Pathophysiology and Treatment of Intraseptal-Course Left Coronary Anomaly: Surgery for All?

Intraseptal-course, ectopic coronary anomalies are not well characterized as to anatomy, function, prognosis, and treatment. Recently, a revolutionary but unsupported new theory is claiming that most patients with a Left Anomalous Coronary Artery originating from the Opposite Sinus with anomalous Intra-Septal course (L-ACAOS-IS)-even small children-have significant stenoses and require open-heart surgery to prevent acute myocardial infarction and death. This surprising view has spurred ongoing discussions among adult and pediatric cardiologists and cardiac surgeons, compelling us (the conservative party in the discussion) to offer an in-depth and comprehensive review of this anomaly, based on objective but opposite data. We and other adult cardiologists have followed numerous L-ACAOS-IS patients for many years and have observed none of the claimed catastrophes. Rather, we have consistently found that L-ACAOS-IS generally has a benign clinical prognosis. We present the general principle of coronary artery dysfunction in anatomical congenital anomalies (that only significant luminal coronary stenosis can have clinical repercussions). We then review anatomical and functional details of L-ACAOS-IS related to prognosis and treatment indications, which could explain many of the clinical presentations recently mentioned. Finally, we encourage our more liberal colleagues to recognize that, compared with normal coronary arteries, those with anomalies of origin and course are associated with frequent coronary spasm. In particular, we underscore that some of the ischemic manifestations and other results might actually be caused by pressure wire-induced artifacts (rigid wires tend to cause coronary spasm when advanced into tortuous coronary arteries).

Can ectopic right coronary from the left sinus have a different course than intramural? A case of ectopic right with retroaortic course.

Retrocardiac course of an ectopic right coronary artery is newly described. The alternative (usual) course of an anomalous right coronary from the left sinus of Valsalva is pre-aortic and intramural, with stenosis. In the present exceptional case, there was no stenosis.

Symptomatic right coronary anomaly with dynamic systolic intramural obliteration and isolated right ventricular ischemia.

A 52-year-old man was referred for an anomalous right coronary artery (RCA) originating from the left sinus of Valsalva with an intramural course (R-ACAOS-IM), accompanied by progressive angina and dyspnea. He had been initially advised to have surgical treatment. Computerized axial tomographic angiography showed he had an ectopic origin from the left sinus of a small RCA, with a course between the aorta and pulmonary artery. His negative treadmill nuclear stress test was prematurely terminated because of angina and dyspnea. At our institution, intravascular ultrasound imaging indicated an intramural course and critically severe phasically changing proximal stenosis (80%-100%). The stenosis was resolved with stent-angioplasty of the intramural segment. He had no complications and returned quickly to an asymptomatic state with unrestricted physical activity.

Imaging Approaches for Coronary Artery Anomalies: Purpose and Techniques.

PURPOSE OF REVIEW: Comprehensive discussion of alternative techniques in imaging coronary artery anomalies (CAAs) in different diagnostic scenarios. RECENT FINDINGS: At primary screening, intramural course essentially correlates with stenosis and clinical repercussion in some types of CAAs. Potential clinical aims in imaging patients with CAAs may be primary screening, severity evaluation, preoperative planning, and postoperative follow-up. Appropriate techniques are echocardiography, magnetic resonance imaging, computed tomography angiography, and intravascular ultrasound (IVUS). Rarely, IVUS may be needed in patients with potentially serious CAAs and has unique advantages and limitations. IVUS data are essential for in-depth knowledge of mechanisms of coronary dysfunction (exercise-related dynamic stenosis of variable severity) and for indicating interventional treatment. In adolescents or adults, intramural course of an anomalous coronary artery is the only important feature accompanied by stenosis of potential severity and is especially relevant in patients with a high-risk status (elite sport athletes, military recruits).

Anatomic spectrum of left coronary artery anomalies and associated mechanisms of coronary insufficiency.

