Purpose of Review: To review the landmark studies in predicting obstructive coronary artery disease (CAD) in symptomatic patients with stable chest pain and identify better prediction tools and propose a simplified algorithm to guide the health care providers in identifying low risk patients to defer further testing. Recent Findings: There are a few risk prediction models described for stable chest pain patients including Diamond-Forrester (DF), Duke Clinical Score (DCS), CAD Consortium Basic, Clinical, and Extended models. The CAD Consortium models demonstrated that DF and DCS models overestimate the probability of CAD. All CAD Consortium models performed well in the contemporary population. PROMISE trial secondary data results showed that a clinical tool using readily available ten very low-risk pre-test variables could discriminate low-risk patients to defer further testing safely. Summary: In the contemporary population, CAD Consortium Basic or Clinical model could be used with more confidence. Our proposed simple algorithm would guide the physicians in selecting low risk patients who can be managed conservatively with deferred testing strategy. Future research is needed to validate our proposed algorithm to identify the low-risk patients with stable chest pain for whom further testing may not be warranted.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24474号 / 医博第4916号 / 新制||医||1062(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 石見 拓, 教授 永井 洋士, 教授 大鶴 繁 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Purpose of Review: Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) have emerged as the invasive diagnostic tools of choice for hemodynamic assessment of the severity of CAD (coronary artery disease). We sought to comprehensively review the evidence on the utility of hemodynamic assessment of the coronary stenoses after percutaneous coronary intervention (PCI) using FFR/iFR, mechanisms of positive post-PCI iFR/FFR, and the clinical impact of significant residual ischemia. Recent Findings: The evidence on the utility of the post-PCI hemodynamic assessment has accumulated over the last few years. The post hoc analysis from the FAME 1 and FAME 2 data shows that higher post-PCI FFR is associated with better symptomatic improvement and lower event rate with larger increase in delta FFR (∆ FFR: post-PCI FFR – pre-PCI FFR). Unlike pre-PCI FFR, a consensus has not been established on the optimal value of post-PCI FFR, though multiple studies point toward better clinical outcomes with higher post-PCI FFR and larger ∆ FFR. Summary: Visual assessment of adequate stent apposition by coronary angiography is insufficient in evaluating for residual ischemia. The hemodynamic evaluation of residual ischemia by post-PCI FFR/iFR yields clinically relevant data and allows for appropriate post PCI optimization.

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Knowledge about cardiac and inflammatory biomarkers in patients with stable coronary artery disease (CAD) is limited. To address this, we analyzed 3072 patients (36% female) with a median follow-up of 10 years in the Leipzig LIFE Heart Study with suspected CAD with coronary angiography. Selected biomarkers included troponin T (hsTNT), N-terminal pro B-type natriuretic peptide (NT-proBNP), copeptin, C-reactive protein (hsCRP), and interleukin-6 (IL-6). Patients were stratified by CAD severity: CAD0 (no sclerosis), CAD1 (non-obstructive, i.e., stenosis < 50%), and CAD2 (one stenosis 50%). Group comparison (GC) included GC1: CAD0 + 1 vs. CAD2; GC2: CAD0 vs. CAD1 + 2. CAD0, CAD1, and CAD2 were apparent in 1271, 631, and 1170 patients, respectively. Adjusted for classical risk factors, hs-cTnT, NT-proBNP, and IL-6 differed significantly in both GC and hsCRP only in GC2. After multivariate analysis, hs-cTnT, NT-proBNP, and IL-6 remained significant in GC1. In GC2, hs-cTnT (p < 0.001) and copeptin (p = 0.014) reached significance. Ten-year survival in groups CAD0, CAD1, and CAD2 was 88.3%, 77.3%, and 72.4%. Incorporation of hs-cTnT, NT-proBNP, copeptin, and IL-6 improved risk prediction (p < 0.001). The studied cardiac and inflammatory biomarkers enable fast and precise non-invasive identification of mortality risk in CAD patients, allowing the tailoring of primary and secondary CAD prevention.

