Epicardial adipose tissue attenuation on computed tomography in women with coronary microvascular dysfunction: A pilot, hypothesis generating study.

BACKGROUND: Patients with myocardial ischemia without obstructive coronary artery disease often have coronary microvascular dysfunction (CMD) and associated increased risk of cardiovascular (CV) events and anginal hospitalizations. Epicardial adipose tissue (EAT) covers much of the myocardium and coronary arteries and when dysfunctional, secretes proinflammatory cytokines and is associated with CV events. While oxidative stress and systemic inflammation are associated with CMD, the relationship between EAT and CMD in women is not well known. METHODS: Women diagnosed with CMD (n = 21) who underwent coronary computed tomography with coronary artery calcium (CAC) scoring were compared to a reference group (RG) of women referred for CAC screening for preventive risk assessment (n = 181). EAT attenuation (Hounsfield units (HU)) was measured adjacent to the proximal right coronary artery, along with subcutaneous adipose tissue (SCAT). Two-sample t-tests with unequal variances were utilized. RESULTS: Mean age of the CMD group was 56 ± 8 years and body mass index (BMI) was 31.6 ± 6.8 kg/m2. CV risk factors in the CMD group were prevalent: 67 % hypertension, 44 % hyperlipidemia, and 33 % diabetes. Both CMD and RG had similar CAC score (25.86 ± 59.54 vs. 24.17 ± 104.6; p = 0.21. In the CMD group, 67 % had a CAC of 0. Minimal atherosclerosis (CAD-RADS 1) was present in 76 % of women with CMD. The CMD group had lower EAT attenuation than RG (-103.3 ± 6.33 HU vs. -97.9 ± 8.3 HU, p = 0.009, respectively). There were no differences in SCAT attenuation. Hypertension, smoking history, age, BMI, and CAC score did not correlate with EAT in either of the groups. CONCLUSIONS: Women with CMD have decreased EAT attenuation compared to RG women. EAT-mediated inflammation and changes in vascular tone may be a mechanistic contributor to abnormal microvascular reactivity. Clinical trials testing therapeutic strategies to decrease EAT may be warranted in the management of CMD.

Coronary Microvascular Disease in Women: Epidemiology, Mechanisms, Evaluation, and Treatment.

Coronary microvascular dysfunction (CMD) involves functional or structural abnormalities of the coronary microvasculature resulting in dysregulation of coronary blood flow (CBF) in response to myocardial oxygen demand. This perfusion mismatch causes myocardial ischemia, which manifests in patients as microvascular angina (MVA). CMD can be diagnosed non-invasively via multiple imaging techniques or invasively using coronary function testing (CFT), which assists in determining the specific mechanisms involving endothelium-independent and dependent epicardial and microcirculation domains. Unlike traditional coronary artery disease (CAD), CMD can often occur in patients without obstructive atherosclerotic epicardial disease, which can make the diagnosis of CMD difficult. Moreover, MVA due to CMD is more prevalent in women and carries increased risk of future cardiovascular events. Successful treatment of symptomatic CMD is often patient-specific risk factor and endotype targeted. This article aims to review newly identified mechanisms and novel treatment strategies for managing CMD, and outline sex-specific differences in the presentation and pathophysiology of the disease.

Comprehensive Management of ANOCA, Part 1-Definition, Patient Population, and Diagnosis: JACC State-of-the-Art Review.

Angina with nonobstructive coronary arteries (ANOCA) is increasingly recognized and may affect nearly one-half of patients undergoing invasive coronary angiography for suspected ischemic heart disease. This working diagnosis encompasses coronary microvascular dysfunction, microvascular and epicardial spasm, myocardial bridging, and other occult coronary abnormalities. Patients with ANOCA often face a high burden of symptoms and may experience repeated presentations to multiple medical providers before receiving a diagnosis. Given the challenges of establishing a diagnosis, patients with ANOCA frequently experience invalidation and recidivism, possibly leading to anxiety and depression. Advances in scientific knowledge and diagnostic testing now allow for routine evaluation of ANOCA noninvasively and in the cardiac catheterization laboratory with coronary function testing (CFT). CFT includes diagnostic coronary angiography, assessment of coronary flow reserve and microcirculatory resistance, provocative testing for endothelial dysfunction and coronary vasospasm, and intravascular imaging for identification of myocardial bridging, with hemodynamic assessment as needed.

