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.

Assessment of coronary vasomotor responses to acetylcholine in German and Japanese patients with epicardial coronary spasm-more similarities than differences?

Coronary spasm is an established cause for angina pectoris. Ethnic differences have been suggested among Asian compared to Caucasian patients regarding prevalence, gender distribution, and angiographic patterns of coronary spasm. The aim of this study was to compare contemporary German and Japanese patients with coronary spasm. Between 2011 and 2015, 149 patients with resting angina and unobstructed coronary arteries with acetylcholine-induced epicardial spasm were enrolled in Stuttgart, Germany (n = 69) and Sendai, Japan (n = 80). All patients underwent intracoronary acetylcholine testing according to a standardized protocol. Comprehensive analysis included type of spasm (focal/diffuse), dose of acetylcholine leading to spasm, and frequency of multivessel spasm. Patients in this study were 61 ± 11 years old, predominantly female (54%), and had normal left ventricular ejection fraction (73 ± 9%). Diffuse spasm was the most prevalent type of spasm (85%) whereas focal spasm was found in the remaining 15% of patients. 31% of patients had multivessel spasm. Comparing the German with the Japanese patients, distribution of spasm type (focal/diffuse, p = 0.19) and frequency of multivessel spasm (p = 0.22) were comparable. Moreover, when Japanese patients were compared with German patients and diffuse spasm with focal spasm patients, respectively, no significant differences were observed regarding the acetylcholine dose required to induce spasm (p = 0.078 and p = 0.46, respectively). In conclusion, diffuse epicardial coronary spasm is the most frequent finding among German and Japanese patients with resting angina, unobstructed coronary arteries, and epicardial spasm on acetylcholine testing. Japanese and German patients share several similarities including comparable types of spasm and frequency of multivessel spasm.

Assessment of Vascular Dysfunction in Patients Without Obstructive Coronary Artery Disease: Why, How, and When.

Ischemic heart disease secondary to coronary vascular dysfunction causes angina and impairs quality of life and prognosis. About one-half of patients with symptoms and signs of ischemia turn out not to have obstructive coronary artery disease, and coronary vascular dysfunction may be relevant. Adjunctive tests of coronary vasomotion include guidewire-based techniques with adenosine and reactivity testing, typically by intracoronary infusion of acetylcholine. The CorMicA (Coronary Microvascular Angina) trial provided evidence that routine management guided by an interventional diagnostic procedure and stratified therapy improves angina and quality of life in patients with angina but no obstructive coronary artery disease. In this paper, the COVADIS study group provide a comprehensive review of why, how, and when coronary vascular dysfunction should be assessed invasively. They discuss the rationale through a shared understanding of vascular pathophysiology and clinical evidence. They propose a consensus approach to how an interventional diagnostic procedure is performed with focus on practical aspects. Finally, the authors discuss the clinical scenarios in patients with stable and acute coronary syndromes in which measurement of coronary vascular function may be helpful for patient care.

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.

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.

Impact of baseline calibration on semiquantitative assessment of myocardial perfusion reserve by adenosine stress MRI.

