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Abstract The development of commercially available assays from the measurement of enzyme activity to mass concentrations of proteins, especially the assays of cardiac troponin I and T, has been the most important innovation in the field of cardiovascular laboratory diagnostics over the decade. The availability of a simple, rapid test using whole blood to facilitate processing and to reduce the turnaround time could improve the management of patients presenting with chest pain. The aim of this study was to evaluate the analytical and clinical performance of a new time-resolved fluorometry-based immunology technology using the cardiac marker and high-sensitivity C-reactive protein assays. In addition, the use of high-sensitivity C-reactive protein assay for the investigation of patients with acute atrial fibrillation and the influence of heparin for cardiac marker assays were studied. The levels of precision attained with pooled serum and plasma samples and control materials were acceptable. The assays were found to be linear within the ranges tested. The correlation coefficient between the Innotrac Aio! 1st generation cTnI and Abbott AxSYM cTnI assays was 0.960, and the slope was 0.07. The correlations between the 2nd generation Innotrac Aio!, Access AccuTnI and Abbott AxSYM assays were good, but there were biases between the methods. The correlation coefficients between the Innotrac Aio! and Abbott AxSYM CK-MB and myoglobin assays were 0.995 and 0.971, respectively, but the Innotrac Aio! CK-MB assay yielded about 9% higher values than the Abbott assay. The correlations between Innotrac Aio! usCRP and Cobas Integra CRP latex and between Innotrac Aio! usCRP and Hitachi CRP (Latex ) HS were good. Furthermore, the sample material correlation studies showed no significant differences when the Innotrac Aio! System was used. However, the mean Abbott AxSYM CK-MB values and the cTnI values for heparin plasma samples were 17% higher and about 15% lower than for serum samples, respectively. In the investigation of CRP levels in patients with acute atrial fibrillation CRP tended to be higher in the patients with acute FA, and there was a positive correlation between the concentrations of CRP and IL-6. The results demonstrate the excellent analytical performance of the Innotrac Aio! 2nd generation cTnI, myoglobin, CK-MB and usCRP assays, and all the matrices, including serum, plasma and whole blood, are suitable sample matrices to be used with these methods without further standardization.

Background-Previous studies have documented a high prevalence of atrial fibrillation (AF) in individuals with obstructive sleep apnea (OSA). Central sleep apnea (CSA) has been associated with AF in patients with heart failure. However, data from prospective cohorts are sparse and few studies have distinguished the associations of obstructive sleep apnea from CSA with AF in population studies. Methods and Results-We assessed the association of obstructive sleep apnea and CSA with incident AF among 2912 individuals without a history of AF in the SHHS (Sleep Heart Health Study), a prospective, community-based study of existing ("parent") cohort studies designed to evaluate the cardiovascular consequences of sleep disordered breathing. Incident AF was documented by 12-lead ECG or assessed by the parent cohort. obstructive sleep apnea was defined by the obstructive apnea-hypopnea index (OAHI). CSA was defined by a central apnea index >= 5 or the presence of Cheyne Stokes Respiration. Logistic regression was used to assess the association between sleep disordered breathing and incident AF. Over a mean of 5.3 years of follow-up, 338 cases of incident AF were observed. CSA was a predictor of incident AF in all adjusted models and was associated with 2-to 3-fold increased odds of developing AF (central apnea index >= 5 odds ratio [OR], 3.00, 1.40-6.44; Cheyne-Stokes respiration OR, 1.83, 0.95-3.54; CSA or Cheyne-Stokes respiration OR, 2.00, 1.16-3.44). In contrast, OAHI was not associated with incident AF (OAHI per 5 unit increase OR, 0.97, 0.91-1.03; OAHI 5 to <15 OR, 0.84, 0.59-1.17; OAHI 15 to <30 OR, 0.93, 0.60-1.45; OAHI >= 30 OR, 0.76, 0.42-1.36). Conclusions-In a prospective, community-based cohort, CSA was associated with incident AF, even after adjustment for cardiovascular risk factors.