Comprehensive Management of ANOCA, Part 2-Program Development, Treatment, and Research Initiatives: JACC State-of-the-Art Review.

Centers specializing in coronary function testing are critical to ensure a systematic approach to the diagnosis and treatment of angina with nonobstructive coronary arteries (ANOCA). Management leveraging lifestyle, pharmacology, and device-based therapeutic options for ANOCA can improve angina burden and quality of life in affected patients. Multidisciplinary care teams that can tailor and titrate therapies based on individual patient needs are critical to the success of comprehensive programs. As coronary function testing for ANOCA is more widely adopted, collaborative research initiatives will be fundamental to improve ANOCA care. These efforts will require standardized symptom assessments and data collection, which will propel future large-scale clinical trials.

The relationships between acetylcholine-induced chest pain, objective measures of coronary vascular function and symptom status.

Background: Acetylcholine-induced chest pain is routinely measured during the assessment of microvascular function. Aims: The aim was to determine the relationships between acetylcholine-induced chest pain and both symptom burden and objective measures of vascular function. Methods: In patients with angina but no obstructive coronary artery disease, invasive studies determined the presence or absence of chest pain during both acetylcholine and adenosine infusion. Thermodilution-derived coronary blood flow (CBF) and index of microvascular resistance (IMR) was determined at rest and during both acetylcholine and adenosine infusion. Patients with epicardial spasm (>90%) were excluded; vasoconstriction between 20% and 90% was considered endothelial dysfunction. Results: Eighty-seven patients met the inclusion criteria. Of these 52 patients (60%) experienced chest pain during acetylcholine while 35 (40%) did not. Those with acetylcholine-induced chest pain demonstrated: (1) Increased CBF at rest (1.6 ± 0.7 vs. 1.2 ± 0.4, p = 0.004) (2) Decreased IMR with acetylcholine (acetylcholine-IMR = 29.7 ± 16.3 vs. 40.4 ± 17.1, p = 0.004), (3) Equivalent IMR following adenosine (Adenosine-IMR: 21.1 ± 10.7 vs. 21.8 ± 8.2, p = 0.76), (4) Increased adenosine-induced chest pain (40/52 = 77% vs. 7/35 = 20%, p < 0.0001), (5) Increased chest pain during exercise testing (30/46 = 63% vs. 4/29 = 12%, p < 0.00001) with no differences in exercise duration or electrocardiographic changes, and (6) Increased prevalence of epicardial endothelial dysfunction (33/52 = 63% vs. 14/35 = 40%, p = 0.03). Conclusions: After excluding epicardial spasm, acetylcholine-induced chest pain is associated with increased pain during exercise and adenosine infusion, increased coronary blood flow at rest, decreased microvascular resistance in response to acetylcholine and increased prevalence of epicardial endothelial dysfunction. These findings raise questions about the mechanisms underlying acetylcholine-induced chest pain.

Worsening of Angina Following Nitroglycerin Administration: A Case Report of the Interplay With Undiagnosed Myocardial Bridge.

Myocardial bridge (MB) is a congenital abnormality where part of a coronary epicardial artery runs under the myocardium fibers and is compressed in systole; this becomes more pronounced when nitroglycerin (NTG) is administered. In this report, we describe the case of a 40-year-old African American man who presented with chest pain that did not respond to NTG or isosorbide mononitrate and was only partially relieved by narcotics. His past medical history was significant for coronary artery disease (CAD) with a stent into the left anterior descending artery (LAD) several months prior, hypertension, hyperlipidemia, paroxysmal atrial fibrillation, sick sinus syndrome, permanent pacemaker, pulmonary embolism, and cerebral vascular accident. No explanation for his angina was found either in the previous outpatient left heart catheterization (LHC) procedures demonstrating LAD stent patency or initial chest pain workup upon admission. Functional LHC procedure with adenosine infusion and acetylcholine provocation demonstrated endothelial dysfunction with notable epicardial spasm and MB of the LAD that worsened with NTG. Cardiology advised dual antiplatelet therapy and a statin as part of treatment for CAD and a calcium channel blocker with a bradycardic effect (e.g., diltiazem, verapamil) for the MB and coronary vasospasm, and avoidance of NTG and long-acting nitrates (e.g., isosorbide mononitrate), which can cause reflex tachycardia and worsen angina from MB. A selective serotonin reuptake inhibitor was added for increased cardiac nociception. The patient's pain resolved, and he was discharged. MB is an important alternate etiology to consider when chest pain does not respond to NTG administration for adjustment of treatment modalities. The initial treatment for this patient's pain with NTG likely exacerbated symptoms by reducing intrinsic coronary wall tension and subsequently increasing reflex sympathetic stimulation of contractility of the left ventricular myocardium, which can, in turn, increase anginal symptoms and ischemia.

