Christopher M. Rembold

Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine.

Continuing Medical Education Course for Use of Carotid Ultrasound to Identify Subclinical Vascular Disease and Evaluate Cardiovascular Disease Risk: A Consensus Statement for the American Society of Echocardiography Carotid Intima-Media Thickness Task Force Accreditation Statement The American Society of Echocardiography is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American Society of Echocardiography designates this educational activity for a maximum of 1 AMA PRA Category 1 Credits ™. Physicians should only claim credit commensurate with the extent of their participation in the activity. ARDMS and CCI recognize ASEs certificates and have agreed to honor the credit hours toward their registry requirements for sonographers. The American Society of Echocardiography is committed to resolving all conflict of interest issues, and its mandate is to retain only those speakers with financial interests that can be reconciled with the goals and educational integrity of the educational program. Disclosure of faculty and commercial support sponsor relationships, if any, have been indicated. Target Audience 1. Physicians, physicians assistants, and nurses with an interest in cardiac and vascular imaging, preventive cardiology, and cardiovascular disease risk assessment. 2. Ultrasonographers with interest in vascular imaging and cardiovascular disease risk assessment. Objectives Upon completing this activity, participants will be able to: 1. Describe the rationale for using carotid ultrasound to identify subclinical vascular disease and to evaluate cardiovascular disease risk. 2. Explain the application of carotid ultrasound to cardiovascular disease risk assessment. 3. Describe the scanning technique for identifying subclinical vascular disease using carotid ultrasound. 4. Explain the key components of interpreting carotid ultrasound studies for cardiovascular disease risk assessment. Authors Disclosures James H. Stein, MD, FASE: Research grants: Siemens Medical Solutions, Sonosite Intellectual property: listed as the inventor of Patent #US 6,730,0235 Ultrasonic Apparatus and Method for Providing Quantitative Indication of Risk of Coronary Heart Disease. It has been assigned to the Wisconsin Alumni Research Foundation. Emile R. Mohler III, MD: Speakers bureau for Merck, BMS-Sanofi and AstraZeneca; Research grant support from BMS-Sanofi, Pfizer and GSK. Christopher M. Rembold, MD: Advisory Board for Sonosite. Estimated Time to Complete This Activity: 1 hour

Reduced time in bed and obstructive sleep-disordered breathing in children are associated with cognitive impairment

OBJECTIVE. The purpose of this study was to determine if reduced time in bed as well as the degree of obstructive sleep-disordered breathing predicted the risk of impaired cognitive function in children with adenotonsillar hypertrophy suspected of having obstructive sleep-disordered breathing. DESIGN. We studied 56 children, aged 6 to 12 years, with adenotonsillar hypertrophy referred for suspected obstructive sleep-disordered breathing. Children were given a sleep diary and underwent wrist actigraphy for 6 consecutive days and nights. On day 7, the children were given general cognitive tests, memory tests, and continuous performance tests followed by attended polysomnography that night. Parents completed snoring and behavior questionnaires. RESULTS. Shorter mean time in bed for 6 nights and a history of nightly snoring were highly predictive of lower scores for the vocabulary and similarities cognitive function tests. Children who had a mean time in bed of 557 minutes and did not snore nightly were predicted to have vocabulary and similarities scores more than 1 standard deviation higher than children who had a mean time in bed of 521 minutes and snored nightly. Shorter mean time in bed and the log of the apnea hypopnea index also predicted lower vocabulary and similarities scores. Greater night to night variability in time in bed was significantly predictive of lower vocabulary and similarities scores, but variability was not as predictive as mean time in bed. Neither mean time in bed nor the coefficient of variation of time in bed predicted other cognitive or behavioral scores. CONCLUSIONS. Short or variable time in bed and nightly snoring or higher apnea hypopnea index predicted impaired vocabulary and similarities scores in children with adenotonsillar hypertrophy suspected of having obstructive sleep-disordered breathing. The degree of cognitive impairment attributable to short time in bed and obstructive sleep-disordered breathing is clinically very significant.

