Genetic associations of cardiovascular risk genes in European patients with coronary artery spasm.

BACKGROUND: Coronary artery spasm (CAS) is a frequent finding in patients presenting with angina pectoris. Although the pathogenesis of CAS is incompletely understood, previous studies suggested a genetic contribution. Our study aimed to elucidate genetic variants in a cohort of European patients with angina and unobstructed coronary arteries who underwent acetylcholine (ACh) provocation testing. METHODS: A candidate association analysis of 208 genes previously associated with cardiovascular conditions was performed using genotyped and imputed variants in patients grouped in epicardial (focal, diffuse) CAS (n = 119) and microvascular CAS (n = 87). Patients with a negative ACh test result (n = 45) served as controls. RESULTS: We found no association below the genome-wide significance threshold of p < 5 × 10-8, thus not confirming variants in ALDH2, NOS3, and ROCK2 previously reported in CAS patients of Asian ancestry. However, the analysis identified suggestive associations (p < 10-05) for the groups of focal epicardial CAS (CDH13) and diffuse epicardial CAS (HDAC9, EDN1). Downstream analysis of the potential EDN1 risk locus showed that CAS patients have significantly increased plasma endothelin-1 levels (ET-1) compared to controls. An EDN1 haplotype comprising rs9349379 and rs2070698 was significantly associated to ET-1 levels (p = 0.01). CONCLUSIONS: In summary, we suggest EDN1 as potential genetic risk loci for patients with diffuse epicardial CAS, and European ancestry. Plasma ET-1 levels may serve as a potential cardiac marker.

Characterization and implications of intracoronary hemodynamic assessment during coronary spasm provocation testing.

BACKGROUND: Current diagnostic criteria for coronary spasm are based on patient's symptoms, ECG shifts and epicardial vasoconstriction during acetylcholine (ACh) spasm testing. AIMS: To assess the feasibility and diagnostic value of coronary blood flow (CBF) and resistance (CR) assessment as objective parameters during ACh testing. METHODS: Eighty-nine patients who underwent intracoronary reactivity testing including ACh testing with synchronous Doppler wire-based measurements of CBF and CR were included. Coronary microvascular and epicardial spasm, respectively, were diagnosed based on COVADIS criteria. RESULTS: Patients were 63 ± 13 years old, predominantly female (69%) and had preserved LV ejection fraction (64 ± 8%). Overall, assessment of CBF and CR during ACh testing revealed a decrease in CBF of 0.62 (0.17-1.53)-fold and an increase of CR of 1.45 [0.67-4.02]-fold in spasm patients compared to 2.08 (1.73-4.76) for CBF and 0.45 (0.44-0.63) for CR in patients without coronary spasm (both p < 0.01). Receiver operating characteristic revealed a high diagnostic ability of CBF and CR (AUC 0.86, p < 0.001, respectively) in identifying patients with coronary spasm. However, in 21% of patients with epicardial spasm and 42% of patients with microvascular spasm a paradoxical response was observed. CONCLUSIONS: This study demonstrates feasibility and potential diagnostic value of intracoronary physiology assessments during ACh testing. We observed opposite responses of CBF and CR to ACh in patients with positive vs. negative spasm test. While a decrease in CBF and an increase in CR during ACh seem pathognomonic for spasm, some patients with coronary spasm demonstrate paradoxical ACh response demanding further scientific investigations.

Myocardial Perfusion PET for the Detection and Reporting of Coronary Microvascular Dysfunction: A JACC: Cardiovascular Imaging Expert Panel Statement.

Angina pectoris and dyspnea in patients with normal or nonobstructive coronary vessels remains a diagnostic challenge. Invasive coronary angiography may identify up to 60% of patients with nonobstructive coronary artery disease (CAD), of whom nearly two-thirds may, in fact, have coronary microvascular dysfunction (CMD) that may account for their symptoms. Positron emission tomography (PET) determined absolute quantitative myocardial blood flow (MBF) at rest and during hyperemic vasodilation with subsequent derivation of myocardial flow reserve (MFR) affords the noninvasive detection and delineation of CMD. Individualized or intensified medical therapies with nitrates, calcium-channel blockers, statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1-receptor blockers, beta-blockers, ivabradine, or ranolazine may improve symptoms, quality of life, and outcome in these patients. Standardized diagnosis and reporting criteria for ischemic symptoms caused by CMD are critical for optimized and individualized treatment decisions in such patients. In this respect, it was proposed by the cardiovascular council leadership of the Society of Nuclear Medicine and Molecular Imaging to convene thoughtful leaders from around the world to serve as an independent expert panel to develop standardized diagnosis, nomenclature and nosology, and cardiac PET reporting criteria for CMD. This consensus document aims to provide an overview of the pathophysiology and clinical evidence of CMD, its invasive and noninvasive assessment, standardization of PET-determined MBFs and MFR into "classical" (predominantly related to hyperemic MBFs) and "endogen" (predominantly related to resting MBF) normal coronary microvascular function or CMD that may be critical for diagnosis of microvascular angina, subsequent patient care, and outcome of clinical CMD trials.