Blood pressure measurement has been and continues to be one of the most important measurements in clinical practice and yet, it remains one of the most inaccurately performed. The use of oscillometric blood pressure measurement monitors has become common in hospitals, clinics and even homes. Typically, these monitors assume that the heartbeat rate remains stable, which is contrary to what happens in atrial fibrillation. In this thesis, a new method that provides a more precise estimate of Mean Arterial Pressure (MAP) is proposed using anon-invasive oscillometric blood pressure monitor. The proposed method is based on calculating a ratio of peak amplitude to trough amplitude for every pulse, then identifying where the ratio first reaches a value of 2. The performance of the proposed method is assessed by comparing the accuracy and variability of the readings against reference monitors -first in healthy subjects, then in atrial fibrillation patients. In healthy subjects and in atrial fibrillation patients, the proposed method achieved a performance accuracy that is well within the ANSI/AAMI SP10 protocol requirements of the reference monitors. The presence of atrial fibrillation diminished the performance of the reference monitor by increasing the variability of the reference readings. The proposed algorithm, on the other hand, performed better by achieving substantially lower variability in the readings than the reference device.

This project set out to derive a prediction rule based on preoperative clinical variables to identify patients with high risk of developing atrial fibrillation following cardiac surgery. Methods: Prospectively collected data from a perioperative database was corroborated with chart review to identify eligible patients who had non-emergent surgery in 2010. Details on 28 preoperative variables were collected and significant predictors (p<0.2) were inserted into multivariable logistic regression and recursive partitioning. Results: 305 (30.5%) of 999 patients developed new onset postoperative atrial fibrillation. Eleven variables were significantly associated with atrial fibrillation, however, both final models included only three: left atrial dilatation, mitral valve disease and age. Bootstrapping with 5000 samples confirmed that both final models provide consistent predictions. Coefficients from the logistic regression model were converted into a simple seven point predictive score. Conclusions: This simple risk score can identify patients at higher risk of developing atrial fibrillation after cardiac surgery.

Calciphylaxis is a late complication of end-stage renal disease (ESRD) affecting ~1–4% patients on hemodialysis, with a mortality rate of >50%. Cutaneous manifestations include necrotic, non-healing ulcers most commonly in the lower extremities. Visceral organ vasculopathy often occurs as well. Warfarin is a possible risk factor due to its effect on the inhibition of Matrix GLa protein. Under the influence of hyperphosphatemia, vascular smooth muscle cells can undergo ectopic calcification in absence of the MGLa protein. The issue of anticoagulation in dialysis patients has therefore been debated, as Warfarin may potentially induce vasculopathy and increase risk of bleeding, such as hemorrhagic strokes and GI bleeds. A 64-year-old male with ESRD, non-compliant with dialysis, presented with lower extremity pain. Patient was noted to have large, malodorous, bilateral lower extremity ulcers with necrosis and eschars. Punch biopsy of the ulcers demonstrated acute inflammation with calcium deposits and thrombi within the blood vessels, suggestive of Calciphylaxis. Patient was started on Sodium Thiosulfate and Sevelamer for hyperphosphatemia. Atrial fibrillation was incidentally found on EKG, and due to high risk of stroke based on the CHA2DS-VASc score, patient was started on Heparin and bridged to Warfarin on discharge. Patient was readmitted 3 months later to the ICU with septic shock. Lower extremity ulcers appeared to be healing, but he reported several episodes of hematochezia (INR=2.0, hemoglobin=5.2). Warfarin was therefore held and patient was transfused. EGD showed no evidence of upper GI bleed, however patient refused colonoscopy. Patients on dialysis are at increased risk of bleeding due to defective primary hemostasis. The most serious source of bleeding is gastrointestinal, which accounts for 3–7% of all deaths in the dialysis population. Current guidelines for management of atrial fibrillation by the American Heart Association recommend warfarin for oral anticoagulation in patients with ESRD who have a CHA2DS2-VASc score of 2 or greater to prevent thromboembolic events. Our patient with ESRD and Calciphylaxis presented with new-onset atrial fibrillation and therefore started on Warfarin due to high CHA2DS2-VASc score. However patient developed a GI bleed with worsening anemia requiring transfusion, prompting discontinuation of Warfarin. It is therefore questionable whether the risk-benefit assessment based on CHA2DS2-VASc is appropriate for dialysis patients. Unfortunately, all the data available on the subject of Warfarin in ESRD patients are observational without any randomized-clinical trials. Therefore no objective criteria exist to modify the anticoagulation guidelines in dialysis patients.

