Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- New White Matter Brain Injury After Infant Heart Surgery Is Associated With Diagnostic Group and the Use of Circulatory Arrest
- Prognostic Significance of Silent Myocardial Infarction in Newly Diagnosed Type 2 Diabetes Mellitus: United Kingdom Prospective Diabetes Study (UKPDS) 79
- Mild Renal Dysfunction and Metabolites Tied to Low HDL Cholesterol Are Associated With Monocytosis and Atherosclerosis
- Functional Consequences of Human Induced Pluripotent Stem Cell Therapy: Myocardial ATP Turnover Rate in the In Vivo Swine Heart With Postinfarction Remodeling
- Calmodulin Mutations Associated With Recurrent Cardiac Arrest in Infants
- Real-Time Left Ventricular Pressure-Volume Loops During Percutaneous Mitral Valve Repair With the MitraClip System
- Cytotoxic and Proinflammatory CD8+ T Lymphocytes Promote Development of Vulnerable Atherosclerotic Plaques in ApoE-Deficient Mice
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New White Matter Brain Injury After Infant Heart Surgery Is Associated With Diagnostic Group and the Use of Circulatory Arrest
This study investigates the nature, timing, and consequences of brain injury on magnetic resonance imaging scan in a cohort of young infants undergoing surgery both with and without cardiopulmonary bypass. We confirmed the findings of previous studies that white matter injury (WMI) is the most prevalent abnormality. WMI before surgery was significantly associated with a less mature brain but not with diagnostic group. The study has revealed some important new findings. First, new WMI after surgery occurred at the same rate in infants undergoing surgery without cardiopulmonary bypass as in those having cardiopulmonary bypass. Second, new WMI was significantly associated with diagnostic group and, in infants having arch surgery, the use of deep hypothermic circulatory arrest. Third, WMI was also associated with a less mature brain and the presence of WMI before surgery. Finally, impaired neurodevelopment at 2 years of age was significantly associated with a less mature brain but not with WMI. This is the first study to include infants having surgery without cardiopulmonary bypass and to investigate the relationship between neurodevelopment and both WMI and brain maturity. The results highlight the potential importance of impaired antenatal brain development on neurodevelopment and on WMI both before and after surgery. The findings suggest that avoiding the use of cardiopulmonary bypass, when that is an option, does not necessarily have benefits in terms of reduced brain injury. They also support the need for a randomized, controlled trial to investigate whether avoidance of deep hypothermic circulatory arrest might be associated with less WMI and improved neurodevelopment. See p 971.
Prognostic Significance of Silent Myocardial Infarction in Newly Diagnosed Type 2 Diabetes Mellitus: United Kingdom Prospective Diabetes Study (UKPDS) 79
In the United Kingdom Prospective Diabetes Study (UKPDS), ≈1 in 6 patients with newly diagnosed type 2 diabetes mellitus had evidence of a silent myocardial infarction (SMI), defined as Q waves on a 12-lead resting ECG in the absence of a history of typical cardiac symptoms. SMI was associated independently with a 58% increased rate of subsequent fatal MI and a 31% increased all-cause mortality rate. Although SMI at diagnosis occurred more often in women, the associated increased rate of a subsequent fatal MI was independent of sex. Some cardiovascular risk factors, including hypertension and microalbuminuria, were more prevalent among patients with SMI. The associations of SMI with increased rates of subsequent fatal MI and all-cause mortality argue for prompt review of the adequacy of management of modifiable cardiovascular risk factors in type 2 diabetes mellitus, but the incremental predictive value of SMI when added to current UKPDS Risk Engine variables (age at diagnosis, sex, ethnicity, smoking, hemoglobin A1c, systolic blood pressure, and ratio of total to high-density lipoprotein cholesterol) is marginal. See p 980.