Meta-analysis and systematic review of coronary vasospasm in ANOCA patients: Prevalence, clinical features and prognosis.

Background: Coronary artery spasm (CAS), encompassing epicardial and microvascular spasm, is increasingly recognized as cause of angina in patients with non-obstructive coronary artery disease (ANOCA). However, various spasm provocation testing protocols and diagnostic criteria are used, making diagnosis and characterization of these patients difficult and interpretation of study results cumbersome. This review provides a structured overview of the prevalence, characterization and prognosis of CAS worldwide in men and women. Methods: A systematic review identifying studies describing ANOCA patients with CAS was performed. Multiple outcomes (prevalence, clinical features, and prognosis) were assessed. Data, except for prognosis were pooled and analysed using random effects meta-analysis models. Results: Twenty-five publications (N = 14.554) were included (58.2 years; 44.2% women). Percentages of epicardial constriction to define epicardial spasm ranged from >50% to >90%. Epicardial spasm was prevalent in 43% (range 16-73%), with a higher prevalence in Asian vs. Western World population (52% vs. 33%, p = 0.014). Microvascular spasm was prevalent in 25% (range 7-39%). Men were more likely to have epicardial spasm (61%), women were more likely to have microvascular spasm (64%). Recurrent angina is frequently reported during follow-up ranging from 10 to 53%. Conclusion: CAS is highly prevalent in ANOCA patients, where men more often have epicardial spasm, women more often have microvascular spasm. A higher prevalence of epicardial spasm is demonstrated in the Asian population compared to the Western World. The prevalence of CAS is high, emphasizing the use of unambiguous study protocols and diagnostic criteria and highlights the importance of routine evaluation of CAS in men and women with ANOCA. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=272100.

Reference values for intracoronary Doppler flow velocity-derived hyperaemic microvascular resistance index.

BACKGROUND: Invasive assessments of microvascular function are rapidly becoming an integral part of physiological assessment in chronic coronary syndromes. OBJECTIVE: We aimed to establish a reference range for Doppler flow velocity-derived hyperaemic microvascular resistance index (HMR) in a cohort of angina with no significant epicardial coronary obstruction (ANOCA) patients with no structural pathophysiological alterations in the coronary circulation. METHODS: The reference population consisted of ANOCA patients undergoing invasive coronary vasomotor function assessment who had a coronary flow reserve (CFR) >2.5, and had either (1) tested negatively for spasm provocation (n = 12) or (2) tested positively with only angina at rest (n = 29). A reference range for HMR was established using a non-parametric method and correlations with clinical characteristics were determined using a spearman rank correlation analysis. RESULTS: In 41 patients median HMR amounted to 1.6 mmHg/cm/s [Q1, Q3: 1.3, 2.2 mmHg/cm/s]. The reference range for HMR that is applicable to 95% of the population was 0.8 mmHg/cm/s (90% CI: 0.8-1.0 mmHg/cm/s) to 2.7 mmHg/cm/s (90% CI: 2.6-2.7 mmHg/cm/s). No significant correlations were found between HMR and clinical characteristics. CONCLUSION: In this reference population undergoing invasive coronary vasomotor function testing, the 90% confidence interval of the HMR upper limit of normal ranges from 2.6 to 2.7 mmHg/cm/s. A > 2.5 mmHg/cm/s HMR threshold can be used to identify abnormal microvascular resistance in daily clinical practice.

Epicardial atherosclerosis and coronary tortuosity in patients with acetylcholine-induced coronary spasm.