Usefulness of carotid intimal medial thickness and Flow-Mediated dilation in a preventive cardiovascular practice

I 1995, the University of Virginia started measuring common/mean carotid intimal medial thickness (IMT) and post–ischemia-induced flow-mediated dilation (FMD) as measures of subclinical arteriosclerosis. These tests were performed in patients with intermediate cardiovascular risk based on standard risk factors. IMT is a direct measure of carotid arteriosclerosis and an indirect measure of generalized atherosclerosis.1 O’Leary et al2 found that increased common carotid IMT predicted myocardial infarctions in elderly patients. FMD is a measure of nitric oxide release from the forearm arterial endothelium.3,4 In patients with a healthy endothelium, forearm ischemia induces greater nitric oxide release, and therefore, greater brachial artery dilation. Endothelial dysfunction is one the first abnormalities found in arteriosclerosis,5 dyslipidemia,6 and type 2 diabetes.7,8 Since 1995, 968 patients had FMD and IMT measured at the University of Virginia. It is known that age is a predictor of IMT9; FMD is less well characterized. Celermajer et al5 studied brachial and superficial femoral artery dilation and found an inverse relation between arterial diameter and percent artery dilation. We sought to more carefully characterize brachial artery FMD in addition to IMT. Therefore, we evaluated our cohort of patients to determine how to best interpret FMD and IMT results based on patient characteristics. • • • This investigation was performed retrospectively. All IMT and FMD studies performed at the University of Virginia were entered into a clinical database. For this analysis, a second database was created on July 17, 2002 that did not include any identifiers to a patients’ identity, as required by the University of Virginia’s Human Investigation Committee. The database included FMD, preischemic brachial artery diameter, common carotid IMT, systolic blood pressure, diastolic blood pressure, age, gender, height, weight, and histories of hypertension, smoking, or diabetes mellitus. The database was analyzed with SAS software (SAS Institute, Cary, North Carolina). There was no outside funding for this investigation. FMD was measured after an overnight fast. A blood pressure cuff was placed on the left upper arm (proximal to the brachial artery), and electrocardiography leads were attached. Blood pressure was measured after a 5-minute rest period. Cross-sectional and longitudinal brachial artery diameter was imaged with a Toshiba Powervision 6000 SSA370A ultrasound machine (Otawara-Shi, Tochigi, Japan) with an 11MHz vascular probe positioned distally to the blood pressure cuff. One cross-sectional brachial artery diFrom the Cardiovascular Division, Departments of Internal Medicine and Physiology, University of Virginia Health System, Charlottesville, Virginia. Dr. Christopher M. Rembold’s address is: Box 801395, Cardiovascular Division, University of Virginia Health System, Charlottesville, Virginia 22908-1395. E-mail: crembold@virginia.edu. Manuscript received December 10, 2003; revised manuscript received and accepted February 27, 2003. TABLE 1 Summary Statistics and Univariate and Multivariate Correlation Coefficients (r values) for Prediction of Brachial Artery Flow-mediated Dilation (FMD) on the Subset of Patients Without Known Arteriosclerosis Vascular Disease and Not Taking Medications (n 313)

Caldesmon and heat shock protein 20 phosphorylation in nitroglycerin- and magnesium-induced relaxation of swine carotid artery

Nitrovasodilators, high extracellular Mg(2+), and some other relaxing agents can cause smooth muscle relaxation without reductions in myosin regulatory light chain (MRLC) phosphorylation. Relaxations without MRLC dephosphorylation suggest that other regulatory systems, beyond MRLC phosphorylation, are present in smooth muscle. We tested whether changes in caldesmon phosphorylation, heat shock protein 20 (HSP20) phosphorylation, or intracellular pH (pH(i)) could be responsible for relaxation without MRLC dephosphorylation. In unstimulated tissues, caldesmon was phosphorylated 1.02+/-0.10 mol P(i)/mol caldesmon (mean+/-1 S.E.M.), HSP20 was phosphorylated 0.005+/-0.003 mol P(i)/mol HSP20, and estimated pH(i) was 7.21+/-0.07. Histamine stimulation induced a contraction, an intracellular acidosis, but did not significantly change caldesmon or HSP20 phosphorylation. Addition of nitroglycerin induced a relaxation, significantly increased HSP20 phosphorylation to 0.18+/-0.02 mol P(i)/mol HSP20, did not significantly change caldesmon phosphorylation, and pH(i) returned to near unstimulated values. Increase in extracellular Mg(2+) to 10 mM induced a relaxation, but did not significantly change HSP20 or caldesmon phosphorylation. These data suggest that changes in caldesmon phosphorylation, HSP20 phosphorylation, or pH(i) cannot be the sole explanation for relaxation without MRLC dephosphorylation. However, it is possible that HSP20 phosphorylation may be involved in nitroglycerin-induced relaxation without MRLC dephosphorylation.