Coronary Microvascular Disease in Contemporary Clinical Practice.

Coronary microvascular disease (CMD) causes myocardial ischemia in a variety of clinical scenarios. Clinical practice guidelines support routine testing for CMD in patients with ischemia with nonobstructive coronary artery disease. Invasive testing to identify CMD requires Doppler or thermodilution measures of flow to determine the coronary flow reserve and measures of microvascular resistance. Acetylcholine coronary reactivity testing identifies concomitant endothelial dysfunction, microvascular spasm, or epicardial coronary spasm. Comprehensive testing may improve symptoms, quality of life, and patient satisfaction by establishing a diagnosis and guiding-targeted medical therapy and lifestyle measures. Beyond ischemia with nonobstructive coronary artery disease, testing for CMD may play a role in patients with acute myocardial infarction, angina following coronary revascularization, heart failure with preserved ejection fraction, Takotsubo syndrome, and after heart transplantation. Additional education and provider awareness of CMD and its role in cardiovascular disease is needed to improve patient-centered outcomes of ischemic heart disease.

Rare Cause of Late Left Aortic Sinus Obstruction Following Transcatheter Aortic Valve Replacement.

A 74-year-old woman with a history aortic stenosis with prior transcatheter aortic valve replacement presented with non-ST-segment elevation myocardial infarction secondary to a delayed left coronary sinus obstruction. With physiology and intravascular ultrasound guidance, the patient was treated with stents through the valve struts and to the left main. (Level of Difficulty: Intermediate.).

Takotsubo syndrome: A current review of presentation, diagnosis, and management.

Takotsubo syndrome is a syndrome of acute heart failure due to left ventricular systolic dysfunction that is associated with increased cardiovascular morbidity and mortality. It occurs in both sexes and at all ages, but predominates in post-menopausal women for reasons that are unclear. In a patient who presents with cardiac symptoms, electrocardiographic changes, and/or biomarker elevation indicating myocardial stress (i.e. troponin elevation), this condition should be considered in the differential diagnosis. Cardiac imaging is critical for a timely diagnosis of this condition and has management implications. This syndrome can occur with or without underlying coronary artery disease, and while there are various characteristic myocardial patterns described on imaging, the most common one is left ventricular dysfunction due to apical stunning with basal hyperkinesis. In the acute phase, Takotsubo syndrome can lead to life-threatening sequelae, including cardiogenic shock, pulmonary edema, thromboembolism, and arrhythmias. Multiple pathophysiologic mechanisms are implicated, including an acute increase in left ventricular afterload in the setting of sympathetic activation with a catecholamine storm, multi-vessel coronary vasospasm, coronary endothelial microvascular dysfunction, and inflammation. In this review, we discuss the current knowledge surrounding presentation, diagnosis, and treatment of this under-diagnosed condition.

Mechanisms of Coronary Ischemia in Women.

PURPOSE OF REVIEW: Obstructive coronary artery disease is a major cause of ischemia in both men and women; however, women are more likely to present with ischemia in the setting of no obstructive coronary arteries (INOCA) and myocardial infarction with no obstructive coronary arteries (MINOCA), conditions that are associated with adverse cardiovascular prognosis despite absence of coronary stenosis. In this review, we focus on mechanisms of coronary ischemia that should be considered in the differential diagnosis when routine anatomic clinical investigation leads to the finding of non-obstructive coronary artery disease on coronary angiography in the setting of acute myocardial infarction. RECENT FINDINGS: There are multiple mechanisms that contribute to MINOCA, including atherosclerotic plaque disruption, coronary artery spasm, coronary microvascular dysfunction (CMD), coronary embolism and/or thrombosis, and spontaneous coronary artery dissection. Non-coronary causes such as myocarditis or supply-demand mismatch should also be considered on the differential when there is an unexplained troponin elevation. Use of advanced imaging and diagnostic techniques to determine the underlying etiology of MINOCA is feasible and helpful, as this has the potential to guide management and secondary prevention. Failure to identify the underlying cause(s) may result in inappropriate treatment and inaccurate counseling to patients. MINOCA predominates in young women and is associated with a guarded prognosis. The diagnosis of MINOCA should prompt further investigation to determine the underlying cause of troponin elevation. Patients with INOCA and MINOCA are heterogeneous, and response to treatments can be variable. Large randomized controlled trials to determine longer-term optimal medical therapy for management of these conditions are under investigation.

