Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Clinical Usefulness, Angiographic Characteristics, and Safety Evaluation of Intracoronary Acetylcholine Provocation Testing Among 921 Consecutive White Patients With Unobstructed Coronary Arteries
- Microstructural Impact of Ischemia and Bone Marrow–Derived Cell Therapy Revealed With Diffusion Tensor Magnetic Resonance Imaging Tractography of the Heart In Vivo
- Microtubule-Mediated Defects in Junctophilin-2 Trafficking Contribute to Myocyte Transverse-Tubule Remodeling and Ca2+ Handling Dysfunction in Heart Failure
- Survey of a Protocol to Increase Appropriate Implementation of Dispatcher-Assisted Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest
- Cyclooxygenase-2 in Endothelial and Vascular Smooth Muscle Cells Restrains Atherogenesis in Hyperlipidemic Mice
- Aberrant Chloride Intracellular Channel 4 Expression Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension
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Clinical Usefulness, Angiographic Characteristics, and Safety Evaluation of Intracoronary Acetylcholine Provocation Testing Among 921 Consecutive White Patients With Unobstructed Coronary Arteries
Coronary spasm can cause myocardial ischemia and angina in patients with and those without obstructive coronary artery disease. However, provocation tests using intracoronary acetylcholine provocation testing (ACH test) are rarely performed in clinical routine in the United States and Europe. In this study, we assessed the clinical usefulness, angiographic characteristics, and safety of the ACH test in white patients with unobstructed coronary arteries. Our study shows that the ACH test is a safe method for the assessment of coronary vasomotor function and that patients with angina and angiographically unobstructed coronary arteries often experience coronary spasm of the epicardial and microvascular coronary vessels. If such an abnormality is diagnosed (eg, with intracoronary acetylcholine provocation testing), this not only leads to reassurance of the patient that a cause for the symptoms is found, but also enables the physician to initiate the appropriate medical therapy (eg, calcium channel blockers and nitrates aimed at reducing morbidity and mortality). Moreover, this may also have important implications on our healthcare systems, because most health care–related costs in patients with unobstructed coronary arteries are due to recurrent or ongoing angina pectoris. However, consistent definitions for coronary vasomotor disorders are needed to be able to compare the frequency of such disorders between different ethnic groups (eg, whites versus Asians). In addition, based on the favorable safety profile of the ACH test as shown in this study, we hope to encourage interventionalists to add the ACH test to their portfolio in search of functional causes for angina, especially in patients with unobstructed coronary arteries. See p 1723.
Microstructural Impact of Ischemia and Bone Marrow–Derived Cell Therapy Revealed With Diffusion Tensor Magnetic Resonance Imaging Tractography of the Heart In Vivo
The myocardium has a complex microstructure. Fibers in the midmyocardium are circumferential, whereas those in the subendocardium form a positive helix and those in the subepicardium a negative helix. Diffusion-weighted magnetic resonance imaging has the ability to resolve this architecture but is extremely challenging to perform in the heart. In the present report, we describe an approach to perform diffusion tensor magnetic resonance imaging tractography of the heart in vivo. Using this technique, we show that the microstructure of the heart is highly perturbed in acute ischemia but can recover to some degree as the edema associated with acute injury resolves. We further show that diffusion tensor magnetic resonance imaging tractography can be used to monitor the response to cell therapy in the heart. In the present study, bone marrow mononuclear cells were used and produced a neutral or negative microstructural response in all but 1 case. Although much of this study involved animal models, we also describe the use of the technique in normal human volunteers. Ongoing technical improvements have the potential to make diffusion tensor magnetic resonance imaging tractography a mainstream clinical tool, which could be used to assess myocardial viability in those not able to receive gadolinium. The technique also has the potential to help guide the development of regenerative and stem cell therapies in the heart, facilitate better risk prediction, and support more individualized therapy of heart failure and arrhythmias. Although diffusion tensor magnetic resonance imaging is complex, no regulatory or economic barriers to its translation exist. The outlook for the technique is thus very promising. See p 1731.
Microtubule-Mediated Defects in Junctophilin-2 Trafficking Contribute to Myocyte Transverse-Tubule Remodeling and Ca2+ Handling Dysfunction in Heart Failure
Evidence from human patients and animal models of heart failure demonstrate that an increase in microtubule density (“densification”) is strongly associated with myocardial dysfunction, and microtubule depolymerization attenuates cardiac dysfunction. However, until now, the mechanism by which microtubule densification results in loss of cardiac function remained poorly understood. We demonstrated recently that disruption of myocyte transverse-tubule (T-tubule) integrity is a key event in the development and progression of heart failure. T-tubules are orderly membrane invaginations that are essential for cardiac excitation–contraction coupling. Using human heart failure samples, in situ imaging of intact rodent hearts, and studies with cultured murine adult cardiomyocytes, to our knowledge, we provide the first evidence for a mechanistic link between densification of microtubules and T-tubule remodeling in heart failure. Our data implicate redistribution of junctophilin-2, a critical safeguard of the cardiac dyad, as a mechanism by which microtubule densification leads to T-tubule disruption, loss of excitation–contraction coupling, and ultimately heart failure. Our study identifies a novel mechanism for junctophilin-2 dysregulation: microtubule densification-mediated junctophilin-2 mistrafficking. We also resolve the long-standing experimental question of how cultured adult cardiomyocytes undergo progressive loss of T-tubule integrity. Together, our findings provide novel insights into the roles of microtubules and junctophilin-2 in the pathogenesis of heart failure. These data have important implications for future development of new therapeutic strategies to ameliorate cardiac remodeling and the progression of heart failure. See p 1742.