This is a novel re-appraisal of an understudied and misunderstood group of important coronary anomalies. The general name of the group is "anomalous origin of the left coronary artery," but several additional details should be included in this group of anomalies and the explanation of their pathophysiology. The most lethal form in young athletes or military recruits features intramural aortic proximal course. This comprehensive review is based on a large experience at a dedicated center for coronary artery anomalies, using evolving knowledge (over 20 years) while employing prospective and disciplined programs of evaluation and treatment, according to the nature and severity of each anomaly. The most common pathogenic mechanism of coronary dysfunction relates to intramural coronary course, with or without ectopic origin, leading to variable lateral compression and stenosis inside the aortic tunica media; this compression is present at rest and worsens with exertion. We propose that such variable and dynamic stenoses can be best studied by examining their specific anatomy and clinical presentation, stress testing, and, most importantly, in vivo evaluation by intravascular ultrasonography. Such methods should be used to support individual risk evaluation and selection among treatment options.

Origin of the right coronary artery from the opposite sinus of Valsalva in adults: characterization by intravascular ultrasonography at baseline and after stent angioplasty.

OBJECTIVES: We attempted to characterize the anatomy, function, clinical consequences, and treatment of right-sided anomalous coronary artery origin from the opposite side (R-ACAOS). BACKGROUND: Anomalous aortic origin of a coronary artery is a source of great uncertainty in cardiology. A recent study by our group found that ACAOS had a high prevalence (0.48%) in a general population of adolescents. METHODS: Sixty-seven consecutive patients were diagnosed with R-ACAOS according to a new definition: ectopic right coronary artery (RCA) with an intramural proximal course. We used intravascular ultrasonograms of the RCA to quantify congenital stenosis (in patients with potentially serious clinical presentations), and we correlated these measurements with clinical manifestations. RESULTS: All patients had some proximal intramural stenosis (mean 50%, range 16-83% of the cross-sectional area). Forty-two patients (62%) underwent stent-percutaneous coronary intervention (PCI) of R-ACAOS because of significant symptoms, positive stress tests, and/or significant stenosis. Stent-PCI was successful in all cases and correlated with improved symptoms at >1-year follow-up in 30 patients (71%) who were available for clinical follow-up. No ACAOS-related deaths occurred. The instent restenosis rate was 4/30 (13%) at a mean follow-up time of 5.0 years. CONCLUSIONS: This preliminary, but large and unprecedented observational study shows that cases angiographically identified as R-ACAOS universally feature an intramural aortic course but only occasionally severe stenosis on resting IVUS imaging. Our data suggest that stent-PCI with IVUS monitoring ameliorates patients' presenting symptoms.

Critical update and discussion of the prevalence, nature, mechanisms of action, and treatment options in potentially serious coronary anomalies.

As widely discussed in recent literature, coronary artery anomalies only occasionally lead to potentially serious myocardial ischemic events. The most important group of coronary anomalies has been called anomalous coronary artery origin from an abnormal sinus or a site in the ascending aorta (ACAOS). Only some cases of right- or left-sided intramural-course ACAOS (R-ACAOS-IM or L-ACAOS-IM) can potentially cause significant symptoms or sudden cardiac death, typically during exertion in athletes. After an ACAOS-IM case is qualitatively identified, it is necessary to establish the severity of associated stenosis (which is always present to some degree in ACAOS-IM). The 3 stages of a comprehensive diagnostic process are: 1. initial screening of high-risk populations (young elite athletes, optimally by use of magnetic resonance imaging [MRI]) to identify the prevalence of similar cases in large populations (the denominator of any risk calculation); 2. evaluating symptoms (chest pain, syncope, or sudden death) and performing stress testing; 3. in patients found to carry ACAOS-IM, evaluating the severity of coronary obstruction by intravascular ultrasonography, which is an objective, definitive, and quantifying imaging modality for this condition, essential in selected carriers of such anomalies. The possible treatment alternatives are discussed and updated.

Can Significant Coronary Artery Disease Coexist With Transient Takotsubo Cardiomyopathy, and How Does Spasm Interrelate?