BACKGROUND: Angina pectoris in the absence of relevant epicardial stenoses is frequently caused by coronary spasm. This mechanism of angina is common yet underdiagnosed in daily clinical practice. The pathophysiology of coronary spasm is complex, multifactorial, and not completely understood. The purpose of this study was to analyze the relationship between macroscopic coronary morphologies and coronary spasm. METHODS: Epicardial atherosclerosis, coronary vessel tortuosity, coronary aneurysms, and myocardial bridges were analyzed angiographically in 610 patients and a potential association with the result of an intracoronary acetylcholine (ACh) provocation test was investigated. RESULTS: The comparison showed that angiographic morphologic variations in the coronary arteries are related to the occurrence of coronary spasm. We observed a strong association between the presence of epicardial atherosclerosis and epicardial spasm [87 patients of 179 with epicardial spasm had epicardial atherosclerosis (49%) vs. 45 patients of 172 with microvascular spasm (26%) vs. 89 patients of 259 with negative/inconclusive ACh test (36%); P < 0.005]. Moreover, we found a higher frequency of coronary tortuosity in patients with microvascular spasm [99 patients of 172 with microvascular spasm had at least moderate coronary tortuosity (58%) vs. 76 patients of 179 with epicardial spasm (43%) vs. 126 patients of 259 with negative/inconclusive ACh test (49%); P = 0.017]. Multivariable analysis revealed epicardial atherosclerosis (<50% stenosis) on coronary angiography as a predictor for epicardial spasm (OR, 2.096; 95% CI, 1.467-2.995; P < 0.0005). Female sex (OR, 5.469; 95% CI, 3.433-8.713; P < 0.0005), and exertional angina (OR, 2.411; 95% CI, 1.597-3.639; P < 0.0005) were predictors of microvascular spasm in multivariable analysis. CONCLUSION: In angina patients with no obstructive coronary artery disease, epicardial atherosclerosis is associated with ACh-induced epicardial coronary spasm. Moreover, coronary microvascular spasm is more prevalent in female patients and those with exertional angina. Our results provide insights into the relationship between coronary morphology and coronary vasomotor function.

Usefulness of wearable electrocardiography devices in patients experiencing paroxysmal cardiac-related symptoms: A case series of the "CardioSecur" system.

Background: Electrocardiograms (ECGs) recorded with wearable devices and additional smartphone apps play an increasing role in cardiology. Case summaries: We present two cases in which it was possible to record an ECG during cardiac-related symptoms using the patients' smartphones. Previous standard resting and 24-hour ECGs had revealed no pathologies. In one case, AV nodal reentry tachycardia was detected and treated accordingly. In the second case, ischemic ECG changes were recorded in a young woman without cardiovascular risk factors during a chest pain episode. Suspecting a coronary vasomotion disorder, an invasive diagnostic procedure was performed. The acetylcholine spasm provocation test revealed coronary microvascular spasm and appropriate therapy was initiated. Discussion: Smartphone-based ECG systems which can be used by the patient independently while experiencing cardiac-related symptoms are a modern diagnostic tool. Considering the use of these systems is beneficial for early diagnosis and appropriate treatment for paroxysmal arrhythmias and coronary vasomotion disorders.

Prognostic association of plasma NT-proBNP levels in patients with microvascular angina -A report from the international cohort study by COVADIS.

BackgroudThe aim of this study was to assess the prognostic association of plasma levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) with clinical outcomes of patients with microvascular angina (MVA). Methods: In this international prospective cohort study of MVA by the Coronary Vasomotor Disorders International Study (COVADIS) group, we examined the association between plasma NT-proBNP levels and the incidence of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. Results: We examined a total of 226 MVA patients (M/F 66/160, 61.9 ± 10.2 [SD] yrs.) with both plasma NT-proBNP levels and echocardiography data available at the time of enrolment. The median level of NT-proBNP level was 94 pg/ml, while mean left ventricular ejection fraction was 69.2 ± 10.9 % and E/e' 10.7 ± 5.2. During follow-up period of a median of 365 days (IQR 365-482), 29 MACEs occurred. Receiver-operating characteristics curve analysis identified plasma NT-proBNP level of 78 pg/ml as the optimal cut-off value. Multivariable logistic regression analysis revealed that plasma NT-proBNP level ≥ 78 pg/ml significantly correlated with the incidence of MACE (odds ratio (OR) [95 % confidence interval (CI)] 3.11[1.14-8.49], P = 0.001). Accordingly, Kaplan-Meier survival analysis showed a significantly worse prognosis in the group with NT-proBNP ≥ 78 (log-rank test, P < 0.03). Finally, a significant positive correlation was observed between plasma NT-proBNP levels and E/e' (R = 0.445, P < 0.0001). Conclusions: These results indicate that plasma NT-proBNP levels may represent a novel prognostic biomarker for MVA patients.

[Management of chronic coronary syndrome]. / Management des chronischen Koronarsyndroms.

