Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Permanent Pacemaker Insertion After CoreValve Transcatheter Aortic Valve Implantation: Incidence and Contributing Factors (the UK CoreValve Collaborative)
- Endogenous Circadian Rhythm in Vasovagal Response to Head-Up Tilt
- Total Arch Replacement Combined With Stented Elephant Trunk Implantation: A New “Standard” Therapy for Type A Dissection Involving Repair of the Aortic Arch?
- Disrupted Junctional Membrane Complexes and Hyperactive Ryanodine Receptors After Acute Junctophilin Knockdown in Mice
- Reversal of Hyperlipidemia With a Genetic Switch Favorably Affects the Content and Inflammatory State of Macrophages in Atherosclerotic Plaques
- MicroRNA-100 Regulates Neovascularization by Suppression of Mammalian Target of Rapamycin in Endothelial and Vascular Smooth Muscle Cells
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Permanent Pacemaker Insertion After CoreValve Transcatheter Aortic Valve Implantation: Incidence and Contributing Factors (the UK CoreValve Collaborative)
Transcatheter aortic valve implantation has entered mainstream interventional cardiology as a treatment for aortic stenosis in patients with prohibitively high operative risk. This is a growing cohort of patients globally, given the increased longevity and prevalence of significant comorbidities. The CoreValve Revalving system (CoreValve Medtronic, Luxembourg) is 1 of the 2 prostheses currently in use, and it has been noted to be associated with an increased need for permanent pacemaker implantation. This study represents the largest analysis of the rates of permanent pacemaker implantation in patients receiving a CoreValve implant and uses clinical ECG data to create an electroanatomic model to explain the phenomenon. Consideration of these factors as addressed in this study has not only implications for the future designs of transcatheter aortic valve implantation devices but also immediate clinical impact on the standard of care of this increasingly numerous patient group. See p 951.
Endogenous Circadian Rhythm in Vasovagal Response to Head-Up Tilt
Vasovagal syncope, the most common type of syncope, displays a daily pattern with more occurrences during the morning (6 am to noon). This pattern could be caused by the daily distribution of behavioral/emotional stimuli and/or modulation of physiological responses by the endogenous circadian system (“body clock”). The present study provides strong evidence that the circadian system could contribute to the daily pattern of vasovagal syncope via its influences on hemodynamic and autonomic responses to tilt stressor. We found that the vulnerability to presyncope caused by head-up tilt has a strong endogenous circadian rhythm, with susceptibility 9 times greater at the circadian times between 10:30 pm and 10:30 am compared with between 10:30 am and 10:30 pm. This finding highlights the importance of performing tilt-table tests at similar circadian times when comparing responses of different individuals or the same person before and after treatments for syncope. Additionally, a higher sensitivity may be achieved by performing tilt-table testing during early morning hours or the nighttime. The identified vulnerable period may have relevance to individuals who remain awake or wake up frequently during the nighttime such as night-shift workers, parents feeding their infants, and elderly people with increased nocturia and insomnia. These people may be at higher risk for syncope as a result of their exposure to postural stress during the nighttime. Moreover, the morning broad peak of vasovagal syncope observed in the epidemiological studies might be a combined effect of the endogenous circadian system and daily patterns of external behavioral stimuli. See p 961.
Total Arch Replacement Combined With Stented Elephant Trunk Implantation: A New “Standard” Therapy for Type A Dissection Involving Repair of the Aortic Arch?
The stented elephant trunk procedure was adapted from the conventional elephant trunk procedure. Integrating the reports of Japanese authors, the Hanover group, our surgical team, and others, the stented elephant trunk (frozen elephant trunk) procedure had 2 primary advantages over the conventional surgical repair: good intraoperative handling and good postoperative recovery. Between January 2003 and September 2008, 291 of 544 patients with type A dissection underwent total arch replacement combined with stented elephant trunk implantation. Our experience demonstrated that it was very easy to implant the stented elephant trunk (which was in a bound, compressed state) into the distal aorta. The intimal tear was sealed off where the surgical graft was reached, and the false lumen in the distal aorta was obliterated with thrombus in most patients. Follow-up data illustrated that shrinkage of the entire aorta was obtained. This stabilized the distal aorta after remodeling of the 2 layers of the dissected aortic wall. Therefore, a low prevalence of reoperation on the remaining aorta was observed. A low prevalence of morbidity and mortality was obtained with this technique at our center. Overall, this procedure had good intraoperative handling, promotion of thrombosis of the false lumen in the distal aorta, a reduction of the prevalence of late formation of thoracoabdominal aneurysms, and a decrease in the prevalence of reoperation. The stented elephant trunk procedure may become the next standard treatment in patients with type A dissection involving repair of the aortic arch. See p 971.