Concurrently Low Coronary Flow Reserve and Low Index of Microvascular Resistance Are Associated With Elevated Resting Coronary Flow in Patients With Chest Pain and Nonobstructive Coronary Arteries.

BACKGROUND: Coronary microvascular function can be distinctly quantified using the coronary flow reserve (CFR) and index of microvascular resistance (IMR). Patients with low CFR can present with low or high IMR, although the prevalence and clinical characteristics of these patient groups remain unclear. METHODS: One hundred ninety-nine patients underwent coronary microvascular assessments using coronary thermodilution techniques. A pressure-temperature sensor-tipped guidewire measured proximal and distal coronary pressure, whereas the inverse of the mean transit time to room temperature saline was used to measure coronary blood flow. The CFR and IMR were quantified during adenosine and acetylcholine hyperemia. RESULTS: Low adenosine and acetylcholine CFR was observed in 70 and 49 patients, respectively, whereas low CFR/low IMR to adenosine and acetylcholine was observed in 39(56%) and 19(39%) patients, respectively. Despite similar adenosine CFR, patients with low CFR/low IMR had increased resting (2.8±1.2 versus 1.3±0.4s-1) and hyperemic coronary blood flow (4.8±1.5 versus 2.1±0.5s-1) compared with patients with low CFR/high IMR (both P<0.01). The same pattern was observed in response to acetylcholine. Patients with low CFR/low IMR to adenosine were younger (56±12 versus 63±10 years), women (84% versus 66%), had fewer coronary risk factors (1.1±1.0 versus 1.6±1.1), lower hemoglobin A1c (5.8±0.7 versus 6.1±0.9 mmol/L), and thinner septal thickness (8.5±2.5 versus 9.9±1.6 mm) compared with patients with low CFR/high IMR to adenosine (all P<0.05). CONCLUSIONS: Low CFR/low IMR to adenosine and acetylcholine are associated with elevated resting coronary blood flow and preserved hyperemic coronary blood flow. These patients present with distinct phenotypic characteristics. Simultaneous CFR and IMR measures appear necessary to differentiate these endotypes.

Characterization of the Human Coronary Microvascular Response to Multiple Hyperaemic Agents.

BACKGROUND: It is unclear whether the coronary microvascular responses to multiple, mechanistically distinct hyperaemic agents exert similar dilatory responses or share common clinical predictors. This study therefore sought to characterize the index of microvascular resistance (IMR) response to multiple hyperaemic agents in the human coronary circulation. METHODS: Thermodilution-derived IMR was determined during intravenous adenosine, intracoronary acetylcholine, and intravenous dobutamine in patients with ischemic symptoms and nonobstructive coronary angiograms. A total of 128 patients were studied (44 with adenosine and acetylcholine, and 84 with all agents). Adenosine IMR >25, acetylcholine IMR >31, and dobutamine IMR >29 were used to define elevated responses. RESULTS: IMR responses demonstrated weak-to-moderate association (adenosine vs acetylcholine IMR: ρ = 0.33; adenosine vs dobutamine IMR: ρ = 0.51; acetylcholine vs dobutamine IMR: ρ = 0.28; all P < 0.01). Logistic regression analyses revealed that: (1) elevated adenosine IMR was associated with increasing age and left ventricle hypertrophy (odds ratio [OR] = 1.27 and 1.58; both P < 0.05, respectively), (2) elevated acetylcholine IMR was associated with increasing plasma uric acid (OR = 1.09; P < 0.05), and (3) elevated dobutamine IMR was associated with hypertension and left atrial volume index (OR = 3.99 and 1.07; both P < 0.05, respectively). Subset analyses to evaluate clinical utility of the acetylcholine and dobutamine IMR, independent of abnormal adenosine IMR, revealed that elevated acetylcholine and/or dobutamine IMR were associated with higher risk exercise stress tests, left atrial volumes, and burden of exertional chest pain. CONCLUSIONS: Microvascular-specific IMR responses to different hyperaemic agents are only moderately associated, whereas the predictors for agent-specific IMR responses varied, suggesting that multiple pharmacologic agents interrogate different microvascular control mechanisms.