In this study, we sought to investigate the impact of baseline calibration, which is used in quantitative cardiac MRI perfusion analysis to correct for surface coil inhomogeneity and noise, on myocardial perfusion reserve index (MPRI) and its contribution to previously reported paradoxical low MPRI < 1.0 in patients with unobstructed coronary arteries. Semiquantitative perfusion analysis was performed in 20 patients with unobstructed coronary arteries undergoing stress/rest perfusion CMR and in ten patients undergoing paired rest perfusion CMR. The following baseline calibration settings were compared: (1) baseline division, (2) baseline subtraction and (3) no baseline calibration. In uncalibrated analysis, we observed ~ 20% segmental dispersion of signal intensity (SI)-over-time curves. Both baseline subtraction and baseline division reduced relative dispersion of t0-SI (p < 0.001), but only baseline division corrected for dispersion of peak-SI and maximum upslope also (p < 0.001). In the assessment of perfusion indices, however, baseline division resulted in paradoxical low MPRI (1.01 ± 0.23 vs. 1.63 ± 0.38, p < 0.001) and rest perfusion index (RPI 0.54 ± 0.07 vs. 0.94 ± 0.12, p < 0.001), respectively. This was due to a reversed ratio of blood-pool and myocardial baseline-SI before the second perfusion study caused by circulating contrast agent from the first injection. In conclusion, baseline division reliably corrects for inhomogeneity of the surface coil sensitivity profile facilitating comparisons of regional myocardial perfusion during hyperemia or at rest. However, in the assessment of MPRI, baseline division can lead to paradoxical low results (even MPRI < 1.0 in patients with unobstructed coronary arteries) potentially mimicking severely impaired perfusion reserve. Thus, in the assessment of MPRI we propose to waive baseline calibration.

Mechanisms and diagnostic evaluation of persistent or recurrent angina following percutaneous coronary revascularization.

Persistence or recurrence of angina after a percutaneous coronary intervention (PCI) may affect about 20-40% of patients during short-medium-term follow-up. This appears to be true even when PCI is 'optimized' using physiology-guided approaches and drug-eluting stents. Importantly, persistent or recurrent angina post-PCI is associated with a significant economic burden. Healthcare costs may be almost two-fold higher among patients with persistent or recurrent angina post-PCI vs. those who become symptom-free. However, practice guideline recommendations regarding the management of patients with angina post-PCI are unclear. Gaps in evidence into the mechanisms of post-PCI angina are relevant, and more research seems warranted. The purpose of this document is to review potential mechanisms for the persistence or recurrence of angina post-PCI, propose a practical diagnostic algorithm, and summarize current knowledge gaps.

Diagnostic value of global myocardial perfusion reserve assessment based on coronary sinus flow measurements using cardiovascular magnetic resonance in addition to myocardial stress perfusion imaging.

AIMS: Myocardial perfusion reserve (MPR) is defined as the maximal possible increase in myocardial blood flow (MBF) above baseline conditions. Global MBF can be measured non-invasively by means of coronary sinus flow velocity encoded cine (VENC) cardiovascular magnetic resonance (CMR). We aimed to explore the relationship between global MBF/MPR and the extent and severity of coronary artery disease (CAD) in patients referred for CAD work-up by adenosine-stress CMR. METHODS AND RESULTS: Fifty-eight patients with suspected obstructive CAD underwent both adenosine-stress CMR and invasive coronary angiography. In addition to standard cine- and late gadolinium enhancement (LGE)-imaging, first-pass myocardial perfusion imaging (MPI) and coronary sinus flow measurements (VENC) were performed at rest and during peak stress (after 140 µg/kg/min adenosine), respectively. Nineteen young patients with a very low CAD pre-test probability and normal adenosine-stress CMR formed the control group. Fifty-nine percent (n = 34) of the study group showed segmental, adenosine-induced myocardial perfusion defects compared to none of the control group (P < 0.001). Global MPR was lower in the study group compared to the control group: 2.3 (1.5-3.1) vs. 3.1 (2.0-4.3), P = 0.016. The SYNTAX score was higher in the study group patients with an impaired MPR (<2) compared to those with a preserved MPR (3.0 vs. 16.0, P = 0.01)-mainly due to higher prevalence of proximal epicardial stenoses (60% vs. 27%, P = 0.02) and multi-vessel disease (56% vs. 24%, P = 0.017). The diagnostic yield of stress CMR for the diagnosis of CAD (>50% stenosis) increased from 65to 88% when global MPR assessment was considered in addition to MPI (P = 0.025). CONCLUSIONS: Global MBF and MPR values correlate with the anatomical extent and complexity of CAD and increase the diagnostic yield of non-invasive stress CMR in the work-up of CAD. CMR-based MBF and MPR measurements may play a future role in the evaluation of the total ischaemic burden-particularly in patients with multi-vessel disease.