Localization of heat shock protein 20 in swine carotid artery

BackgroundCyclic nucleotides can relax vascular smooth muscle by mechanisms distal to myosin regulatory light chain (MRLC) phosphorylation. This mechanism, termed relaxation without MRLC dephosphorylation, may be regulated by ser16 phosphorylation of heat shock protein 20 (HSP20).ResultsConfocal imaging of HSP20 in smooth muscle tissues revealed that HSP20 was present throughout the cytoplasm, although some focal regions of the cytoplasm were found to contain more HSP20 than the remaining cytoplasm. The distribution of HSP20 within the cytoplasm was not altered by histamine, forskolin, or nitroglycerin.ConclusionCytoplasmic localization of HSP20 is consistent with a potential function of HSP20 as a regulator of smooth muscle contractile force.

Heat induced HSP20 phosphorylation without increased cyclic nucleotide levels in swine carotid media

BackgroundHeat pretreatment of swine carotid artery has been shown to increase ser16-heat shock protein 20 (HSP20) phosphorylation and suppress force, i.e., reduce force with only minimal reduction in ser19-myosin regulatory light chain (MRLC) phosphorylation.ResultsWe further investigated this response in intact histamine stimulated swine carotid artery rings. There was a heat threshold such that increased ser16-HSP20 phosphorylation and force suppression were observed between 43°C and 46°C. The increased ser16-HSP20 phosphorylation persisted up to 16 hours after 44.5°C heat treatment. Pretreatment of swine carotid media at 44.5°C increased ser16-HSP20 phosphorylation without increases in [cAMP] or [cGMP], suggesting an alternate mechanism, perhaps phosphatase inhibition, for the increase in ser16-HSP20 phosphorylation. Heat pretreatment at 47.5°C reduced force by decreasing MRLC phosphorylation rather than by large increases in ser16-HSP20 phosphorylation. HSP20 phosphorylation at the putative PKC site did not change with any treatment.ConclusionThese results demonstrate that multiple mechanisms can induce force suppression that is correlated with ser16-HSP20 phosphorylation: 1) nitrovasodilators via cGMP, 2) forskolin via cAMP, and 2) thermal stress in a cyclic nucleotide independent manner.

Force augmentation and stimulated actin polymerization in swine carotid artery

The phenomenon of posttetanic potentiation, in which a single submaximal contraction or series of submaximal contractions strengthens a subsequent contraction, has been observed in both skeletal and cardiac muscle. In this study, we describe a similar phenomenon in swine carotid arterial smooth muscle. We find that a submaximal K(+) depolarization increases the force generation of a subsequent maximal K(+) depolarization; we term this force augmentation. Force augmentation was not associated with a significant increase in crossbridge phosphorylation or shortening velocity during the maximal K(+) depolarization, suggesting that the augmented force was not caused by higher crossbridge phosphorylation or crossbridge cycling rates. We found that the characteristics of the tissue before the maximal K(+) depolarization predicted the degree of force augmentation. Specifically, measures of stimulated actin polymerization (higher prior Y118 paxillin phosphorylation, higher prior F-actin, and transition to a more solid rheology evidenced by lower noise temperature, hysteresivity, and phase angle) predicted the subsequent force augmentation. Increased prior contraction alone did not induce force augmentation since readdition of Ca(2+) to Ca(2+)-depleted tissues induced a partial contraction that was not associated with changes in noise temperature or with subsequent force augmentation. These data suggest that stimulated actin polymerization may produce a substrate for increased crossbridge mediated force, a process we observe as force augmentation.