Coronary artery disease remains the leading cause of death in developed countries. This CME article addresses and comments on important aspects from the current guidelines for the diagnosis and management of chronic coronary syndrome of the European Society of Cardiology (ESC) and the current guidelines for the evaluation and diagnosis of chest pain of the American Heart Association (AHA)/the American College of Cardiology (ACC).

Management of patients with ST-segment myocardial infarction and multivessel disease: what are the options in 2022?

Multivessel coronary disease is a frequent finding in patients with STEMI. However, choosing the optimal treatment strategy for these patients can be challenging. The benefit of complete versus culprit-vessel-only revascularization demonstrated by several studies led to a change in the current 2018 ESC/EACTS revascularization guidelines recommending treatment of nonculprit lesions before hospital discharge. This article summarizes current data in this area, looks at remaining knowledge gaps and gives an outlook regarding ongoing trials. The latter will provide further robust evidence for the optimal management of patients with STEMI and multivessel disease.

Epicardial and microvascular coronary artery spasm in biopsy-proven viral myocarditis.

BACKGROUND: Coronary spasm has been suggested to be the underlying mechanism of chest pain in patients with myocarditis and unobstructed coronary arteries. Here we sought to investigate a potential association between virus type and coronary spasm endotype in patients with biopsy-proven viral myocarditis. METHODS: A total of 618 consecutive patients with unobstructed coronary arteries who underwent endomyocardial biopsy between 2008 and 2018 were screened. Viral myocarditis defined as (immuno-)histological evidence of myocardial inflammation and proof of viral genome by PCR was confirmed in 114 patients. Of these, 34 patients had undergone additional intracoronary acetylcholine (ACh) testing and served as the final study cohort. RESULTS: Patients in this study were 51 ± 27 years old, 41% were female and mean left ventricular ejection fraction was 58 ± 23%. Most frequently, virus DNA was detected by PCR from parvovirus B19 (PVB19, 59%) and human herpesvirus 6 (HHV6, 26%). ACh testing revealed epicardial spasm in 10 patients (29%) and microvascular spasm in 11 patients (32%). The rate of coronary spasm was higher in patients with PVB19-associated myocarditis compared to those with HHV6-associated myocarditis (80% vs. 33%, p = 0.031). In particular, there was a higher prevalence of microvascular spasm in patients with PVB19 compared to HHV6 infection (45% vs. 0%, p = 0.018). CONCLUSION: Coronary spasm is a frequent finding in patients with biopsy-proven viral myocarditis supporting the hypothesis that coronary spasm may contribute to chest pain in these patients. We observed a particular association of microvascular spasm with PVB19 infection.

Update on coronary artery spasm 2022 - A narrative review.

IMPORTANCE: In today's era of precision medicine a renaissance of functional coronary disease including coronary artery spasm (CAS) can be observed. This development is fueled by novel diagnostic methods as well as first evidence from randomized trials regarding targeted treatment approaches. The present review provides a contemporary update on advances in the pathophysiological understanding, diagnosis, treatment and prognosis of CAS. OBSERVATIONS: A MEDLINE/PubMed search within the period from 2010 to 2021 was performed focusing on original articles, randomized clinical trials, meta-analyses and systematic reviews on CAS. Among 1.639 citations, articles that were considered to contain the most important and novel data on CAS were included in this narrative review. These articles comprise reports on new insights into the complex pathophysiology of CAS, state-of-the-art invasive diagnostic procedures, reports on diagnosis of microvascular spasm and diagnosis of CAS in special conditions such as MINOCA, post-PCI angina or myocarditis. Moreover, novel treatment approaches are included such as nebivolol, endothelin-1-receptor antagonists and soluble guanylate cyclase stimulators. Furthermore, recent follow-up studies have provided new data on long-term prognosis of affected patients. CONCLUSIONS: Scientific progress during the last decade has led to a better understanding of CAS. Today, standardized international diagnostic criteria are available and promising randomized treatment trials are on their way. Moreover, there has been increasing evidence regarding the prognostic value of CAS testing. However, despite many advances, CAS remains a complex and not fully understood condition and more research is needed to better characterize and treat affected patients.

Prevention of epicardial coronary artery spasm with intracoronary nitroglycerine during acetylcholine testing in a female patient with resting angina-implications for optimal pharmacological management.