Cardiac rehabilitation (CR) exercise training, which traditionally involves the prescription of moderate intensity continuous exercise, can slow the progression of heart disease and improve cardiorespiratory fitness (CRF). Cardiac function is typically investigated using calculations of ejection fraction (EF) from echocardiography, yet EF measures do not provide information about the unique twisting motion of the heart. Novel measures of cardiac function, such as LV twist, myocardial performance index (MPI) and global longitudinal strain (GLS), may provide additional information about changes in LV mechanics associated with exercise training for individuals with coronary artery disease (CAD). The aims of this study were to investigate the changes in cardiac function, using both standard and novel measures, at baseline (0 weeks; T1), post-initial training (4 weeks; T2), and post-training (12 weeks; T3) in response to either stair climbing-based high intensity interval training (STAIR) or traditional moderate intensity continuous training (TRAD). We recruited 16 individuals with CAD (61±7years; 1W) and randomized them into TRAD and STAIR groups (n=8/group). Standard (CRF and EF), and novel (LV twist, MPI, GLS), measures of cardiovascular function were assessed at all three timepoints. CRF improved in both groups, after 4 and 12 weeks (STAIR: T1:22.1±4.2, T2:24.7±4.9, T3:25.4±5.2 and TRAD: T1:22.8±2.5, T2:25.2±4.9, T3:26.0±5.0 mL/kg/min; P<0.005) of CR exercise. We observed an increase in apical rotation (P=0.01) and LV twist (P=0.03), but no changes in either traditional (EF P=0.15), or novel (MPI P=0.19; GLS P=0.81) measures of cardiac function over time, in either group. It is possible that the relatively short training period (12 weeks) was not sufficient to result in significant changes in cardiac function, despite improvements in CRF. Future research should assess both standard and novel indices of cardiac function over longer exercise training periods to determine the ideal indices for tracking changes over time with interventions in this population. / Thesis / Master of Science (MSc) / Cardiac rehabilitation exercise is an important part of recovery after a heart attack, and it has been shown to improve heart function measured using standard ultrasound assessments. Studies have suggested that novel measures of heart function may be more sensitive in comparison to these standard ultrasound measures, yet these novel measures have not been examined in individuals completing stair-climbing based high intensity cardiac rehabilitation exercise training. This work examined the changes in both novel and standard ultrasound measures of heart function after either stair climbing-based high intensity interval training or traditional moderate intensity exercise training in individuals who have heart disease. While this study found that both stair climbing based high intensity interval training and traditional cardiac rehabilitation both resulted in increases in cardiorespiratory fitness after 12 weeks of training, no changes were observed in any of the standard measures of heart function. Supporting the concept that novel measures of heart function might be more sensitive, as some training associated changes were observed in the novel measures of heart function.

Les biomarqueurs plasmatiques constituent des outils essentiels, mais rares, utilisés pour diagnostiquer les maladies, comme les maladies cardiovasculaires (MCV), et stratifier le niveau de risque associé. L’identification de nouveaux biomarqueurs plasmatiques susceptibles d’améliorer le dépistage et le suivi des MCV représente ainsi un enjeu majeur en termes d’économie et de santé publique. Le projet vise à identifier de nouveaux biomarqueurs plasmatiques prédictifs ou diagnostiques des MCV, à déterminer le profil protéomique plasmatique de patients atteints de MCV et à développer des méthodes innovantes d’analyse d’échantillon plasmatique. L’étude a été effectuée sur une large banque de plasma provenant de 1006 individus de souche Canadienne-Française recrutés à différents stades de la MCV et qui ont été suivis sur une période de 5 ans. Des séries de déplétions ont été réalisées afin de dépléter les 14 protéines majoritaires (colonne IgY14TM) de l’échantillon avant son analyse par trois approches effectuées en parallèle: 1) Une chromatographie liquide (LC) en 2 dimensions qui fractionne les protéines selon le point isoélectrique puis selon le degré d’hydrophobicité, via le système PF2D, suivie par une chromatographie liquide couplée avec une spectrométrie de masse en tandem (LC-MS/MS). 2) Une séparation classique sur gel 1D-SDS-PAGE suivie d’une LC-MS/MS; 3) Par une déplétion plus poussée du plasma avec l’utilisation en tandem avec la colonne IgY14TM d’une colonne SupermixTM permettant de dépléter également les protéines de moyenne abondance, suivie d’une séparation sur gel 1D-SDS-PAGE et d’une analyse LC-MS/MS de la portion déplétée (3a) et de la portion liée à la SupermixTM (3b). Les résultats montrent que le système PF2D permet d’identifier plusieurs profils protéiques spécifiques au groupe MCV. Sur un total de 1156 fractions (équivalent à 1172 pics protéiques pour le groupe contrôle et 926 pics pour le groupe MCV) recueillies, 15 fractions (23 pics protéiques) présentaient des différences quantitativement significatives (p<0,05) entre les 2 groupes. De plus, 6 fractions (9 pics) sont uniquement présentes dans un groupe, représentant d’autres signatures protéomiques et biomarqueurs potentiellement intéressants. Les méthodes 2, 3a et 3b ont permis l’identification