Comprehensive Cardiovascular Magnetic Resonance Assessment in Patients With Sarcoidosis and Preserved Left Ventricular Ejection Fraction.

BACKGROUND: Cardiac sarcoidosis (CS) may manifest as arrhythmia or even sudden cardiac death. Because patients with CS often present with nonspecific symptoms, normal electrocardiography, and preserved left ventricular ejection fraction, a reliable diagnostic tool for the work-up of CS is needed. Late gadolinium enhancement-cardiovascular magnetic resonance has proven diagnostic value in CS but has some limitations that may be overcome by adding newer cardiovascular magnetic resonance mapping techniques. The aim of our study was to evaluate a comprehensive cardiovascular magnetic resonance protocol, including late gadolinium enhancement and mapping sequences in sarcoid patients with no symptoms or unspecific symptoms and preserved left ventricular ejection fraction. METHODS AND RESULTS: Sixty-one sarcoid patients were prospectively enrolled and underwent comprehensive cardiovascular magnetic resonance imaging. Twenty-six healthy volunteers served as control group. Mean left ventricular ejection fraction was 65%; late gadolinium enhancement was only present in sarcoid patients (n=15). Sarcoid patients had a higher median native T1 (994 versus 960 ms; P<0.001), lower post contrast T1 (491 versus 526 ms; P=0.001), expanded extracellular volume (28 versus 25%; P=0.001), and higher T2 values (52 versus 49 ms; P<0.001) compared with controls. Among patients with values higher than the 95% percentile of healthy controls, most significant differences were observed for native T1 and T2 values. Most of these patients were late gadolinium enhancement negative. CONCLUSIONS: Patients with sarcoidosis demonstrate higher T1, extracellular volume, and T2 values compared with healthy controls, with most significant differences for native T1 and T2. While promising, the clinical significance of the newer mapping techniques with respect to early diagnosis and therapy of CS will have to be determined in future studies.

Intracoronary Acetylcholine Provocation Testing for Assessment of Coronary Vasomotor Disorders.

Intracoronary acetylcholine provocation testing (ACH-test) is an established method for assessment of epicardial coronary artery spasm in the catheterization laboratory which was introduced more than 30 years ago. Due to the short half-life of acetylcholine it can only be applied directly into the coronary arteries. Several studies have demonstrated the safety and clinical usefulness of this test. However, acetylcholine testing is only rarely applied in the U.S. or Europe. Nevertheless, it has been shown that 62% of Caucasian patients with stable angina and unobstructed coronary arteries on coronary angiography suffer from coronary vasomotor disorders that can be diagnosed with acetylcholine testing. In recent years it has been appreciated that the ACH-test not only assesses the presence of epicardial spasm but that it can also be useful for the detection of coronary microvascular spam. In such cases no epicardial spasm is seen after injection of acetylcholine but ischemic ECG shifts are present together with a reproduction of the patient's symptoms during the test. This article describes the experience with the ACH-test and its implementation in daily clinical routine.

Transradial left ventricular endomyocardial biopsy: assessment of safety and efficacy.

BACKGROUND: We aimed at assessing the safety and efficacy of a systematic transradial approach for left ventricular endomyocardial biopsy using a new hydrophilic sheathless guiding catheter. METHODS AND RESULTS: Forty-two consecutive patients were included. The transradial success rate was 98% (41 of 42). In one case, cross over to femoral access due to irreversible spasm of the right radial artery was necessary. No radial spasm was observed in the other 41 patients. Depending on the indication, several other procedures, such as coronary angiography or ventricular angiography, were additionally performed through the same transradial access site. Median fluoroscopy time was 7.9 min. The mean dose area product was 1867 cGy × cm(2). All biopsy samples were graded as good or excellent quality. No patient had any complications. Immediate post-procedural ambulation could be achieved in all patients. Radial artery patency was confirmed by duplex sonography 24 h after removal of the guide. CONCLUSION: The present study demonstrates safety and efficacy of a systematic transradial access for left ventricular EMB using a highly hydrophilic sheathless guiding catheter. This is of clinical importance since this new technique may overcome critical limitations of the common approach.

