BACKGROUND: Previous research has shown that the ventilatory threshold (VT) correlates highly with onset of lactate accumulation and maximal steady-state exercise (MSS) level. Also, studies have shown the VT is useful in prescribing exercise for cardiac patients in that it gives an exercise intensity at which the patient is metabolically stable. METHODS: The purpose of this study was to determine if a MSS response could be achieved at an exercise intensity corresponding to the VT for patients with CAD. A group of 31 patients with CAD performed a maximal effort treadmill exercise test in which respiratory gas exchange was measured. The VT was determined using the V-slope method of computer regression analysis of the plot of carbon dioxide production versus oxygen consumption. Subjects then performed a constant load treadmill test a speed and grade that corresponded to the VT. Heart rate (HR), systolic blood pressure (SBP), and rating of perceived exertion (RPE) evaluated for steady-state responses. If subjects showed a steady-state response in two of these three parameters they were scored as having achieved a maximal steady-state (MSS+) response; those not meeting this standard were scored as failing to achieve maximal steady-state (MSS-) response. Subjects were analyzed as an entire group (N=31), as well as analyzed in subsets according to history of myocardial infarction (MI+, N=20; MI-, N=11) and administration of beta-blocker medications (BB+, N=16; BB-, N=15). RESULTS: Overall, subjects demonstrated significantly more MSS+ responses than MSS- responses (80% Vs 20%, P<0.05). Analysis of the subgroup data showed that it was the patient s with a history of MI (MI+ =85%, P<0.05) and those not receiving beta-blocker medications (BB- = 93%, P<0.05) who had significantly greater proportions of subject achieving MSS+ responses in the fixed load exercise condition. Conversely patient in the MI- (73 %, P < 0.05) and BB (69% P < 0.05) groups showed no significant differences in the number of MSS+ and MSS- responses. CONCLUSIONS: The VT, as measured during ramp exercise testing on the treadmill, provided a basis for establishing a maximal steady-state load in terms of cardiovascular and perceptual variables for 80% of the patients in the CAD study group. The measurements of HR, SBP, and RPE are easily obtained in a clinical setting and thus enable the VT to be used in bringing about a more efficacious exercise prescription. The validity of this method may be questioned, however, for patient with out a history of MI and for those receiving beta-blocker medications. / Master of Science

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20283号 / 医博第4242号 / 新制||医||1021(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 湊谷 謙司, 教授 福原 俊一, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21666号 / 医博第4472号 / 新制||医||1035(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 松田 文彦, 教授 佐藤 俊哉, 教授 Shohab YOUSSEFIAN / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Medicine. Johannesburg, October 2017. / Background: Positron Emission Tomography (PET) is an imaging modality that guides the revascularization management of patients with left ventricular systolic dysfunction secondary to coronary artery disease. Segments of the myocardium demonstrating reduced perfusion and increased or preserved 18FFluorodeoxyglucose (18F-FDG) uptake are considered to be viable and thus suitable for revascularization. The aim of our study was to determine the prevalence of myocardial viability as determined by FDG-PET in our local cohort and to compare our prevalence of myocardial viability to data published elsewhere. Methods: We retrospectively reviewed 240 consecutive 99mTc-sestamibi myocardial perfusion Gated Single Photon Emission Tomography (SPECT) and 18FFDG PET reports of patients referred for evaluation of myocardial viability between January 2009 and June 2015. Results: 236 patients met the inclusion criteria. There were 194 (82.2%) males. The mean age was 59.1 (SD 11.0) years. A total of 4012 segments of the left ventricle were analyzed on the gated SPECT and reduced perfusion was noted in 1862 (46.4%) segments. Perfusion-metabolism mismatch (viable myocardium) was observed in 586 (31.5%) out of 1862 perfusion defects. The prevalence of myocardial viability in the study population was 61.4%. On the multivariate logistic regression model, aspirin intake [OR:0.37; CI:0.16-0.83; p=0.016] and hypertension [OR:0.26; CI:0.12-0.58; p=0.001] were associated with the presence of viable myocardium. Smoking was associated with the likelihood of having non-viable myocardium [OR:2.31; CI:1.01-5.29; p=0.048] Conclusion: The prevalence of myocardial viability as detected by 18F FDG PET in our local cohort is similar to prevalence rates reported in the developed world. / LG2018

A newly discovered activity in human serum protects porcine aortic endothelial cells in culture from injury by very low density lipoproteins (VLDL). This factor, toxicity-preventing activity (TxPA), was measured in 29 relatively young men (43 ± 8 years) who had undergone coronary angiography. The level of TxPA was found to be significantly reduced (P < 0.001) in men who demonstrated more than 15% narrowing of their coronary arteries. Men (n = 18) who had 15% or less narrowing were found to have 104 ± 48 units of TxPA while men (n = 11) with coronary artery disease had 48 ± 24 units of TxPA. A value derived from the product of TxPA and the high density lipoprotein cholesterol (HDL-C) level divided by the non-HDL-C (total cholesterol-HDL-C) accurately separated 97% of the men into 2 groups. TxPA thus appears to be a new protective factor in coronary artery disease, which, when combined with total cholesterol and high density lipoprotein cholesterol values, provides an accurate classification of established coronary artery disease in these subjects.

