- Efficacy and Safety of Automatic Remote Monitoring for Implantable Cardioverter-Defibrillator Follow-Up: The Lumos-T Safely Reduces Routine Office Device Follow-Up (TRUST) Trial
- Enalapril in Infants With Single Ventricle: Results of a Multicenter Randomized Trial
- Aging-Related Early Changes in Markers of Ventricular and Matrix Remodeling After Reperfused ST-Segment Elevation Myocardial Infarction in the Canine Model: Effect of Early Therapy With an Angiotensin II Type 1 Receptor Blocker
- Prospective Study of Obstructive Sleep Apnea and Incident Coronary Heart Disease and Heart Failure: The Sleep Heart Health Study
- Ablation of C/EBP Homologous Protein Attenuates Endoplasmic Reticulum–Mediated Apoptosis and Cardiac Dysfunction Induced by Pressure Overload
- Mineralocorticoid Accelerates Transition to Heart Failure With Preserved Ejection Fraction Via “Nongenomic Effects”
- Endothelial Dysfunction and Subsequent Decline in Glomerular Filtration Rate in Hypertensive Patients
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Efficacy and Safety of Automatic Remote Monitoring for Implantable Cardioverter-Defibrillator Follow-Up: The Lumos-T Safely Reduces Routine Office Device Follow-Up (TRUST) Trial
Cardiac implantable electronic devices are increasing in prevalence. Postimplantation follow-up is important for monitoring both device function and patient condition. Currently, follow-up care follows guidelines that lack supporting data, leading to inconsistent clinical practice. Conventional in-person evaluation, if performed every 3 to 6 months, generates a huge clinical burden, but its efficacy with regard to patient safety, adherence, incidence of unscheduled encounters, and rate of problem detection remains untested. The absence of monitoring between hospital interrogations permits potentially important clinical data to remain concealed. Remote monitoring technology incorporated into devices holds the promise of resolving these problems. The Lumos-T Safely Reduces Routine Office Device Follow-Up (TRUST) trial in patients with defibrillators confirmed significant limitations of conventional care but, in contrast, affirmed the safety, efficacy, and early warning capability (ie, within 24 hours) of automatic remote monitoring. The outcome measure of hospital use was reduced by almost 50% compared with conventional care. The alert capability and archiving power of this remote management system suit it for system performance monitoring and management of devices placed under advisory notices. The results are important for heart failure patients in whom continuous surveillance with the ability to self-declare parameter deviations may permit early clinical intervention. The trial results have significant implications for the management of patients receiving implantable electronic cardiac devices. See p 325.
Enalapril in Infants With Single Ventricle: Results of a Multicenter Randomized Trial
Infants with complex heart lesions that lead to single-ventricle physiology are at risk for abnormalities in ventricular systolic and diastolic function and for poor growth. Extrapolation of data from the adult literature has led to the empiric use of angiotensin-converting enzyme inhibitor therapy in this population; however, its efficacy has never been studied. The Pediatric Heart Network conducted a multicenter, double-blind, placebo-controlled trial involving 230 infants with single-ventricle physiology randomized to receive enalapril (target dose 0.4 mg · kg−1 · d−1) or placebo and followed up to 14 months of age. Overall, the majority of the study population had normal ventricular function and no clinical heart failure at 14 months of age, regardless of the treatment group. Growth was significantly impaired, and there were neurodevelopmental abnormalities noted. The incidence of death or transplantation was 13% and did not differ between treatment groups. Administration of enalapril did not improve somatic growth, ventricular function, or heart failure severity. The results of this randomized trial do not support the routine use of enalapril in this population. See p 333.
Aging-Related Early Changes in Markers of Ventricular and Matrix Remodeling After Reperfused ST-Segment Elevation Myocardial Infarction in the Canine Model: Effect of Early Therapy With an Angiotensin II Type 1 Receptor Blocker
Prevention of early left ventricular remodeling during ST-segment-elevation myocardial infarction is of critical importance, especially in the elderly. Early remodeling leads to progressive ventricular enlargement that affects outcome, and elderly ST-segment-elevation myocardial infarction patients are at greater risk for remodeling. Acute ST-segment-elevation myocardial infarction patients reperfused by percutaneous coronary intervention after 90 minutes of ischemia develop left ventricular remodeling that persists despite medical therapy initiated during recovery. Although reperfusion has proven benefits, it results in injury with myocardial and extracellular matrix damage. Although increased matrix metalloproteinase is a generally accepted pathway leading to early extracellular matrix damage and ventricular remodeling, failure of metalloproteinase inhibition initiated during recovery after ST-segment-elevation myocardial infarction to limit ventricular remodeling suggests that damage had occurred earlier and/or other matrix proteins besides metalloproteinases contributed to damage. We present evidence that aging increases reperfusion damage and markers of left ventricular structural remodeling (echocardiographic ventricular enlargement and dysfunction) and matrix remodeling (novel matrix proteins besides metalloproteinases), as well as inflammatory cytokines that contribute to early extracellular matrix degradation and early ventricular remodeling and dysfunction. Because angiotensin II is known to increase with aging, to exacerbate ischemic injury, and to regulate extracellular matrix homeostasis, we tested early therapy, given intravenously at the time of reperfusion (as a relevant clinical approach at the time of percutaneous coronary intervention), with an angiotensin II receptor blocker and demonstrate attenuation, but not abolition, of the deleterious aging-related changes. Because elderly ST-segment-elevation myocardial infarction patients are seldom reperfused before 90 minutes of ischemia, this strategy may be relevant but requires clinical confirmation. See p 341.