Magnetic resonance of the heart in a muscular dystrophy patient with an MR conditional ICD: assessment of safety, diagnostic value and technical limitations.

Cardiovascular magnetic resonance (CMR) studies in patients with pacemakers or implantable cardioverter/defibrillators (ICD) are increasingly required in daily clinical practice. Therefore, in the last years the manufacturers developed not only MR-conditional pacemakers, but also MR-conditional ICDs. However, the clinical experience regarding the feasibility and limitations of MR studies of the heart in patients with ICDs is still limited. In particular, there are hardly any CMR studies in the same patients performed prior to and post ICD implantation allowing a one-to-one comparison of the obtained CMR images. This is the first presentation of a CMR study in a patient with the world's first and so far only MR-conditional ICD. In our case, a major problem related to the presence of the MR conditional ICD was an image artifact caused by the device's generator which hampered the visualization of the midventricular and apical anterior and antero-lateral segments in all sequences performed. Considering previous studies, right chest implantation of the ICD could probably have helped in this setting and may be preferred in future ICD implantations. Our case report nicely illustrates the real clinical need for specially designed implantable devices that ensure safe and high-quality imaging in patients in whom serial CMR is required.

Prognostic value of routine cardiac magnetic resonance assessment of left ventricular ejection fraction and myocardial damage: an international, multicenter study.

BACKGROUND: Cardiac magnetic resonance (CMR) is considered the reference standard for assessment of left ventricular ejection fraction (LVEF) and myocardial damage. However, few studies have evaluated the relationship between CMR findings and patient outcome, and of these, most are small and none multicenter. We performed an international, multicenter study to assess the prognostic importance of routine CMR in patients with known or suspected heart disease. METHODS AND RESULTS: From 10 centers in 6 countries, consecutive patients undergoing routine CMR assessment of LVEF and myocardial damage by cine and delayed-enhancement imaging (DE-CMR), respectively, were screened for enrollment. Clinical data, CMR protocol information, and findings were collected at all sites and submitted to the data coordinating center for verification of completeness and analysis. The primary end point was all-cause mortality. A total of 1560 patients (age, 59±14 years; 70% men) were enrolled. Mean LVEF was 45±18%, and 1049 (67%) patients had hyperenhanced tissue (HE) on DE-CMR indicative of damage. During a median follow-up time of 2.4 years (interquartile range, 1.2, 2.9 years), 176 (11.3%) patients died. Patients who died were more likely to be older (P<0.0001), have coronary disease (P=0.004), have lower LVEF (P<0.0001), and have more segments with HE (P<0.0001). In multivariable analysis, age, LVEF, and number of segments with HE were independent predictors of mortality. Among patients with near-normal LVEF (≥50%), those with above-median HE (>4 segments) had reduced survival compared to patients with below- or at-median HE (P=0.02). CONCLUSIONS: Both LVEF and amount of myocardial damage as assessed by routine CMR are independent predictors of all-cause mortality. Even in patients with near-normal LVEF, significant damage identifies a cohort with a high risk for early mortality.

Impact of remote telemedical management on mortality and hospitalizations in ambulatory patients with chronic heart failure: the telemedical interventional monitoring in heart failure study.