Fragmented QRS (fQRS) is a marker of conduction block due to myocardial scar that presents in electrocardiography (ECG) as an additional one or more R wave (R') or notching in the S wave nadir in contiguous leads. However, fQRS description on premature ventricular contractions (PVCs) has not been previously described. We describe a case of a 67-year-old male with a past medical history of prediabetes, hypertension and coronary artery disease who presented after an ophthalmic procedure with asymptomatic PVCs and episodes of bigeminy. Initial ECG showed an isolated fQRS in V2. However, during PVCs significant extrasystoles fragmentation was seen in other coronary territories. Upon reviewing his most recent cardiac catheterization, it showed a 40% ostial and 70% distal left anterior descending stenosis with a mid-segment patent stent, 95% first diagonal stenosis and totally occluded proximal right coronary artery. Identification of diffuse fQRS known to be associated with myocardial scar, sustained arrhythmic events and sudden cardiac death, particularly when seen in the inferior leads, became extremely relevant in our patient. We noted that ejection fraction reduction from 52% to 34% on his last coronary intervention was crucial to decide if an implantable cardioverter-defibrillator would be needed. PVC fragmentation might be a new ECG marker that could uncover both scar and arrhythmia potential in patients at risk of adverse cardiac events.

Background and objectives: Coronary artery disease (CAD) is the leading cause of death among women both nationally and internationally. Despite increased knowledge regarding CAD in women, early diagnosis remains a difficult clinical task. A correlation between peripheral arterial disease (PAD) and CAD has been noted in previous research; however, these studies were either retrospective or did not focus on women. This research investigates the correlation of ankle brachial index (ABI), measurements used to diagnose PAD, and presence of CAD in women, in an effort to determine the predictive value of ABI specifically in women. Subjects and methods: A prospective correlation design was used to study women (n = 30) who were undergoing a diagnostic cardiac catheterization. Ankle brachial index readings were obtained prior to the catheterization procedure. Catheterization findings were grouped according to absence of CAD or presence of 1-vessel or multivessel CAD and coupled with each woman's ABI and recorded cardiovascular risk factors. Results: Peripheral arterial disease (based on ABI of <0.90 mm Hg) was found in 13.3% of the women. A significant correlation was found between ABI of less than 0.90 mm Hg and increasing age (t = -2.30, P =.029). Coronary artery disease was found in 82.1% of the women; more than half (57.1%) had multivessel disease. Absence of CAD was noted in 17.9%. Women with CAD were older than women without CAD (F = 3.86, P =.035). No significant differences were found between presence or absence of PAD based on ABI and diagnosis of no coronary disease or 1-vessel or multivessel coronary disease. Conclusions: This study failed to show the expected correlation between ABI of less than 0.90 mm Hg and CAD, but did show a significant correlation of age with presence of both PAD and CAD. Further research that focuses specifically on women is needed and should include a larger sample, additional unique cardiovascular risk factors, and innovative diagnostic tests to determine presence of CAD in women early in the disease process.