de 108, 125 et 91 protéines respectivement avec des chevauchements partiels (31% entre la méthode 2 et 3a, 61% entre 2 et 3b et 19% entre 3a et 3b). Les méthodes 2 et 3 ont permis l’identification de 12 protéines qui présentaient des différences quantitatives significatives entre les 2 groupes. L’utilisation de plusieurs approches protéomiques complémentaires nous ont d’ores et déjà permis d’identifier des candidats biomarqueurs des angines instables avec récidive d’infarctus du myocarde (IM). / Coronary artery disease (CAD) is a major cause of mortality in Canada. Biomarkers are precious tools to diagnosis and risk stratification, and the identification of new candidates may substantially impact on public health and health economics. Due to its complexity, the human blood proteome remains challenging to explore. Our study aims at combining various complementary methods to determine the plasma proteome signature of patients at various stages of CAD. The total cohort includes 1006 French-Canadian, 500 controls with a normal coronary angiography, and 506 patients with documented CAD. Two pools were reconstituted to represent the extremes of our population: 1) patients with a previous myocardial infarction (MI) and a recurrent MI over a 5 years follow-up and 2) controls without CAD and no events during follow-up matched for age and sex to the CAD pool (N=18). After a depletion of highly abundant proteins, pools were analyzed using 3 different proteomic methods: i) PF2D system followed by a liquid chromatography tandem mass spectrometry analysis (LC-MS/MS); ii) 1D-SDS-PAGE followed by LC-MS/MS; iii) Further depletion of proteins followed by 1D-SDS-PAGE and LC-MS/MS analysis of both flow through (3a) and retained fractions (3b). Methods 2, 3a, and 3b allowed identification of 108, 125 and 91 proteins respectively. Overlapping proteins (31% between methods 2 and 3a, 61% between 2 and 3b and 19% between 3a and 3b) showed significant absolute and relative expressions with various methods. A total of 12 proteins were significantly (p<0.05) different in amounts (number of peptides identified) between the 2 pools. Analyses with the PF2D elution spectra (method 1) displayed numerous different profiles between the two groups. Over a total of 1156 fractions (control: 1172 peaks ACS: 926 peaks) generated, 370 fractions (674 peaks) overlapped between the two pools. 15 fractions (23 peaks) differed significantly (p<0,05) in amounts while some other peaks were uniquely present in one pool, representing biomarkers of potential interest. We conclude that plasma proteome signatures are significantly modeled by the methods serving their recognition. Cost of analyses can be reduced with the PF2D method by performing a pre-selection before MS analysis. Detection of less abundant proteins can be improved by using further depletion. Taking profit of these finding, we are now testing in our population the hypothesis that a combination of methods will sharpen our ability to detect clinically relevant proteins tailored to various clinical situations and to disease staging.

Les maladies cardio et cérébro-vasculaires représentent la première cause de mortalité et de handicap dans le monde. Du fait des progrès thérapeutiques dans la prise en charge de ces pathologies à la phase aigüe, le nombre de patients porteurs de formes chroniques de ces affections limitant leurs capacités d’effort est en augmentation constante. La problématique de ce travail de thèse s’articule autour de l’utilisation des tests de marche standardisés dans l’évaluation des capacités d’effort des patients porteurs de pathologies coronariennes. Nous avons dans un premier temps rappelé les notions de handicap et de qualité de vie appliqués aux maladies chroniques, et la nécessité d’évaluations fonctionnelles spécifiques pour en apprécier le retentissement et l’évolution. Puis nous avons fait le point sur les modalités actuelles de la réadaptation cardiaque, en développant plus particulièrement la place de l’activité physique. Nous avons entrepris ensuite l’étude des sollicitations physiologiques induites par un test de marche rapide de 200 mètres (TMR200) chez des sujets âgés sains, puis sur une population de patients coronariens. Ce test s’est avéré bien toléré, et correspond à une intensité d’exercice intermédiaire entre le premier seuil ventilatoire et les capacités maximales d’exercice. Il apparaît ainsi particulièrement intéressant pour apprécier les capacités à effectuer des efforts fréquents de la vie quotidienne, plus intenses que ceux correspondant à la marche à vitesse spontanément adoptée au cours du classique tes de marche de 6 minutes (correspondant à un effort essentiellement aérobie). Par la suite nous avons cherché à définir la différence minimale cliniquement pertinente du test de marche (MCID) de 6 minutes (TM6) et du TMR200, afin de mieux interpréter les progrès fonctionnels des patients intégrés dans les programmes de réadaptation cardiaque après un syndrome coronarien aigu. Cette dernière a été estimée à 25 mètres pour le TM6. Enfin, nous avons étudié l’intérêt de ces tests de marche dans l’aide à l’individualisation de la prescription de l’intensité du réentraînement chez les patients coronariens. Ces modalités permettent aux patients d’être plus souvent proches des intensités d’entraînement conventionnellement préconisées, en aboutissant à des résultats comparables, sans la nécessité de pratiquer un test d’effort maximal mobilisant des moyens significatifs en personnel et en matériel. Au total, ce travail apporte des arguments pour l’utilisation en pratique