Survey of a Protocol to Increase Appropriate Implementation of Dispatcher-Assisted Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest
Dispatcher-assisted cardiopulmonary resuscitation (DA-CPR), called “just in time” instruction, has great potential to increase the rate of bystander CPR and to possibly improve survival rate. The American Heart Association announced a standard protocol for dispatchers’ recognition of cardiac arrest that recommended 2 key questions. One concerned the patient’s loss of consciousness, and the other concerned the patient’s quality of breathing. In 2007, we implemented the new 2007 DA-CPR protocol designed to improve dispatchers’ recognition of cardiac arrest. Because the 2007 protocol encouraged dispatchers to initiate CPR instructions using supplementary key words suggestive of cardiac arrest, in addition to the 2 key questions, dispatchers initiated DA-CPR instructions even when consciousness or respiration was unknown. This study shows that our 2007 protocol using the supplementary key word system is safe and may be more sensitive than the standard protocol using the 2 key question system. We also identified some key words that may be useful for detecting out-of-hospital cardiac arrest and elucidated the characteristics of out-of-hospital cardiac arrests and bystanders that were associated with the provision of DA-CPR and bystander compliance with DA-CPR. To further improve the rates of providing DA-CPR and survival, dispatchers should be aware of these characteristics. Moreover, the public perception that a dispatcher is merely a staff person who sends an ambulance should be altered. Systematic education of both dispatchers and citizens is essential. We believe that the application of our approach in areas with a low incidence of DA-CPR will increase the rates of bystander CPR and survival from out-of-hospital cardiac arrest. See p 1751.
Cyclooxygenase-2 in Endothelial and Vascular Smooth Muscle Cells Restrains Atherogenesis in Hyperlipidemic Mice
Placebo-controlled trials of cyclooxygenase-2 (COX-2)–selective nonsteroidal anti-inflammatory drugs have revealed higher cardiovascular risks associated with myocardial infarction, hypertension, heart failure, and stroke consequent to the suppression of cardioprotective prostanoids, particularly prostacyclin. We have reported previously that global postnatal deletion of COX-2 accelerates atherogenesis and that deletion of the receptor for prostaglandin I2 leads to initiation and early development of atherosclerosis in mice. Because of the contrasting biological impact of products of COX-2 and their varied predominance in cells during disease evolution, we have attempted to address the role of COX-2 in a tissue-specific manner. We have reported that deletion of COX-2 in myeloid cells retarded atherogenesis and that deletion in T cells had a minimal effect on lesion burden. In the present study, when mice were placed on a high-fat diet, deletion of COX-2 in endothelial or vascular smooth muscle cells or both increased systolic blood pressure and accelerated atherogenesis coincident with suppression of prostaglandin I2 biosynthesis. Suppression of COX-2 removes a constraint on enzyme expression in lesional macrophages, reflecting the interplay of the enzyme in cells relevant to the disease. Having a better understanding of the cell-specific biology of COX-2 deletion, we may advance the prospect for cell-targeted nonsteroidal anti-inflammatory drug delivery and minimize the cardiovascular adverse effects of these drugs. See p 1761.
Aberrant Chloride Intracellular Channel 4 Expression Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension
The endothelial layer of the pulmonary vasculature acts as a barrier to the underlying tissue, limiting the influx of inflammatory cells, growth factors, and cytokines. Endothelial dysfunction with changes in vascular endothelial permeability is thought to occur early in the pathogenesis of pulmonary hypertension in both animal models and human pulmonary arterial hypertension. Chloride intracellular channel 4 (CLIC4) is a redox-sensitive intracellular protein that interacts with cytoskeletal proteins, regulating cell morphology and endothelial tube formation during vasculogenesis. It is highly expressed in the endothelium of remodeled pulmonary vessels, including plexiform lesions, in the lungs of patients with pulmonary arterial hypertension, and in blood-derived endothelial cells from this patient group. We show that overexpression of CLIC4 in pulmonary vascular endothelial cells in culture is proproliferative and proangiogenic and compromises endothelial barrier integrity via the activation of the transcription factors hypoxia inducible factor and nuclear factor-κB. Inhibiting CLIC4 expression restores normal angiogenic behavior in blood-derived endothelial cells from patients with pulmonary arterial hypertension. CLIC4 gene deletion protects mice from hypoxia-induced pulmonary hypertension. Collectively, these observations argue that CLIC4 has a major role in pulmonary vascular homeostasis. Strategies that restore normal pulmonary endothelial CLIC4 expression may be beneficial in patients with pulmonary arterial hypertension. See p 1770.
- © 2014 American Heart Association, Inc.
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