Mild Renal Dysfunction and Metabolites Tied to Low HDL Cholesterol Are Associated With Monocytosis and Atherosclerosis
Patients with chronic kidney disease have a markedly increased risk of atherosclerotic cardiovascular disease. The number of circulating monocytes and their differentiation into lipid-laden macrophages in the arterial wall are fundamental factors involved in plaque formation. In small studies of patients with end-stage renal disease, total monocyte counts and certain monocyte subsets are increased cross-sectionally compared with healthy control subjects, and specific subsets are associated with cardiovascular events and mortality in end-stage renal disease and chronic kidney disease. In a large population-based cohort, we now report in >4500 individuals the novel finding that mild renal dysfunction measured by cystatin C is strongly and independently associated with monocytosis at baseline. We also demonstrate that low high-density lipoprotein cholesterol and amino acid metabolites tied to low high-density lipoprotein cholesterol are independently associated with the monocytosis of mild renal dysfunction, and we show a strong relationship of monocyte count with carotid intima-media thickness, which suggests a direct mechanism of accelerated atherogenesis in mild renal dysfunction. The ability of high-density lipoprotein to stimulate removal of cholesterol from macrophages, “cholesterol efflux,” is thought to be central to its antiatherogenic mechanism, and in mouse models, the absence of ATP-binding cassette transporters that promote cholesterol efflux leads to proliferation of hematopoietic stem and progenitor cells, myeloid progenitor cells, and blood monocytes in association with accelerated atherosclerosis. High levels of high-density lipoprotein cholesterol suppress myelopoiesis in animal models. In individuals with mild renal dysfunction, low high-density lipoprotein cholesterol may be causally related to defective cholesterol efflux in hematopoietic stem and progenitor cells and myeloid cells, promoting increased monocyte formation and accelerated atherosclerosis. See p 988.
Functional Consequences of Human Induced Pluripotent Stem Cell Therapy: Myocardial ATP Turnover Rate in the In Vivo Swine Heart With Postinfarction Remodeling
The present study introduces a novel magnetic resonance spectroscopy–magnetization saturation transfer approach for obtaining in vivo measurements of the myocardial ATP hydrolysis rate. The myocardial ATP hydrolysis rate was linearly related to the left ventricular rate-pressure product but was significantly reduced in the border zone of infarction, perhaps because of increases in wall stress in this region. Transplantation of human induced pluripotent stem cell–derived vascular cells significantly increased the activation of endogenous cardiac progenitor cells in response to myocardial infarction injury and was associated with significant improvements in vascular density, infarct size, left ventricular wall stress, and contractile function. Cell therapy also restored the border zone ATP hydrolysis rate to near-normal levels, which may impede progression from the compensated phase of heart disease to heart failure. Because the severity of the reduction in myocardial ATP turnover rate is linearly related to the severity of left ventricular dilatation, and the improvement of myocardial ATP turnover rate is linearly related to the improvement in myocardial contractile performance, the new nuclear magnetic resonance methodology has the potential to add another dimension to our ability to evaluate the prognosis of patients with postinfarction left ventricular remodeling in response to different therapeutic interventions. See p 997.
Calmodulin Mutations Associated With Recurrent Cardiac Arrest in Infants
Calmodulin is a ubiquitous calcium binding protein essential for myriad intracellular signaling processes in eukaryotic cells. In heart, calmodulin transduces Ca2+ signals to influence the activity of ion channels, kinases, and other target proteins that contribute importantly to cardiac function. Given that calmodulin is essential to fundamental cell processes, mutations are expected to have severe consequences. Here, we report calmodulin mutations in 2 unrelated infants with recurrent cardiac arrest and features of severe long-QT syndrome who were both negative for mutations in known arrhythmia-predisposing genes. Using next-generation sequencing technologies to scan coding exons across the genome (eg, exomes), we discovered de novo mutations in 2 distinct genes (CALM1, CALM2) encoding identical calmodulin proteins. Screening of calmodulin genes in a cohort of long-QT syndrome patients without a defined genetic origin identified 2 additional subjects with de novo mutations in CALM1. Mutation carriers had recurrent cardiac arrest secondary to ventricular tachyarrhythmias, severely prolonged QTc interval, and evidence of electrically unstable myocardium (T-wave alternans). Most carriers exhibited neurological deficits (epilepsy, neurodevelopmental delays) of variable severity that could be attributed to brain injury secondary to cardiac arrest or possibly to enhanced susceptibility to neuronal injury in the setting of circulatory insufficiency. Mutant calmodulin proteins exhibited reduced affinity for Ca2+ predicted to disrupt critical functions of calmodulin that would be arrhythmogenic. Our findings provide a genetic origin for ventricular arrhythmias during infancy and illustrate the phenotypic and biochemical consequences of human calmodulin mutations. Calmodulin genes should perhaps be screened in severe, early-onset cardiac arrhythmias. See p 1009.