CONTEXTE: On ne sait pas vraiment si les réponses microvasculaires coronariennes à de multiples agents hyperémiques aux modes d'action distincts ont des effets vasodilatateurs similaires ou partagent des facteurs prédictifs cliniques communs. Cette étude visait donc à caractériser la réponse selon l'indice de résistance microvasculaire (IMR) aux multiples agents hyperémiques dans la circulation coronarienne chez l'humain. MÉHODOLOGIE: L'IMR obtenu par thermodilution a été déterminé pendant l'administration intraveineuse d'adénosine, intracoronarienne d'acétylcholine et intraveineuse de dobutamine chez des patients présentant des symptômes ischémiques et par angiogrammes coronariens non obstructifs. Un total de 128 patients (44 avec l'adénosine et l'acétylcholine, et 84 avec tous les agents) ont fait partie de l'étude. Des réponses élevées étaient définies par un IMR à l'adénosine > 25, un IMR à l'acétylcholine > 31 et un IMR à la dobutamine > 29. RÉSULTATS: Les réponses selon l'IMR ont révélé une association faible à modérée (IMR à l'adénosine vs IMR à l'acétylcholine : ρ = 0,33; IMR à l'adénosine vs IMR à la dobutamine : ρ = 0,51; IMR à l'acétylcholine vs IMR à la dobutamine : ρ = 0,28; tous : p < 0,01). Des analyses de régression logistique ont révélé que : 1) un IMR à l'adénosine élevé était associé à l'avancement en âge et à une hypertrophie ventriculaire gauche (rapport des cotes [RC] = 1,27 et 1,58; p < 0,05 respectivement pour les deux), 2) un IMR à l'acétylcholine élevé était associé à l'augmentation de la concentration plasmatique d'acide urique (RC = 1,09; p < 0,05) et 3) un IMR à la dobutamine élevé était associé à l'hypertension et à l'indice de volume auriculaire gauche (RC = 3,99 et 1,07; p < 0,05 respectivement pour les deux). Des analyses par sous-groupes visant à évaluer l'utilité clinique de l'IMR à l'acétylcholine et à la dobutamine, indépendamment d'un IMR à l'adénosine anormal, ont révélé que des IMR à l'acétylcholine et/ou à la dobutamine élevés étaient associés à une augmentation du risque lors des épreuves à l'effort, à un volume auriculaire gauche plus élevé et à une augmentation du fardeau associé à la douleur thoracique à l'effort. CONCLUSIONS: Les réponses microvasculaires selon l'IMR à différents agents hyperémiques sont seulement modérément associées, alors que les facteurs prédictifs des réponses selon l'IMR spécifique de l'agent varient, ce qui laisse croire que les multiples agents pharmacologiques font appel à différents mécanismes de contrôle microvasculaire.

Antithrombotic therapy after transcatheter aortic valve replacement: current perspective.

PURPOSE OF REVIEW: Transcatheter aortic valve replacement (TAVR) has expanded as a treatment option for severe aortic stenosis throughout the surgical risk spectrum. Decreasing procedural risk and inclusion of lower risk population has shifted the focus to optimization of postprocedural management and balancing the thrombotic and bleeding complications. In this review, we outline various patient and procedure related factors affecting choice of antithrombotic therapy post TAVR and provide an update of recent development in this area. RECENT FINDINGS: Multiple studies have confirmed the high incidence of both ischemic and bleeding complications in the early to midterm post-TAVR. In addition, new data has emerged for the role of high resolution computed tomography to detect decreased leaflet mobility and leaflet micro thrombi associated with implications for bioprosthetic valve dysfunction and cerebrovascular events post TAVR. Randomized clinical trials have reported increased bleeding with dual antiplatelet therapy (DAPT) and oral anticoagulation (OAC) plus antiplatelet therapy. These findings suggest that aspirin monotherapy or OAC monotherapy likely provides the appropriate balance for antithrombotic protection and risk of bleeding. SUMMARY: Majority of patients undergoing TAVR have multiple comorbidities and are at increased risk of ischemic and bleeding complications. In the absence of robust clinical evidence, there is significant variability among guideline recommendations and antithrombotic therapy post TAVR across institutions. The available evidence confirms a high rate of bleeding with more potent and prolonged antithrombotic regimens without a documented benefit for clinical endpoints. The authors favor a conservative anti thrombotic approach and suggest monotherapy with aspirin or systemic anticoagulation based upon an individual's risk of thromboembolic complications. DAPT is reserved for patients with recent stenting and OAC plus aspirin is prescribed for patients with established CAD in the post TAVR setting.