An 86-year-old woman being treated for metastatic breast cancer developed severe chest pain at rest during a follow-up visit at a hospital's outpatient oncology clinic. An electrocardiogram showed severe ST-segment elevation. The patient was given sublingual nitroglycerin and was transferred to the emergency department. Diagnostic coronary angiography revealed moderate coronary artery disease with calcific stenoses and transient spastic occlusion of the left anterior descending coronary artery. For this patient, sublingual nitroglycerin aborted the spastic event and apparent transient takotsubo cardiomyopathy. Chemotherapy can potentially cause endothelial dysfunction and increased coronary spasticity, which could result in takotsubo cardiomyopathy.

COVID-19 and the Heart: Could Transient Takotsubo Cardiomyopathy Be Related to the Pandemic by Incidence and Mechanisms?

Typical emergency hospital care during the COVID-19 pandemic has centered on pulmonary-focused services. Nonetheless, patients with COVID-19 frequently develop complications associated with the dysfunction of other organs, which may greatly affect prognosis. Preliminary evidence suggests that cardiovascular involvement is relatively frequent in COVID-19 and that it correlates with significant worsening of clinical status and mortality in infected patients. In this article, we summarize current knowledge on the cardiovascular effects of COVID-19. In particular, we focus on the association between COVID-19 and transient takotsubo cardiomyopathy (TTC)-two conditions that preliminarily seem epidemiologically associated-and we highlight cardiovascular changes that may help guide future investigations toward full discovery of this new, complex disease entity. We hypothesize that coronary endothelial dysfunction, along with septic state, inflammatory storm, hypercoagulability, endothelial necrosis, and small-vessel clotting, may represent a fundamental hidden link between COVID-19 and TTC. Furthermore, given the likelihood that new genetic mutations of coronaviruses or other organisms will cause similar pandemics and endemics in the future, we must be better prepared so that a substantial complication such as TTC can be more accurately recognized, its pathophysiology better understood, and its treatment made more justifiable, timely, and effective.

Trigger related outcomes of takotsubo syndrome in a cancer population.

Background: Takotsubo syndrome (TTS) occurs more frequently in cancer patients than in the general population, but the effect of specific TTS triggers on outcomes in cancer patients is not well studied. Objectives: The study sought to determine whether triggering event (chemotherapy, immune-modulators vs. procedural or emotional stress) modifies outcomes in a cancer patient population with TTS. Methods: All cancer patients presenting with acute coronary syndrome (ACS) between December 2008 and December 2020 at our institution were enrolled in the catheterization laboratory registry. Demographic and clinical data of the identified patients with TTS were retrospective collected and further classified according to the TTS trigger. The groups were compared with regards to major adverse cardiac events, overall survival and recovery of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) after TTS presentation. Results: Eighty one of the 373 cancer patients who presented with ACS met the Mayo criteria for TTS. The triggering event was determined to be "cancer specific triggers" (use of chemotherapy in 23, immunomodulators use in 7, and radiation in 4), and "traditional triggers" (medical triggers 22, and procedural 18 and emotional stress in 7). Of the 81 patients, 47 died, all from cancer-related causes (no cardiovascular mortality). Median survival was 11.9 months. Immunomodulator (IM) related TTS and radiation related TTS were associated with higher mortality during the follow-up. Patients with medical triggers showed the least recovery in LVEF and GLS while patients with emotional and chemotherapy triggers, showed the most improvement in LVEF and GLS, respectively. Conclusion: Cancer patients presenting with ACS picture have a high prevalence of TTS due to presence of traditional and cancer specific triggers. Survival and improvement in left ventricular systolic function seem to be related to the initial trigger for TTS.

White Clot Formation at Acetylcholine Testing: A Change of Heart in MINOCA?

Coronary intraluminal white clot formation, apparently in response to acetylcholine testing, may explain a woman's long-term history of daily chest pain and multiple myocardial infarctions. Acetylcholine testing reproduced chest pain and revealed luminal filling defects in multiple vessels; imaging showed fresh white platelet clots. Antiplatelet prasugrel has substantially suppressed her symptoms. (Level of Difficulty: Advanced.).

Pathophysiology of Takotsubo Cardiomyopathy: Reopened Debate.

