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.

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.

Coronary artery spasm and impaired myocardial perfusion in patients with ANOCA: Predictors from a multimodality study using stress CMR and acetylcholine testing.

BACKGROUND: Functional coronary disorders such as coronary spasm and microvascular dysfunction (including microvascular spasm and impaired microvascular dilatation) are frequent findings among patients with angina and non-obstructed coronary arteries (ANOCA). In this study, we investigated a potential association of coronary spasm and myocardial perfusion abnormalities as well as predictors of such functional coronary disorders in ANOCA patients using a multimodality diagnostic strategy including adenosine stress CMR and intracoronary acetylcholine testing. METHODS: We enrolled 129 patients with ANOCA who underwent acetylcholine testing and adenosine stress perfusion CMR. Patients were allocated to 3 groups according to their spasm testing result with regard to standardized COVADIS criteria: 1) epicardial spasm, 2) microvascular spasm, and 3) no spasm. The myocardial perfusion reserve index (MPRI) was semiquantitatively determined from adenosine stress perfusion CMR. Multivariate regression analyses were performed to identify predictors of coronary functional disorders. RESULTS: Patients with epicardial spasm had lower MPRI than patients without, whereas MPRI was preserved in patients with microvascular spasm. Multivariate analyses revealed age, previous myocardial infarction, LVEF and epicardial spasm as independent predictors of diminished MPRI, whereas previous PCI was associated with epicardial spasm, and female sex was a strong predictor of microvascular spasm. CONCLUSIONS: Our results demonstrate coexistence of different functional coronary disorder endotypes involving the macro- and microvascular level of the coronary circulation in patients with ANOCA. We demonstrate that epicardial spasm is associated with diminished myocardial perfusion reserve and report further predictors of coronary functional disorders.

Repurposing Riociguat for Treatment of Refractory Angina Resulting From Coronary Spasm.

Coronary spasm is a frequent cause of angina despite unobstructed coronary arteries, and symptom control with recommended drugs is limited. We report the case of a 77-year-old woman who had refractory angina despite conventional antianginal treatment. Repurposing riociguat, a soluble guanylate cyclase stimulator, resulted in improvement of symptoms and prevention of spasm. (Level of Difficulty: Intermediate.).

[Detection of ECG alterations typical for myocardial ischemia : New methods 2021]. / Erkennung ischämietypischer EKG-Veränderungen : Neue Methoden 2021.

BACKGROUND: The electrocardiogram (ECG) represents an essential diagnostic tool in cardiology and beyond. Classical ECG devices enable the registration of up to 12 leads, whereas modern ECG systems enable additional leads even with a reduced number of electrodes. Additionally, "smart" devices even enable patients to record an ECG at home. OBJECTIVE: Evaluation of a potential additional benefit of using various modern ECG systems for the detection of ECG alterations typical for myocardial ischemia. MATERIAL AND METHODS: Presentation of various signs of ischemia in the ECG according to the latest guidelines. Demonstration of modern ECG systems and their potential advantage in the detection of signs of ischemia in the ECG based on current study results. RESULTS: Modern ECG systems with vector-based electrocardiography can facilitate and optimize the detection of ischemic ECG alterations. Smart nonvector-based devices for patients are primarily useful for detection of arrhythmias and do not replace the 12-lead ECG for detection of ischemia, even though they can be useful for documentation of temporary ECG alterations also within the ST-segment. CONCLUSION: The ECG systems based on vector electrocardiography can improve the detection of ECG alterations typical for ischemia compared to the conventional 12-lead ECG.

Different vasoreactivity of arterial bypass grafts versus native coronary arteries in response to acetylcholine.

BACKGROUND: Coronary angiography is often performed in patients with recurrent angina after successful coronary artery bypass grafting (CABG) in search of the progression of atherosclerosis. However, in many of these patients, no relevant stenosis can be detected. We speculate that coronary spasm may be associated with angina in these patients. METHODS: From 2307 patients with unobstructed coronaries who underwent intracoronary acetylcholine spasm provocation testing (ACh-test) between 2012 and 2016, 54 consecutive patients who fulfilled the following inclusion criteria were included in this cohort study: previous left internal thoracic artery (LITA) bypass on the left anterior descending (LAD) coronary artery, ongoing/recurrent angina pectoris, no significant (< 50%) coronary artery or bypass stenosis. In all participants, the ACh-test was performed via the LITA bypass. RESULTS: In 14 patients (26%) the ACh-test elicited epicardial spasm of the LAD distal to the anastomosis (≥ 90% diameter reduction with reproduction of the patient's symptoms and ischemic ECG shifts). Microvascular spasm (reproduction of symptoms and ischemic ECG-changes but no epicardial spasm) was seen in 30 patients (55%). The ACh-test was normal in the remaining 10 patients (19%). ACh-testing did not elicit any relevant vasoconstriction in the LITA bypasses in contrast to the LAD on quantitative coronary analyses (4.89 ± 7.36% vs. 52.43 ± 36.07%, p < 0.01). CONCLUSION: Epicardial and microvascular coronary artery spasm are frequent findings in patients with ongoing or recurrent angina after CABG but no relevant stenosis. Vasoreactivity to acetylcholine is markedly different between LITA bypasses and native LAD arteries with vasoconstriction almost exclusively occurring in the LAD.