The first appearance deceives many: Isolated RV infarct masquerading as an anterior STEMI.

Although ST-segment elevation in the precordial leads on an EKG is highly suggestive of occlusion of the left anterior descending artery, the pattern can also result from isolated right ventricular (RV) infarction.

Inequity in Access to Transcatheter Aortic Valve Replacement: A Pan-Canadian Evaluation of Wait-Times.

BACKGROUND: There has been an exponential increase in the demand for transcatheter aortic valve replacement (TAVR). Our goal was to examine trends in TAVR capacity and wait-times across Canada. METHODS: All TAVR cases were identified from April 1, 2014, to March 31, 2017. Wait-time was defined as the duration in days from the initial referral to the TAVR procedure. TAVR capacity was defined as the number of TAVR procedures per million population/province/fiscal year. We performed multivariable multilevel Cox proportional hazards modelling of the time to TAVR as the dependant variable and the effect of provinces as random effects. We quantified the variation in wait-times among provinces using the median hazard ratio. RESULTS: We identified a total of 4906 TAVR procedures across 9 provinces. Despite a year over year increase in overall capacity, there was a greater than 3-fold difference in capacity between provinces. Crude median wait-times increased over time in all provinces, with marked variation from 71.5 days in Newfoundland to 190.5 and 203 days in Manitoba and Alberta, respectively. This suggests increasing demand outpaced the growth in capacity. We found a median hazard ratio of 1.62, indicating that in half of the possible pairwise comparisons, the time to TAVR for identical patients was at least 62% longer between different provinces. CONCLUSION: We found substantial geographic inequity in TAVR access. This calls for policy makers, clinicians, and administrators across Canada to address this inequity through revaluation of provincial funding mechanisms, as well as implementation of efficient care pathways.

Spinal Epidural Hematoma Secondary to Tenecteplase for ST-Elevation Myocardial Infarction in the Setting of Trauma and Cervical Endplate Fracture.

A 78-year-old woman presented with an inferior ST-segment elevation myocardial infarction in the setting of a fall resulting in facial trauma causing an unrecognized C6 cervical endplate fracture. After administration of tenecteplase, she developed a spinal epidural hematoma requiring intubation for airway protection and cessation of antiplatelet therapies. The need to delay coronary intervention in this setting led to a recurrent inferolateral ST-segment elevation myocardial infarction that eventually required coronary bypass grafting. In the first report of a spinal epidural hematoma after tenecteplase for ST-segment elevation myocardial infarction, we emphasize the need for imaging after significant trauma before initiating thrombolysis.

Une femme de 78 ans a été vue en consultation pour un infarctus du myocarde inférieur avec élévation du segment ST, dans un contexte de trauma facial entraîné par une chute, causant une fracture du plateau vertébral de C6 non diagnostiquée. Après avoir reçu du ténectéplase, la patiente a présenté un hématome épidural rachidien ayant nécessité l'intubation pour protéger les voies respiratoires et l'arrêt des traitements antiplaquettaires. La nécessité de retarder l'intervention coronarienne dans ce contexte a entraîné un nouvel infarctus du myocarde inférolatéral avec élévation du segment ST, ayant par la suite nécessité un pontage aortocoronarien. Relativement au premier rapport d'hématome épidural rachidien survenu après l'administration de ténectéplase pour le traitement de l'infarctus du myocarde avec élévation du segment ST, nous insistons sur l'importance de procéder, avant d'instaurer la thrombolyse, à des examens d'imagerie chez les patients ayant subi un trauma important.