The underlying pathological process of coronary artery disease (CAD) is the development of coronary artery atherosclerotic occlusions and associated myocardial infarction. Both increased chronic inflammation and plasma low-density lipoprotein (LDL) cholesterol levels promote atherosclerosis. Inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) is widely known for its role in enhancing LDL receptor (LDLR)-mediated cholesterol lowering when the LDLR-apolipoprotein E (APOE) axis is intact and protecting against atherosclerosis progression by reducing plasma cholesterol levels. In this thesis, we sought to test the effects of PCSK9 inhibition mediated cholesterol lowering on pre-existing CAD as well as the plasma cholesterol independent effects of PCSK9 inhibition on CAD by utilizing different mouse models. One year old scavenger receptor class B type I (Sr-b1) knockout (KO) mice which have an intact LDLR-APOE axis, develop coronary artery atherosclerosis and myocardial fibrosis induced by a high fat, high cholesterol and cholate containing (HFCC) diet. Weekly anti-PCSK9 antibody treatment initiated one week before switching to an HFCC diet increased hepatic LDLR protein levels, and reduced plasma cholesterol levels and the progression of atherosclerosis in both the aortic sinus and coronary arteries in one year old Sr-b1 KO mice (maintained on an HFCC diet for 7 weeks). Weekly anti-PCSK9 antibody treatment initiated 7 weeks after switching to an HFCC diet also increased hepatic LDLR protein levels and reduced plasma cholesterol levels in one year old Sr-b1 KO mice (maintained on an HFCC diet for 12 weeks). More importantly, anti-PCSK9 antibody treatment during the last 5 weeks of the 12-week HFCC diet feeding period also slowed down the growth of pre-existing atherosclerosis in both the aortic sinus and coronary arteries and reduced myocardial fibrosis and damage. Mice deficient in both Sr-b1 and ApoE (Sr-b1/ApoE double KO (dKO) mice) spontaneously and rapidly develop features reminiscent of human CAD. Whole body Pcsk9 genetic KO in both female and male Sr-b1/ApoE dKO mice did not affect plasma cholesterol levels despite increased hepatic LDLR protein levels, presumably due to the lack of APOE. However, genetic Pcsk9 inactivation significantly attenuated atherosclerosis in both the aortic sinus and coronary arteries, myocardial fibrosis and damage, left ventricle (LV) dysfunction and cardiac enlargement in both female and male Sr-b1/ApoE dKO mice. Restoring circulating PCSK9 by a recombinant adeno associated virus 8 (AAV8)-mediated hepatic expression of a Pcsk9 cDNA in Pcsk9/Sr-b1/ApoE triple KO mice reversed the plasma cholesterol independent protective effects of genetic PCSK9 KO on aortic sinus and coronary artery atherosclerosis and myocardial fibrosis and damage in both females and males. Treatment of Sr-b1/ApoE dKO mice with an anti-PCSK9 antibody which disrupts the interaction between the LDLR and PCSK9 protected against aortic sinus and coronary artery atherosclerosis in males but not in females and did not protect either males or females against myocardial fibrosis and damage, LV dysfunction or cardiac enlargement. My thesis demonstrates that anti-PCSK9 antibody mediated plasma cholesterol lowering delays the continued development of pre-existing CAD. My thesis also demonstrates that liver-derived, circulating PCSK9 promotes CAD in a plasma cholesterol independent manner in Sr-b1/ApoE dKO mice and these effects appear to be largely independent of the PCSK9-LDLR interaction, particularly in females. / Thesis / Doctor of Philosophy (PhD)

The purpose of this thesis investigation was to evaluate the effectiveness of dynamic strength training as an additional mode of exercise rehabilitation, in patients with coronary artery disease and well documented evidence of a previous myocardial infarction. The effects of 10 weeks (20 sessions) of combined weightlifting and aerobic training (WtAer) (n=10) were compared with aerobic training (Aer) (n=8) alone, on indices of strength and aerobic exercise capacity in 18 male patients with coronary artery disease (CAD). Initial test(s) performance was similar between groups. Post Aer, the maximum weightlifting strength (1RM) in single-arm curl, single-leg press, and single-knee extension exercises increased by 13% (x = 11.8 to 13.3 kg; P < 0.01), 4% (x = 97 to 101 kg; N.S.), and 5% (x = 28.2 to 29.7 kg; N.S.) respectively; corresponding gains with AerWt were 43% (x = 12.2 to 17.4 kg; P < 0.01), 21% (x = 99 to 120 kg; P <0.01) , and 24% (x = 29 to 36 kg; P < 0.01) . Following Aer the initial 1RM could be lifted an average of 4 times, compared to 14 times after AerWt. Neither Aer nor AerWt showed significant improvements in peak torque in either isokinetic single-knee extension at 90°/s and 180°/s or single-leg press exercise at 30°/s and 75°/s. Maximum progressive incremental cycle ergometer performance (Wmax)increased by 2% with Aer (x = 1088 to 1113 kpm/min; N.S.) and by 15% (x = 1030 to 1180 kpm/min; P < 0.05) with AerWt.Cycling time at 80% of initial Wmax before attaining a Borg RPE of 7 for the legs, increased by 11% (x = 604 to 672s; N.S.) and by 109% (x = 541 to 1128s; P < 0.05) with Aer and AerWt respectively. In these patients with CAD, AerWt was a more effective method of increasing aerobic performance and strength than Aer alone. In order for cardiac exercise rehabilitation therapy to optimize the strength and functional capacities of CAD patients it may be useful to incorporate appropriately monitored weightlifting training into the traditional aerobic exercise regimen. / Thesis / Master of Science (MS)

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