clinique courante de ces tests de marche standardisés. Ils apparaissent complémentaires dans le cadre de l’évaluation objective des capacités fonctionnelles et de la qualité de vie perçue des patients âgés et coronariens. Ces résultats ouvrent des perspectives pour poursuivre l’étude de leurs propriétés métrologiques et de leurs applications cliniques au cours des affections chroniques incapacitantes. / Cardiovascular and cerebrovascular diseases remain the first cause of mortality and handicap in the world. With the improvements in the management of the acute phase, the number of patients with limited exercise capacity due to chronic cardiovascular disease is increasing. The aim of this thesis was to conduct a thorough study of the use of standardized walk tests to assess exercise capacity in coronary artery disease patients. We first explain the concepts of handicap and quality of life in chronic diseases, and the need for functional evaluations in order to assess their impact and evolution. We then present the current modalities of cardiac rehabilitation, emphasizing the importance of physical activity. We studied the physiological demands of a 200-meter fast-walk test (200MFWT) in healthy elderly subjects, and in coronary artery disease patients. This test was well tolerated, and corresponds to an effort intensity lying between the ventilatory threshold and maximal exercise capacity. It therefore appears interesting to assess the capacities of an individual to perform activities encountered in daily life that are more intense than walking at a self-selected comfortable speed, as during the 6-minute walk test (6-MWT) (corresponding to a moderate submaximal intensity solicitation, mainly aerobic). We then investigated the minimal clinically important difference of the 6MWT and 200MFWT, in order to better appraise functional improvements in patients undergoing cardiac rehabilitation after an acute coronary syndrome. This difference has been estimated at 25 metres for the 6MWT. Finally, we studied the interest of using these walk tests to individualize training intensity prescription in these patients. These modalities bring patients closer to the recommended intensity, while leading to results comparable to those of more traditional training programs, without the need for repeated expensive tests. In conclusion, this work supports the use of these standardized walk tests in routine clinical setting. They bring complementary information in the assessment of functional capacity and perceived quality of life in elderly patients and those with coronary artery disease. These results are a basis for further investigations regarding their metrological properties and clinical applications in various chronic diseases that reduce exercise capacity.

Cardiovascular disease is the leading cause of death worldwide and ischemic heart disease is the most common manifestation. Despite improved outcomes during the last decades, patients with acute coronary syndromes (ACS) are still at substantial risk of recurrent ischemic events and mortality. The aims of this thesis were to investigate the effect of the novel antiplatelet agent ticagrelor versus clopidogrel in patients with non-ST-elevation ACS (NSTE-ACS), overall and in relation to initial revascularization, and to explore this effect in relation to cardiac biomarkers. The impact of timing of revascularization in non-ST-elevation myocardial infarction (NSTEMI) was also studied, by assessing risk of mortality and recurrent myocardial infarction in relation to delay of percutaneous coronary intervention (PCI) in a nation-wide cohort. Finally, a novel clinical prediction model based on angiographic findings, biomarkers, and clinical characteristics was developed to estimate risk of ischemic events after performed revascularization. Ticagrelor treatment compared with clopidogrel was associated with a reduction in the composite endpoint of cardiovascular death/myocardial infarction/stroke and mortality alone, without any increase in overall major bleeding, but increased non-CABG-related major bleeding. The effect of ticagrelor over clopidogrel was consistent independent of initial revascularization. Elevated high-sensitivity cardiac troponin-T predicted benefit of ticagrelor over clopidogrel, while no difference between treatments was detected at normal levels. In patients with NSTEMI, PCI treatment within two days after hospital admission was associated with lower risk of all-cause death and recurrent myocardial infarction compared with delayed PCI. The new clinical prediction model included the following variables: prior vascular disease, extent of coronary artery disease, level of N-terminal pro-B-type natriuretic peptide and estimated glomerular filtration rate; and showed good discriminatory ability for the risk prediction of cardiovascular death/myocardial infarction/stroke and cardiovascular death alone. In conclusion, these results show that ticagrelor reduces the risk of recurrent ischemic events and mortality in patients with NSTE-ACS when compared with clopidogrel, and this effect seems independent of performed revascularization. The results also indicate that biomarkers could be used to select patients who would benefit most from more intense platelet inhibition. Furthermore, early PCI in NSTEMI seems to be associated with improved outcome. Finally, the novel clinical prediction model based only on four variables showed good discriminatory ability, which makes it a potentially effective and simple tool for tailored treatment based on individual risk of recurrent events.