Takotsubo cardiomyopathy (TTC), a persistently obscure dysfunctional condition of the left ventricle, is uniquely transient but nevertheless dangerous. It features variable ventricular patterns and is predominant in women. For 30 years, pathophysiologic investigations have progressed only slowly and with inadequate focus. It was initially proposed that sudden-onset spastic obliteration of coronary flow induced myocardial ischemia with residual stunning and thus TTC. Later, it was generally accepted without proof that, in the presence of pain or emotional stress, the dominant mechanism for TTC onset was a catecholamine surge that had a direct, toxic myocardial effect. We think that the manifestations of TTC are more dynamic and complex than can be assumed from catecholamine effects alone. In addition, after reviewing the recent medical literature and considering our own clinical observations, especially on spasm, we theorize that atherosclerotic coronary artery disease modulates and physically opposes obstruction during spasm. This phenomenon may explain the midventricular variant of TTC and the lower incidence of TTC in men. We continue to recommend and perform acetylcholine testing to reproduce TTC and to confirm our theory that coronary spasm is its initial pathophysiologic factor. An improved understanding of TTC is especially important because of the condition's markedly increased incidence during the ongoing COVID-19 pandemic.

Young athletes: Preventing sudden death by adopting a modern screening approach? A critical review and the opening of a debate.

Preventing sudden cardiac death (SCD) in athletes is a primary duty of sports cardiologists. Current recommendations for detecting high-risk cardiovascular conditions (hr-CVCs) are history and physical examination (H&P)-based. We discuss the effectiveness of H&P-based screening versus more-modern and accurate methods. In this position paper, we review current authoritative statements and suggest a novel alternative: screening MRI (s-MRI), supported by evidence from a preliminary population-based study (completed in 2018), and a prospective, controlled study in military recruits (in development). We present: 1. Literature-Based Comparisons (for diagnosing hr-CVCs): Two recent studies using traditional methods to identify hr-CVCs in >3,000 young athletes are compared with our s-MRI-based study of 5,169 adolescents. 2. Critical Review of Previous Results: The reported incidence of SCD in athletes is presently based on retrospective, observational, and incomplete studies. H&P's screening value seems minimal for structural heart disease, versus echocardiography (which improves diagnosis for high-risk cardiomyopathies) and s-MRI (which also identifies high-risk coronary artery anomalies). Electrocardiography is valuable in screening for potentially high-risk electrophysiological anomalies. 3. Proposed Project : We propose a prospective, controlled study (2 comparable large cohorts: one historical, one prospective) to compare: (1) diagnostic accuracy and resulting mortality-prevention performance of traditional screening methods versus questionnaire/electrocardiography/s-MRI, during 2-month periods of intense, structured exercise (in military recruits, in advanced state of preparation); (2) global costs and cost/efficiency between these two methods. This study should contribute significantly toward a comprehensive understanding of the incidence and causes of exercise-related mortality (including establishing a definition of hr-CVCs) while aiming to reduce mortality.

Left main-like bifurcation primary percutaneous coronary intervention case report: anomalous right coronary artery ostium from the left anterior descending.

BACKGROUND: A single coronary artery ostium (SCAO) is estimated to be present in 0.066% of the general population. The proximal coronary course and the relationship with surrounding structures are related to malignant vs. benign prognoses. We present a case of SCAO with the right coronary artery (RCA) arising from the mid-left anterior descending (LAD), complicated by anterior and inferior STEMI because of acute thrombotic occlusion at the bifurcation and its percutaneous management. CASE SUMMARY: A 56-year-old male was admitted with sudden onset of resting chest pain. His ECG showed an anterior, inferior, and right ventricular STEMI. Via trans-radial access, coronary angiography showed significant stenoses at the left main and the circumflex but also a thrombotic occlusion at the proximal segment of the LAD while no RCA was seen. After crossing the LAD occlusion, the dominant RCA appeared from the mid-LAD. A provisional stent technique was performed achieving good results. Coronary computed tomography angiography showed an SCAO congenital anomaly with a patent stent in the bifurcation accompanied by diffuse coronary artery disease causing mild stenosis of the left main, proximal, and distal circumflex. DISCUSSION: The RCA arising from the mid-LAD with pre-pulmonic course has been described in only 37 cases. One reported an LAD/RCA bifurcation treatment with two stents technique in a stable scenario. The present is the first case reported of an acute thrombotic occlusion of an LAD/RCA bifurcation clinically resulting in a left main equivalent STEMI treated successfully with primary percutaneous coronary intervention using a bifurcation technique.