Safety assessment and results of coronary spasm provocation testing in patients with myocardial infarction with unobstructed coronary arteries compared to patients with stable angina and unobstructed coronary arteries.

BACKGROUND: Coronary spasm is an established cause for myocardial infarction with unobstructed coronary arteries, and can be diagnosed using intracoronary acetylcholine testing. However, it has been questioned whether such testing is feasible and safe in the acute phase. The aim of this study was to assess the frequency of coronary spasm and the safety of the acetylcholine test in patients with myocardial infarction with unobstructed coronary arteries compared to patients with stable angina and unobstructed coronaries. METHODS: One hundred and eighty selected patients (52% women, mean age 62±13 years) with either myocardial infarction with unobstructed coronary arteries (n=80) or stable angina and unobstructed coronaries (n=100) were enrolled from 2007-2018. All patients underwent the acetylcholine test according to a standardised protocol immediately after diagnostic angiography. Apart from assessment of clinical, demographic and risk factor data, side effects and complications during the acetylcholine test were recorded. RESULTS: Overall, epicardial spasm was found in 26% with a higher prevalence among the myocardial infarction with unobstructed coronary arteries compared to the stable angina patients (35% vs 19%, p=0.017). Microvascular spasm was found in 42% with a higher prevalence among the stable patients compared to the myocardial infarction with unobstructed coronary arteries cohort (53% vs 29%, p=0.0014). There were no statistically significant differences in the rate of side effects (16% vs 14%, p=0.674) or complications (1% vs 2.5%, p=0.438) between the two groups. None of the patients experienced irreversible complications. CONCLUSION: Coronary spasm is a frequent cause for myocardial infarction with unobstructed coronary arteries. Spasm provocation testing using acetylcholine is feasible in such patients in the acute phase. The complication rate during acetylcholine testing in myocardial infarction with unobstructed coronary arteries patients is low and comparable to patients with stable angina.

[STEMI equivalents on the ECG - a case-based presentation]. / STEMI-Äquivalente im EKG ­ eine fallbasierte Darstellung.

The 12-lead resting ECG remains an indispensable diagnostic tool in patients with acute chest pain. This is particularly important as the identification of ST-segment elevations leads to the diagnosis of ST-segment elevation myocardial infarction (STEMI) and subsequent, immediate coronary reperfusion (usually via primary PCI). However, correct interpretation of the 12-lead ECG in patients with acute chest pain remains challenging. Apart from "classical" ST-segment elevations there are several "equivalents" in the ECG pointing towards an acute coronary occlusion. Among these, hyperacute T-waves, subtle ST-segment elevations, ST-segment elevation in leads aVR/V1 with concomitant ST-segment depression in ≥ 8 other leads and high R-peak with positive T-waves combined with horizontal ST-segment depression in leads V1/V2 can be found. This article provides a case-based presentation of STEMI equivalents on the ECG in order to improve correct ECG interpretation and prognosis of such patients.

Coronary Microvascular Spasm as the Underlying Cause of the Angiographic Slow Flow Phenomenon.

Slow coronary flow is frequently seen during angiography in patients with angina and unobstructed coronary arteries. However, the pathophysiology of this finding remains largely unclear. We report a case of a 52-year-old woman with slow coronary flow caused by acetylcholine-induced microvascular spasm, as confirmed by intracoronary flow measurements. (Level of Difficulty: Beginner.).

Safety assessment and results of coronary spasm provocation testing in patients with myocardial infarction with unobstructed coronary arteries compared to patients with stable angina and unobstructed coronary arteries.

BACKGROUND: Coronary spasm is an established cause for myocardial infarction with unobstructed coronary arteries, and can be diagnosed using intracoronary acetylcholine testing. However, it has been questioned whether such testing is feasible and safe in the acute phase. The aim of this study was to assess the frequency of coronary spasm and the safety of the acetylcholine test in patients with myocardial infarction with unobstructed coronary arteries compared to patients with stable angina and unobstructed coronaries. METHODS: One hundred and eighty selected patients (52% women, mean age 62±13 years) with either myocardial infarction with unobstructed coronary arteries (n=80) or stable angina and unobstructed coronaries (n=100) were enrolled from 2007-2018. All patients underwent the acetylcholine test according to a standardised protocol immediately after diagnostic angiography. Apart from assessment of clinical, demographic and risk factor data, side effects and complications during the acetylcholine test were recorded. RESULTS: Overall, epicardial spasm was found in 26% with a higher prevalence among the myocardial infarction with unobstructed coronary arteries compared to the stable angina patients (35% vs 19%, p=0.017). Microvascular spasm was found in 42% with a higher prevalence among the stable patients compared to the myocardial infarction with unobstructed coronary arteries cohort (53% vs 29%, p=0.0014). There were no statistically significant differences in the rate of side effects (16% vs 14%, p=0.674) or complications (1% vs 2.5%, p=0.438) between the two groups. None of the patients experienced irreversible complications. CONCLUSION: Coronary spasm is a frequent cause for myocardial infarction with unobstructed coronary arteries. Spasm provocation testing using acetylcholine is feasible in such patients in the acute phase. The complication rate during acetylcholine testing in myocardial infarction with unobstructed coronary arteries patients is low and comparable to patients with stable angina.