Prospective Study of Obstructive Sleep Apnea and Incident Coronary Heart Disease and Heart Failure: The Sleep Heart Health Study
Prior clinic-based observational studies have reported that obstructive sleep apnea (OSA) is associated with an increased incidence of coronary heart disease and an increased prevalence of heart failure in men. In the present study, we assessed the relation of OSA to incident coronary heart disease and heart failure in a general community sample of adult men and women. In this prospective study of 1927 men and 2495 women 40 years of age or older and free of coronary heart disease and heart failure at baseline, we found that over a median follow-up period of 8.7 years, OSA was a significant independent predictor of incident heart failure in men but not in women (adjusted hazard ratio 1.58 for men with an apnea-hypopnea index ≥30 compared with men with an apnea-hypopnea index <5). OSA predicted incident coronary heart disease only in men ≤70 years old (adjusted hazard ratio 1.68 for those with an apnea-hypopnea index ≥30 compared with those with an apnea-hypopnea index <5). The finding of an increased incidence of heart failure in individuals with severe OSA is novel; whether women are truly at lower risk of heart failure than are men with similarly severe OSA requires further study. The association of OSA with incident coronary heart disease in this study is much weaker than that reported from previous clinic-based studies, which possibly reflects the older age of this cohort. See p 352.
Ablation of C/EBP Homologous Protein Attenuates Endoplasmic Reticulum–Mediated Apoptosis and Cardiac Dysfunction Induced by Pressure Overload
Heart failure is a major and growing public health problem worldwide. Although cardiac hypertrophy is a risk factor for the development of heart failure, it is largely unknown how prolonged cardiac hypertrophy causes heart failure. Recently, accumulating evidence has demonstrated that a number of diseases, including neurodegenerative diseases and diabetes mellitus, are associated with the impairment of protein folding in the endoplasmic reticulum (ER). The ER responds to stress by upregulating ER chaperones or attenuating global protein synthesis, but prolonged and/or excess ER stress leads to apoptosis. Here, we provide evidence that C/EBP homologous protein (CHOP), a transcriptional factor that mediates ER-initiated apoptotic cell death, and the ER chaperone were elevated in human failing heart samples, suggesting that ER stress is induced human failing hearts. Pressure overload induced cardiac hypertrophy and failure, along with increased expression in the ER chaperone and CHOP in mice heart. Interestingly, CHOP-deficient mice showed less cardiac hypertrophy and better cardiac function after pressure overload. One possible mechanism for reduced cardiac hypertrophy was enhanced phosphorylation of eukaryotic translation initiation factor 2α, which reduces protein translation and is negatively regulated by CHOP, in pressure-overloaded hearts of CHOP-deficient mice. Furthermore, CHOP decreased Bcl2 protein levels and other Bcl2 family members in cardiomyocytes, suggesting that the ER-mitochondria pathway would play an important role in cell death in pressure-overloaded hearts. In conclusion, the present findings suggest that CHOP may be a logical target for development of drugs to prevent cardiac hypertrophy and cardiomyocyte cell death in failing hearts. See p 361.
Mineralocorticoid Accelerates Transition to Heart Failure With Preserved Ejection Fraction Via “Nongenomic Effects”
A wealth of data from human systolic heart failure and experimental models of hypertension and heart failure suggests that mineralocorticoid receptor antagonists reduce mortality and attenuate hypertrophy, fibrosis, and diastolic dysfunction. These data have led to the ongoing multicenter randomized Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT). Although aldosterone levels are elevated in heart failure with preserved ejection fraction, whether aldosterone itself causes adverse cardiac remodeling, which could promote the transition from hypertensive heart disease to overt heart failure with preserved ejection fraction, is controversial. In this study, we show that oxidative stress is induced in the hypertensive heart and sensitizes the heart to exogenous mineralocorticoids. In normal mice, exogenous mineralocorticoid had little effect on cardiac structure or function. Mice with pressure-overload hypertrophy had increased myocardial oxidative stress, and in these mice, exogenous mineralocorticoid accentuated hypertrophy, fibrosis, and diastolic dysfunction, suggesting an interaction between excess mineralocorticoid (inappropriate for salt status) and oxidative stress. Interestingly, this effect was observed without evidence of classic mineralocorticoid receptor–mediated gene transcription in the heart (“nongenomic” effects) and independently of changes in the magnitude of pressure overload. These results suggest that aldosterone excess may promote the transition from compensated hypertensive heart disease to heart failure with preserved ejection fraction via nongenomic effects or alternatively through effects on noncardiac cells. Because the nongenomic effects of aldosterone are exerted both via the mineralocorticoid receptor and independent from the mineralocorticoid receptor, development of novel antagonists that target both genomic and nongenomic effects may have benefit beyond mineralocorticoid receptor antagonists. See p 370.
Endothelial Dysfunction and Subsequent Decline in Glomerular Filtration Rate in Hypertensive Patients
Endothelial dysfunction is associated with cardiovascular risk factors and with future cardiovascular events. In this study, we examined the relationship of endothelial dysfunction to the decline in renal function in patients with uncomplicated hypertension and a baseline serum creatinine of less than 1.5 mg/dL. Endothelial dysfunction was associated with a greater decline in renal function even after adjustment for the known adverse effects of elevated systolic blood pressure. These data suggest that endothelial dysfunction may exacerbate the decline in renal function in patients with hypertension and that therapies to improve endothelial function may help prevent the development of hypertensive kidney disease. Although not tested in the present study, the prevention of progressive renal disease in patients with hypertension may not only rely on intensive blood pressure control but also on other interventions known to improve endothelial function, such as lifestyle modification, treatment of dyslipidemia, and smoking cessation. See p 379.
- Enalapril in Infants With Single Ventricle: Results of a Multicenter Randomized Trial
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