Is Transient Takotsubo Syndrome Associated With Cancer? Why, and With What Implications for Oncocardiology?

See Article Cammann et al.

Embryology of coronary arteries and anatomy/pathophysiology of coronary anomalies. A comprehensive update.

OBJECTIVES: This paper reviews new findings in both embryology of coronary arteries and in clinical observations of coronary artery anomalies. FOCUS: Our presentation emphasizes studies based on: 1) newer methods of coronary development in animals and humans, and 2) intravascular ultrasonography to interpret pathophysiology and guide treatment of coronary anomalies. CONCLUSIONS: New data reveal the roles of many cellular interactions and signaling pathways involved in the normal and abnormal formation of the coronary arterial system and the consequences of their defective formation. Pathogenetic developmental mechanisms include dysfunction of the Notch and Hypo signaling pathways, angiogenic and arteriogenic molecules, and neural crest cells. We addressed numerous clinically significant coronary anomalies and their prevalence in a general population (especially those characterized by an ectopic origin with aortic intramural course), and point out the critical relevance of understanding the variable mechanisms of coronary dysfunction, especially, fixed versus phasic stenoses or intermittent spasm, and individual severity of clinical presentations.

Low Origin of the Coronary Arteries and a Small Aortic Annulus Complicating Aortic Valve Replacement.

Low origin of the coronary arteries, defined as an origin less than 10 mm above the functional aortic annulus, is not usually considered to be a notable anomaly because functional impairment is not intrinsic. We describe a case of severe complications after surgical aortic valve replacement in a 59-year-old woman who had symptomatic aortic valve stenosis, low origin of both main coronary arteries, and a hypoplastic aortic annulus less than 19 mm in diameter. The aortic prosthesis had to be implanted above the hypoplastic anatomic annulus. An inferior-wall myocardial infarction, hypotension, right-sided heart failure, and atrial fibrillation developed during the early perioperative period. Coronary angiograms showed occlusion of the right coronary artery ostium and critical stenosis of the left coronary ostium. During reoperation, posterior aortic patch annuloplasty enabled lower reimplantation of the prosthetic aortic valve, jointly with right coronary artery-venous grafting. To prevent potentially severe complications, we recommend that low origin of the coronary arteries be reported before patients undergo surgical aortic valve replacement. If the ostia are not seen when routine coronary angiography is used, computed tomography should be prospectively performed to characterize this anomaly.

Coronary artery anomalies: an entity in search of an identity.

Coronary artery anomalies (CAAs) are a diverse group of congenital disorders whose manifestations and pathophysiological mechanisms are highly variable. The subject of CAAs is undergoing profound evolutionary changes related to the definition, morphogenesis, clinical presentation, diagnostic workup, prognosis, and treatment of these anomalies. To understand the clinical impact of CAAs, the fundamental challenge is the firm establishment, for a particular type of CAA, of a mechanism capable of interference with the coronary artery's function, which is to provide adequate blood flow to the dependent myocardium. The present review focuses on anomalous origination of a coronary artery from the opposite sinus--the subgroup of CAAs that has the most potential for clinical repercussions, specifically sudden death in the young. For this subgroup, solid diagnostic screening protocols should be established, especially for athletes and other young individuals subjected to extreme exertion. Intravascular ultrasonography is the preferred means to evaluate the mechanisms responsible for ischemia in anomalous origination of a coronary artery from the opposite sinus and other potentially significant CAAs. Patients symptomatic of anomalous origination of a coronary artery from the opposite sinus may undergo medical treatment/observation, coronary angioplasty with stent deployment, or surgical repair. To be competent to advise CAA carriers, especially in the context of sporting or military activities, cardiologists should undergo specific training in these disorders. Only multicenter collaboration on protocols dedicated to CAAs can give rise to the large-scale studies needed to define the prognosis and optimal treatment of these disorders.