Oral L-arginine can reverse digital necrosis in Raynaud’s phenomenon

Raynauds phenomenon is characterized by transient reduction in blood supply through the small arteries in the hands and feet. Severe Raynauds phenomenon can cause digital necrosis. It has been hypothesized that nitric oxide may have a role in Raynauds phenomenon. We report two cases in which oral L-arginine reversed digital necrosis in Raynauds phenomenon and two additional cases in which the symptoms of severe Raynauds phenomenon were improved with oral L-arginine. These reports suggest that a defect in nitric oxide synthesis or metabolism is present in Raynauds phenomenon. They also suggest a potential role for oral L-arginine therapy in Raynauds phenomenon, especially in Raynauds phenomenon with digital necrosis.

Mechanisms involved in increased sensitivity to adenosine A2A receptor activation and hypoxia-induced vasodilatation in porcine coronary arteries

Hypoxia-induced coronary vasorelaxation is a compensatory mechanism increasing blood flow. We hypothesized that hypoxia shares pathways with adenosine and causes vasorelaxation through the adenosine A(2A) receptor and force suppression by increasing cAMP and phosphorylated heat shock protein (HSP)20. Adenosine receptors in porcine left anterior descending coronary arteries (LAD) were examined by RT-PCR and isometric tension recording in myographs. Vasorelaxation was induced by adenosine, 1% oxygen, or both in the absence or presence of ZM241385, an adenosine A(2A) receptor antagonist. cAMP was determined by ELISA and p-HSP20/HSP20 and p-MLC/MLC were determined by immunoblotting and densitometric analyses. In coronary arteries exposed to 1% oxygen, there was increased sensitivity to adenosine, the adenosine A2 selective agonist NECA, and the adenosine A(2A) selective receptor agonist CGS21680. ZM241385 shifted concentration-response curves for CGS21680 to the right, whereas the adenosine A1 antagonist DPCPX, the adenosine A2B receptor antagonist MRS1754 and the adenosine A3 receptor antagonist MRS1523 failed to reduce vasodilatation induced by CGS21680. 1% oxygen or adenosine increased cAMP accumulation and HSP20 phosphorylation without changing T850-MYPT1 and MLC phosphorylation. ZM241385 failed to change 1% oxygen-induced vasodilation, cAMP accumulation, HSP20 phosphorylation and MLC phosphorylation. The PKA inhibitor Rp-8-CPT-cAMPS significantly reduced vasorelaxation induced by 1% oxygen or CGS21680. Our findings suggest that the increased sensitivity to adenosine, NECA, and CGS21680 at 1% oxygen involves adenosine A(2A) receptors. Adenosine and 1% oxygen induce vasorelaxation in PGF2α-contracted porcine coronary arteries partly by force suppression caused by increased cAMP and phosphorylation of HSP20.

Coenzyme Q10 Supplementation in Orthostatic Hypotension and Multiple-System Atrophy: A Report on 7 Cases

BACKGROUNDnMultiple-system atrophy is a neurologic disorder characterized by orthostatic hypotension, Parkinsonian signs, and cerebellar signs. Mutations in COQ2, an enzyme involved in coenzyme Q10 synthesis, were recently associated with familial and sporadic cases of multiple-system atrophy. I hypothesized that people with orthostatic hypotension with or without other symptoms of multiple-system atrophy might benefit from oral coenzyme Q10 administration.nnnMETHODSnSeven patients with symptomatic orthostatic hypotension were treated in an unrandomized manner with 257xa0±xa037xa0mg coenzyme Q10 daily for 10xa0±xa03 months.nnnRESULTSnBefore starting coenzyme Q10, patients systolic blood pressure fell 30xa0±xa04xa0mmxa0Hg upon standing from a sitting position. After treatment with coenzyme Q10, their systolic blood pressure decreased 7xa0±xa05xa0mmxa0Hg upon standing from a sitting position (Pxa0=xa0.007 for change in systolic blood pressure decrease by paired t test).nnnCONCLUSIONSnThese data suggest that orthostatic hypotension could improve with coenzyme Q10 administration and that a randomized clinical trial to test this hypothesis should be begun.