We here present the case of a 55-year old woman who presented with recurrent angina at rest followed by presyncopal attacks and nausea to our clinic. Her only cardiovascular risk factor was arterial hypertension. High-sensitive troponin T was 3 pg/ml (n < 14 pg/ml) and the 12-lead resting ECG was unremarkable. Differential diagnoses included stenosing coronary artery disease and coronary artery spasm. Thus, invasive coronary angiography was performed showing unobstructed coronary arteries. Acetylcholine (ACh) provocation testing in search of coronary spasm showed diffuse epicardial spasm of the left anterior descending coronary artery (LAD) and focal spasm of the left circumflex coronary artery (LCX), which could be resolved by intracoronary administration of 0.2 mg nitroglycerine (NTG). To evaluate the potential protective effect of NTG, ACh provocation testing was repeated after NTG injection. This rechallenge showed no more epicardial spasm, suggesting that NTG had a protective antispastic effect on the epicardial arteries in this patient. Symptom control in patients with angina due to coronary artery spasm can be challenging as pharmacological agents are often prescribed on a trial and error basis. With this case, we present a novel approach toward a more individualized pharmacotherapy in coronary artery spasm using a modified protocol for invasive coronary spasm testing, which could avoid ineffective treatment trials in such patients.

Acetylcholine Rechallenge: A First Step Toward Tailored Treatment in Patients With Coronary Artery Spasm.

OBJECTIVES: The present study aimed to assess the feasibility and clinical value of acetylcholine (ACh) rechallenge for the detection of coexisting epicardial and microvascular spasm and to determine the efficacy of nitroglycerin in these spasm endotypes. BACKGROUND: The coexistence of epicardial and microvascular spasm is difficult to identify; thus, its frequency is unknown. Nitroglycerin treatment is equally recommended for both epicardial and microvascular coronary spasm despite contradictory data. METHODS: In this multicenter study, 95 patients with coronary spasm were included to undergo ACh rechallenge, which consisted of repeated ACh provocation 3 minutes after intracoronary nitroglycerin administration using the same dose that previously induced spasm. RESULTS: In total, 95 patients (age 61 ± 12 years, 69% female) were included. Fifty-five patients (58%) had microvascular spasm, and 40 patients (42%) had epicardial spasm during initial ACh provocation. In 48% of patients with epicardial spasm, ACh rechallenge revealed coexisting nitroglycerin-persistent microvascular spasm. Nitroglycerin administration before ACh rechallenge prevented reinducibility of epicardial spasm in all patients with focal spasm and in 80% of patients with diffuse spasm. Microvascular spasm was prevented in only 20% by prior nitroglycerin administration but was attenuated in another 49% of patients. CONCLUSIONS: This study demonstrates a high frequency of epicardial spasm with coexisting nitroglycerin-persistent microvascular spasm. Intracoronary nitroglycerin was very effective in preventing reinducibility of epicardial spasm, whereas it prevented microvascular spasm in only 20% of patients. ACh rechallenge is a novel method that facilitates the detection of coexisting spasm endotypes and may pave the way towards tailored treatment of vasospastic angina.

Effect of Aortic Valve Type on Patients Who Undergo Type A Aortic Dissection Repair.

Aortic valve replacement (AVR) is common in the setting of type A aortic dissection (TAAD) repair. Here, we evaluated the association between prosthesis choice and patient outcomes in an international patient cohort. We reviewed data from the International Registry of Acute Aortic Dissection (IRAD) interventional cohort to examine the relationship between valve choice and short- and mid-term patient outcomes. Between January 1996 and March 2016, 1290 surgically treated patients with TAAD were entered into the IRAD interventional cohort. Of those, 364 patients undergoing TAAD repair underwent aortic valve replacement (AVR; mean age, 57 years). The mechanical valve cohort consisted of 189 patients, of which 151 (79.9%) had a root replacement. The nonmechanical valve cohort consisted of 5 patients who received homografts and 160 patients who received a biologic AVR, with a total of 118 (71.5%) patients who underwent root replacements. The mean follow-up time was 2.92 ± 1.75 years overall (2.46 ± 1.69 years for the mechanical valve cohort and 3.48 ± 1.8 years for the nonmechanical valve cohort). After propensity matching, Kaplan-Meier estimates of 4-year survival rates after surgery were 64.8% in the mechanical valve group compared with 74.7% in the nonmechanical valve group (p = 0.921). A stratified Cox model for 4-year mortality showed no difference in hazard between valve types after adjusting for the propensity score (p = 0.854). A biologic valve is a reasonable option in patients with TAAD who require AVR. Although this option avoids the potential risks of anticoagulation, long-term follow up is necessary to assess the effect of reoperations or transcatheter interventions for structural valve degeneration.