Real-Time Left Ventricular Pressure-Volume Loops During Percutaneous Mitral Valve Repair With the MitraClip System
There is a lack of physiologic understanding of the mechanisms by which mitral valve repair may affect hemodynamic profiles, left ventricular (LV) loading conditions, and contractility. The MitraClip system is increasingly used for mitral valve repair in patients at high surgical risk and allows us to study the acute effects of reducing mitral regurgitation on the LV in a human beating heart model. This is clinically important because >50% of patients treated worldwide by percutaneous mitral valve repair are patients with functional mitral regurgitation and reduced LV ejection fraction. Additionally, surgical studies have reported poor hemodynamic outcomes in patients with low LV ejection fraction after surgical mitral valve repair or replacement. In contrast, the present study demonstrates, using advanced hemodynamic monitoring with real-time pressure-volume loops, that percutaneous mitral valve repair has no adverse effect on LV contractility, reduces LV preload, and slightly increases LV afterload. These effects translate into favorable hemodynamic outcomes (decrease in pulmonary pressures, increase in cardiac index) even in patients with very low ejection fraction at baseline. Thus, the present study suggests that percutaneous mitral valve repair is safe in patients with poor LV contractility and could be considered a therapeutic option in patients who are poor candidates for surgery. Furthermore, real-time pressure-volume measurements may be used to monitor immediate changes in LV loading conditions and contractility during the MitraClip procedure, particularly in high-risk patients with very low ejection fraction. See p 1018.
Cytotoxic and Proinflammatory CD8+ T Lymphocytes Promote Development of Vulnerable Atherosclerotic Plaques in ApoE-Deficient Mice
Rupture of vulnerable advanced atherosclerotic plaques complicated by thrombotic arterial occlusion is the leading cause of global mortality arising from myocardial infraction and stroke. Rupture-prone plaques are characterized by abundant apoptosis, large necrotic cores, and thin fibrous caps, the genesis of which is unknown. Arterial infiltration by inflammatory immune cells, initiated by lipid entry, is fundamental for the development of atherosclerosis. Although CD8+ T cells compose up to 50% of lymphocytes in advanced human atherosclerotic lesions, their role in atherosclerosis remains poorly understood. Given that CD8 T cells are professional cytotoxic T cells, we examined their role in the genesis of vulnerable, atherosclerotic plaques. With the use of loss and gain of function approaches, we provide definitive evidence that CD8+ T cells promote atherosclerosis development by perforin and granzyme B–dependent cytotoxic cell death of macrophages, vascular smooth muscle cells, and endothelial cells that contribute to the abundant apoptosis, necrotic cores, and thinned caps of vulnerable plaques. The atherogenic role of CD8 T cells is further augmented by their production of tumor necrosis factor α that promotes inflammation in the plaque. Thus CD8+ T cells, being the most abundant lymphocyte population in advanced human atherosclerotic lesions, is important not only for accelerating inflammatory changes in lesions but also in destabilizing the plaque. Our findings have implications for clinical practice. CD8+ T cell–targeted depletion, alone or in combination with lipid reduction by statins, has potential to reduce mortality from heart attacks and strokes by limiting plaque progression and reducing the risk of plaque rupture and associated thrombotic events. See p 1028.
- © 2013 American Heart Association, Inc.
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- Calmodulin Mutations Associated With Recurrent Cardiac Arrest in Infants
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