BACKGROUND: This study was designed to determine whether physician-led remote telemedical management (RTM) compared with usual care would result in reduced mortality in ambulatory patients with chronic heart failure (HF). METHODS AND RESULTS: We enrolled 710 stable chronic HF patients in New York Heart Association functional class II or III with a left ventricular ejection fraction ≤35% and a history of HF decompensation within the previous 2 years or with a left ventricular ejection fraction ≤25%. Patients were randomly assigned (1:1) to RTM or usual care. Remote telemedical management used portable devices for ECG, blood pressure, and body weight measurements connected to a personal digital assistant that sent automated encrypted transmission via cell phones to the telemedical centers. The primary end point was death from any cause. The first secondary end point was a composite of cardiovascular death and hospitalization for HF. Baseline characteristics were similar between the RTM (n=354) and control (n=356) groups. Of the patients assigned to RTM, 287 (81%) were at least 70% compliant with daily data transfers and no break for >30 days (except during hospitalizations). The median follow-up was 26 months (minimum 12), and was 99.9% complete. Compared with usual care, RTM had no significant effect on all-cause mortality (hazard ratio, 0.97; 95% confidence interval, 0.67 to 1.41; P=0.87) or on cardiovascular death or HF hospitalization (hazard ratio, 0.89; 95% confidence interval, 0.67 to 1.19; P=0.44). CONCLUSIONS: In ambulatory patients with chronic HF, RTM compared with usual care was not associated with a reduction in all-cause mortality. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00543881.

Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies.

Non-ischaemic cardiomyopathies (NICMs) are chronic, progressive myocardial diseases with distinct patterns of morphological, functional, and electrophysiological changes. In the setting of cardiomyopathy (CM), determining the exact aetiology is important because the aetiology is directly related to treatment and patient survival. Determining the exact aetiology, however, can be difficult using currently available imaging techniques, such as echocardiography, radionuclide imaging or X-ray coronary angiography, since overlap of features between CMs may be encountered. Cardiovascular magnetic resonance (CMR) imaging has recently emerged as a new non-invasive imaging modality capable of providing high-resolution images of the heart in any desired plane. Delayed contrast enhanced CMR (DE-CMR) can be used for non-invasive tissue characterization and may hold promise in differentiating ischaemic from NICMs, as the typical pattern of hyperenhancement can be classified as 'ischaemic-type' or 'non-ischaemic type' on the basis of pathophysiology of ischaemia. This article reviews the potential of DE-CMR to distinguish between ischaemic and NICM as well as to differentiate non-ischaemic aetiologies. Rather than simply describing various hyperenhancement patterns that may occur in different disease states, our goal will be (i) to provide an overall imaging approach for the diagnosis of CM and (ii) to demonstrate how this approach is based on the underlying relationships between contrast enhancement and myocardial pathophysiology.

Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology.

BACKGROUND: Myocarditis can occasionally lead to sudden death and may progress to dilated cardiomyopathy in up to 10% of patients. Because the initial onset is difficult to recognize clinically and the diagnostic tools available are unsatisfactory, new strategies to diagnose myocarditis are needed. METHODS AND RESULTS: Cardiovascular MR imaging (CMR) was performed in 32 patients who were diagnosed with myocarditis by clinical criteria. To determine whether CMR visualizes areas of active myocarditis, endomyocardial biopsy was taken from the region of contrast enhancement and submitted to histopathologic analysis. Follow-up was performed 3 month later. Contrast enhancement was present in 28 patients (88%) and was usually seen with one or several foci in the myocardium. Foci were most frequently located in the lateral free wall. In the 21 patients in whom biopsy was obtained from the region of contrast enhancement, histopathologic analysis revealed active myocarditis in 19 patients (parvovirus B19, n=12; human herpes virus type 6 [HHV 6], n=5). Conversely, in the remaining 11 patients, in whom biopsy could not be taken from the region of contrast enhancement, active myocarditis was found in one case only (HHV6). At follow-up, the area of contrast enhancement decreased from 9+/-11% to 3+/-4% of left ventricular mass as the left ventricular ejection fraction improved from 47+/-19% to 60+/-10%. CONCLUSIONS: Contrast enhancement is a frequent finding in the clinical setting of suspected myocarditis and is associated with active inflammation defined by histopathology. Myocarditis occurs predominantly in the lateral free wall. Contrast CMR is a valuable tool for the evaluation and monitoring of inflammatory heart disease.