Disrupted Junctional Membrane Complexes and Hyperactive Ryanodine Receptors After Acute Junctophilin Knockdown in Mice
Impaired cardiac muscle contraction is a hallmark of congestive heart failure. At the cellular level, excitation-contraction coupling requires proper communication of plasmalemmal voltage-gated Ca2+ channels and Ca2+ release channels on the sarcoplasmic reticulum within junctional membrane complexes (JMC). Disruption of the JMC structure is commonly seen in heart failure and is thought to contribute to contractile failure. Junctophilin-2 (JPH2) has recently been proposed to provide a structural connection between the plasma membrane and sarcoplasmic reticulum within the JMC, although its function has remained unclear because of the lack of adequate animal models. We have developed a novel approach to conditionally reduce JPH2 protein levels using RNA interference. Our studies revealed that acute knockdown of JPH2 leads to loss of cardiac contractility and heart failure in mice. JPH2 was found to determine the spacing between the plasmalemma and sarcoplasmic reticulum membrane, in addition to being required for the structural integrity of JMCs within myocytes. Computational analysis provided further quantitative insights into the relative importance of each of these subcellular defects related to impaired excitation-contraction coupling. Finally, our data showed that JPH2 associates with and facilitates type 2 ryanodine receptor inactivation, thereby preventing diastolic sarcoplasmic reticulum Ca2+ leak that could promote heart failure. Taken together, our studies suggest that downregulation of JPH2 could play an important role in the development of contractile dysfunction in heart failure. See p 979.
Reversal of Hyperlipidemia With a Genetic Switch Favorably Affects the Content and Inflammatory State of Macrophages in Atherosclerotic Plaques
The ultimate cure for atherosclerosis would be the regression of arterial plaques. Discovery research toward this goal has been hampered by limited and sometimes cumbersome animal models. The Reversa mouse combines a standard model of human atherosclerosis, the hyperlipidemic low-density lipoprotein receptor-deficient mouse, with a genetic switch that electively shuts off low-density lipoprotein production. In the present study, arterial plaques were allowed to develop in Reversa mice to a stage mimicking advanced human coronary artery disease, and then the elevated low-density lipoprotein level was severely reduced, thereby simulating aggressive lipid management. The major findings after such lipid reduction were decreases in the content and inflammatory state of the central cell of plaques, macrophages, with the change in total plaque size more modest because of compensatory increases in collagen content. The improvement in macrophage inflammatory status was augmented by treatment with pioglitazone, consistent with the effects of peroxisome proliferator-activated receptor-γ agonists on macrophages in vitro. The results may explain why plaque volume decreases have been modest in recent statin trials despite significant reduction in events and may provide one basis for the cardioprotective effects of pioglitazone in clinical studies. Continued study of this convenient model should lead to an improved understanding of plaque regression at the molecular level. See p 989.
MicroRNA-100 Regulates Neovascularization by Suppression of Mammalian Target of Rapamycin in Endothelial and Vascular Smooth Muscle Cells
The adaptive growth of blood vessels is an important protective mechanism in patients with chronic vascular occlusive disease, and many studies have attempted the therapeutic stimulation of this process as a potential treatment option. However, cytokine- or cell-based approaches have shown limited success so far. Recently, a new regulatory mechanism that determines gene expression was discovered: microRNA (miRNA). miRNAs are short, noncoding regulatory RNAs that regulate protein expression mostly by posttranscriptional repression. In this study, we identified several differentially expressed miRNAs after induction of ischemia in a mouse hind-limb model of neovascularization, among them the downregulated miR-100. We found miR-100 to be a novel regulator of endothelial cell proliferation, sprouting, and tube formation, which is partly mediated by suppression of its proangiogenic target gene the mammalian target of rapamycin (mTOR). In addition, miR-100 is highly expressed in vascular smooth muscle cells and attenuates their proliferation and migration. MiR-100 inhibition in vivo by specific modified oligonucleotide inhibitors (antagomirs) results in the stimulation of blood vessel growth and hind-limb perfusion recovery after femoral artery occlusion. Our data show that miR-100 has antiangiogenic and antiarteriogenic functions and is an endogenous suppressor of mTOR in endothelial cells. Functional control of miR-100 could allow us to develop new tools to treat vascular occlusive diseases in the future by stimulating adaptive blood vessel growth. In addition, our data suggest a potential role of miR-100 in other mTOR-dependent processes such as restenosis and tumor angiogenesis. See p 999.
- © 2011 American Heart Association, Inc.
- Endogenous Circadian Rhythm in Vasovagal Response to Head-Up Tilt
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