Atrial fibrillation is the most common type of serious dysrhythmia, with increasing prevalence in older age groups. Thromboembolism is a serious complication seen with atrial fibrillation and can range from ischemic stroke, mesenteric ischemia to acute limb ischemia. The annual incidence of acute limb ischemia secondary to atrial fibrillation is 0.14%[1]. Here we report a case of critical limb ischemia with brachial artery occlusion due to an embolus in a patient with new onset atrial fibrillation. A 90 year-old female patient presented to the hospital with complaints of shortness of breath on exertion, orthopnea and palpitations of one week duration. She denied any chest pain, dizziness, or syncope. Past medical history was significant for longstanding hypertension well controlled with amlodipine and a provoked deep vein thrombosis of the leg 40 years prior to presentation complicated by heparin-induced thrombocytopenia. On examination, she had an irregularly irregular rhythm and an HR in 120s, no murmurs or gallops were appreciated. 12 lead EKG was suggestive of atrial fibrillation with rapid ventricular response. She was started on metoprolol tartrate for rate control and Apixaban for anticoagulation. TSH was normal and serial troponins returned negative. A Transthoracic echocardiogram was obtained and showed an ejection fraction of 55-60%, mildly dilated left atrium, mild MR, there was no evidence of a thrombus or patent foramen ovale. Three hours after the first dose of Apixaban, and right prior to discharge, the patient started complainig of sudden onset sharp pain and paresthesia of the left upper extremity below the elbow. On Inspection, the left upper extremity was pale and cold to touch. Radial and ulnar pulses were absent, confirmed by doppler ultrasound. A stat computed tomography angiography of the left upper extremity showed complete occlusion of the brachial artery at the level of the elbow joint. She was started on Argatroban drip en route for emergent brachial embolectomy after Vascular Surgery consultation. Blood circulation to the arm was fully restored. Apixaban was resumed post-operatively and with clinical improvement, the patient was safely discharged home. Atrial fibrillation, irrespective of the type (persistent, paroxysmal, permanent or silent) leads to increased risk of thromboembolism owing to atrial clot formation[2]. However, the timing of initiation of antithrombotic therapy has been widely discussed and needs to be individualized based on the presence of risk factors for thromboembolism and bleeding. Acute limb ischemia may be defined as sudden loss of blood flow to the limb. The cause being either thrombotic (60%) or embolic (30%). It has been noted that 80% of peripheral emboli originate in the heart secondary to atrial fibrillation[3]. A timely diagnosis and treatment is of utmost importance to decrease morbidity and mortality and to salvage the limb’s functionality. References 1.Thromboembolism in atrial fibrillation Menke J1, Lüthje L, Kastrup A, Larsen J. 2.Writing Committee Members, January CT, Wann LS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014;130(23):e199-e267. doi:10.1161/CIR.0000000000000041. 3.Callum K, Bradbury A. Acute limb ischaemia. BMJ : British Medical Journal. 2000;320(7237):764-767.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13302号 / 論医博第2191号 / 新制||医||1040(附属図書館) / (主査)教授 福原 俊一, 教授 湊谷 謙司, 教授 松村 由美 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13370号 / 論医博第2207号 / 新制||医||1047(附属図書館) / (主査)教授 大鶴 繁, 教授 中山 健夫, 教授 髙橋 良輔 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background: Atrial fibrillation (AF) confers high risk of stroke, but often goes undiagnosed due to difficulties in its diagnosis. AF detection is important in post-stroke populations for secondary prevention and smartwatches have emerged as a promising modality for detecting AF, but little is known about their use in older adults who have experienced a stroke. Methods: This dissertation uses data from the Pulsewatch study, a two-phased trial assessing accuracy, usability, and adherence of smartwatch-based AF detection among older patients after stroke. Analyses performed include: descriptive statistics, linear and logistic regressions, qualitative and mixed-methods analyses, mixed effects modeling, and group-based trajectory modeling. Results: The Pulsewatch system was 91% accurate in detecting AF compared to a clinical gold-standard. Participants found the system easy to use, but indicated that streamlining the smartwatch’s functionalities to focus on passive cardiac monitoring is crucial. Improving battery life to allow for longer wear time would alleviate anxiety in some participants. Participants with previous experience using cardiac rhythm monitors rated the system lower on usability, but overwhelmingly preferred it to previous monitors due to the watch’s comfort, appearance, and convenience. Watch wear decreased over time, and we observed three distinct patterns of decline. No individual-level characteristics were associated with usability or adherence to watch wear. Conclusions: Smartwatches are promising for AF detection in older adults after stroke, though while they offer high accuracy and usability, adherence to wear is low. Strategies to encourage extended watch wear are necessary to realize the potential of smartwatches as a viable cardiac monitoring modality.