among patients referred for right heart catheterization with fluid challenge, E velocity and E/e' are associated with occult diastolic dysfunction after fluid challenge. These findings suggest that routine echocardiographic measurements may help identify patients like to have occult diastolic dysfunction non-invasively.
Anthracyclines are the cornerstone for many oncologic treatments, but their cardiotoxicity has been recognized for several decades. Female subjects, especially before puberty and adolescence, or after menopause, seem to be more at increased risk, with the prognostic impact of this sex issue being less consistent compared to other cardiovascular risk factors. Several studies imply that sex differences could depend on the lack of the protective effect of sex hormones against the anthracycline-initiated damage in cardiac cells, or on differential mitochondria-related oxidative gene expression. This is also reflected by the results obtained with different diagnostic methods, such as cardiovascular biomarkers and imaging techniques (echocardiography, magnetic resonance, and nuclear medicine) in the diagnosis and monitoring of cardiotoxicity, confirming that sex differences exist. The same is true about protective strategies from anthracycline cardiotoxicity. Indeed, first studied to withstand oxidative damage in response to ischemia/reperfusion (I/R) injury, cardioprotection has different outcomes in men and women. A number of studies assessed the differences in I/R response between male and female hearts, with oxidative stress and apoptosis being shared mechanisms between the I/R and anthracyclines heart damage. Sex hormones can modulate these mechanisms, thus confirming their importance in the pathophysiology in cardioprotection not only from the ischemia/reperfusion damage, but also from anthracyclines, fueling further cardio-oncologic research on the topic.
BACKGROUND - The cardiac sodium channel (SCN5A) mutation R222Q neutralizes a positive charge in the domain I voltage sensor. Mutation carriers display very frequent ectopy and dilated cardiomyopathy.
OBJECTIVES - To describe the effect of SCN5A R222Q on murine myocyte and Purkinje fiber electrophysiology, and identify underlying mechanisms.
METHODS - We generated mice carrying humanized wild-type (H) and mutant (RQ) SCN5A channels. We characterized whole-heart and isolated ventricular and Purkinje myocyte properties.
RESULTS - RQ/RQ mice were not viable. I from RQ/H ventricular myocytes displayed increased "window current" and hyperpolarizing shifts in both inactivation and activation compared to H/H, as previously reported in heterologous expression systems. Surprisingly, action potentials were markedly abbreviated in RQ/H myocytes (action potential durations at 90% repolarization: 12.6 ± 1.3 ms vs 29.1 ± 1.0 ms in H/H, P < .01, n = 10 each). We identified a large [K]-dependent outward gating pore current in RQ/H but not H/H myocytes, and decreasing [K] elicited early afterdepolarizations (EADs) and triggered activity in isolated myocytes and ectopic beats in whole hearts. Further, RQ/H Purkinje cells displayed striking, consistent low-voltage EADs. In vivo, however, RQ/H mice displayed little ectopy and contractile function was normal.
CONCLUSION - While SCN5A R222Q increases plateau inward sodium current, action potentials were unexpectedly shortened, likely reflecting an outward gating-pore current. Low extracellular potassium increased this pore current, and was arrhythmogenic in vitro and ex vivo.
Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
Sepsis costs the healthcare system $23 billion annually and has a mortality rate between 10 and 40%. An early indication of sepsis is the onset of hyperglycemia, which is the result of sepsis-induced insulin resistance in skeletal muscle. Previous investigations have focused on events in the myocyte (e.g., insulin signaling and glucose transport and subsequent metabolism) as the causes for this insulin-resistant state. However, the delivery of insulin to the skeletal muscle is also an important determinant of insulin action. Skeletal muscle microvascular blood flow, which delivers the insulin to the muscle, is known to be decreased during sepsis. Here we test whether the reduced capillary blood flow to skeletal muscle belies the sepsis-induced insulin resistance by reducing insulin delivery to the myocyte. We hypothesize that decreased capillary flow and consequent decrease in insulin delivery is an early event that precedes gross cardiovascular alterations seen with sepsis. This hypothesis was examined in mice treated with either lipopolysaccharide (LPS) or polymicrobial sepsis followed by intravital microscopy of the skeletal muscle microcirculation. We calculated insulin delivery to the myocyte using two independent methods and found that LPS and sepsis rapidly reduce insulin delivery to the skeletal muscle by ~50%; this was driven by decreases in capillary flow velocity and the number of perfused capillaries. Furthermore, the changes in skeletal muscle microcirculation occur before changes in both cardiac output and arterial blood pressure. These data suggest that a rapid reduction in skeletal muscle insulin delivery contributes to the induction of insulin resistance during sepsis.
BACKGROUND - Although studies involving preterm infants ≤34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results.
METHODS - We used preterm baboons, mice, and humans (≤27 weeks gestation) to examine betamethasone's effects on ductus gene expression and constriction both in vitro and in vivo.
RESULTS - In mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone's effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally regulated genes that mediate oxygen-induced constriction (K channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born ≤25 weeks gestation, betamethasone's contractile effects were only apparent when prostaglandin signaling was inhibited, whereas at 26-27 weeks gestation, betamethasone's contractile effects were apparent even in the absence of prostaglandin inhibitors.
CONCLUSIONS - We speculate that betamethasone's contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone's effects vary according to the infant's developmental age at birth.
OBJECTIVES - This study sought to assess long-term left atrial appendage (LAA) closure efficacy of the Atriclip applied via totally thoracoscopic (TT) approach with computed tomographic angiography.
BACKGROUND - LAA closure is associated with a low risk for atrial fibrillation-related embolic stroke. The Atriclip exclusion device allows epicardial LAA closure, avoiding the need for post-operative oral anticoagulation. Previous data with Atriclip during open chest procedures show a high efficacy rate of closure >95%.
METHODS - Three-dimensional volumetric 2-phase computed tomographic angiography ≥90 days post-implantation was independently assessed by chest radiology for complete LAA closure on all consented subjects identified retrospectively as having had a TT-placed Atriclip at Vanderbilt University Medical Center from June 13, 2011, to October 6, 2015.
RESULTS - Complete LAA closure (defined by complete exclusion of the LAA with no exposed trabeculations, and clip within 1 cm from the left circumflex artery) was found in 61 of 65 subjects (93.9%). Four cases had incomplete closure (6.2%). Two clips were placed too distally, leaving a large stump with exposed trabeculae. Two clips failed to address a secondary LAA lobe. No major complications were associated with TT placement of the Atriclip. Follow-up over 183 patient-years revealed 1 stroke in a patient with complete LAA closure and no thrombus (hypertensive cerebrovascular accident).
CONCLUSIONS - Angiographic LAA closure efficacy with a TT-placed Atriclip is high (93.9%). The clinical significance of a remnant stump is unknown. Confirmation of complete LAA occlusion should be made before cessation of systemic anticoagulation.
Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Pulmonary transit time (PTT) obtained from contrast echocardiography is a marker of global cardiopulmonary function. Pulmonary blood volume (PBV), derived from PTT, may be a noninvasive surrogate for left-sided filling pressures, such as pulmonary artery wedge pressure (PAWP). We sought to assess the relationship between PBV obtained from contrast echocardiography and PAWP.
METHODS - Participants were adult survivors of childhood cancer that had contrast echocardiography performed nearly simultaneously with right-heart catheterization. PTT was derived from time-intensity curves of contrast passage through the right ventricle (RV) and left atrium (LA). PBV relative to overall stroke volume (rPBV) was estimated from the product of PTT and heart rate during RV-LA transit. PAWP was obtained during standard right-heart catheterization. The Spearman correlation coefficient was used to assess the relationship between rPBV and PAWP.
RESULTS - The study population consisted of 7 individuals who had contrast echocardiography and right-heart catheterization within 3 hours of each other. There was a wide range of right atrial (1-17 mm Hg), mean pulmonary artery (18-42 mm Hg), and PAW pressures (4-26 mm Hg) as well as pulmonary vascular resistance (<1-6 Wood Units). We observed a statistically significant correlation between rPBV and PAWP (r = .85; P = .02).
CONCLUSION - Relative PBV derived from contrast echocardiography correlates with PAWP. If validated in larger studies, rPBV could potentially be used as an alternative to invasively determine left-sided filling pressure.
© 2018 Wiley Periodicals, Inc.
Diastolic dysfunction (DD), an abnormality in cardiac left ventricular (LV) chamber compliance, is associated with increased morbidity and mortality. Although DD has been extensively studied in older populations, co-morbidity patterns are less well characterized in middle-aged subjects. We screened 156,434 subjects with transthoracic echocardiogram reports available through Vanderbilt's electronic heath record and identified 6,612 subjects 40 to 55 years old with an LV ejection fraction ≥50% and diastolic function staging. We tested 452 incident and prevalent clinical diagnoses for associations with early-stage DD (n = 1,676) versus normal function. There were 44 co-morbid diagnoses associated with grade 1 DD including hypertension (odds ratio [OR] = 2.02, 95% confidence interval [CI] 1.78 to 2.28, p <5.3 × 10-29), type 2 diabetes (OR 1.96, 95% CI 1.68 to 2.29, p = 2.1 × 10-17), tachycardia (OR 1.38, 95% CI 0.53 to 2.19, p = 2.9 × 10-6), obesity (OR 1.76, 95% CI 1.51 to 2.06, p = 1.7 × 10-12), and clinical end points, including end-stage renal disease (OR 3.29, 95% CI 2.19 to 4.96, p = 1.2 × 10-8) and stroke (OR 1.5, 95% CI 1.12 to 2.02, p = 6.9 × 10-3). Among the 60 incident diagnoses associated with DD, heart failure with preserved ejection fraction (OR 4.63, 95% CI 3.39 to 6.32, p = 6.3 × 10-22) had the most significant association. Among subjects with normal diastolic function and blood pressure at baseline, a blood pressure measurement in the hypertensive range at the time of the second echocardiogram was associated with progression to stage 1 DD (p = 0.04). In conclusion, DD was common among subjects 40 to 55 years old and was associated with a heavy burden of co-morbid disease.
Copyright © 2018 Elsevier Inc. All rights reserved.
Inactivation of the retinoblastoma gene () product, pRB, is common in many human cancers. Targeting downstream effectors of pRB that are central to tumorigenesis is a promising strategy to block the growth of tumors harboring loss-of-function mutations. One such effector is retinoblastoma-binding protein 2 (RBP2, also called JARID1A or KDM5A), which encodes an H3K4 demethylase. Binding of pRB to RBP2 has been linked to the ability of pRB to promote senescence and differentiation. Importantly, genetic ablation of RBP2 is sufficient to phenocopy pRB's ability to induce these cellular changes in cell culture experiments. Moreover, germline deletion significantly impedes tumorigenesis in mice. The value of RBP2 as a therapeutic target in cancer, however, hinges on whether loss of RBP2 could block the growth of established tumors as opposed to simply delaying their onset. Here we show that conditional, systemic ablation of RBP2 in tumor-bearing mice is sufficient to slow tumor growth and significantly extend survival without causing obvious toxicity to the host. These findings show that established -null tumors require RBP2 for growth and further credential RBP2 as a therapeutic target in human cancers driven by inactivation.