The effect of statin therapy on reducing adverse cardiovascular events in vasospastic angina (VSA) has been inconsistent. Therefore, we investigated the association between statin therapy and adverse cardiovascular events in a large, prospective VSA cohort. The Variant Angina Korea registry consecutively enrolled 2960 patients suspected VSA. Among them, we included 1713 patients who were diagnosed with VSA based on coronary provocation test. We divided the patients into the statin (n = 744) and no-statin group (n = 914) according to the medication prescribed at discharge. The primary outcome was a composite of cardiac death, acute coronary syndrome, and new-onset life-threatening arrhythmia during a 3-year follow-up period. The primary outcome occurred in 32 patients (4.3%) in the statin and 28 patients (3.1%) in the no-statin group. In Kaplan-Meier analysis before and after propensity score matching, there was no significant difference in the cumulative incidence of primary outcomes between both groups. Multivariate Cox regression analysis demonstrated that the focal type of VSA was independent predictor of primary outcomes, but statin therapy was not. Furthermore, the lack of benefit of statin therapy for primary outcomes was consistently observed across the statin intensity and spasm characteristics. In conclusion, the present study demonstrated that statin therapy did not reduce adverse cardiovascular events in patients with VSA.

Coronary endothelial and circulatory dysfunction plays important roles in the pathogenesis of vasospastic angina (VSA). However, a complete understanding of the entire coronary circulation including microvasculature in patients with VSA is lacking.

A total of 32 patients without obstructive coronary artery disease in the left descending coronary artery, who underwent an intracoronary acetylcholine (ACh) provocation test for diagnosis of VSA, were enrolled prospectively. A positive diagnosis of the ACh test was defined as total/subtotal coronary artery narrowing accompanied by chest pain and/or ischemic ECG changes. Angina frequency and severity at baseline, and 1 and 3 months were recorded. Coronary circulation was evaluated invasively using a thermodilution method by obtaining the mean transit time (Tmn) at rest and hyperemia, coronary flow reserve, and index of microcirculatory resistance. Systemic endothelial function was assessed by the reactive hyperemia index.

There were 14 (44%) and 18 (56%) patients with and without a positive ACh provocation test. The baseline characteristics did not differ significantly between the two groups. Patients with VSA had a significantly lower reactive hyperemia index compared with those without VSA (1.70±0.33 vs. 2.12±0.53, P=0.02). Coronary flow reserve, index of microcirculatory resistance, and hyperemic Tmn were not different between the two groups, whereas resting Tmn was significantly longer in patients with VSA (1.20±0.44 vs. 0.71±0.37, P=0.002). Although the frequency and severity of angina improved from baseline to 1 and 3 months in patients with both positive and negative ACh tests, there was no difference between the two groups.

Patients with VSA had decreased resting coronary flow and impaired endothelial function.

It is well known that patients with gastroesophageal reflux disease (GERD) experience GERD-related chest pain, but little is known about the relationship between GERD and coronary artery disease (CAD). We evaluated medical history of GERD in patients with suspected CAD and its association with types of CAD. We enrolled 236 patients who underwent coronary angiography (CAG). We assessed past medical history of each patient, making note of esophageal or stomach diseases such as GERD including reflux esophagitis and non-erosive reflux disease. The patients were divided into the following three subgroups based on the CAG results. Group I, patients with o-CAD (> 50% stenosis with ischemic findings, n = 141); Group II, patients with vasospastic angina (VSA, with positive spasm provocation test without organic coronary stenosis, n = 52); and Group III, patients without organic coronary stenosis or VSA (n = 43). Group I included more men than women (p < 0.001) and the frequencies of smoking, lipid disorders, and diabetes mellitus in this group were higher than those in the other groups (p < 0.01). The frequency of medical history of GERD was significantly higher in Group II (21%) than in Group I (3%) or Group III (7%, p < 0.0001). Logistic regression analysis showed that a medical history of GERD (OR 7.8; p < 0.01) was one of the factors associated with the presence of VSA. Our findings showed that a medical history of GERD was frequently observed in approximately one-fifth of patients with VSA, indicating that VSA may be present in patients with chest pain and a medical history of GERD.

The aim of this single-arm pilot study was to determine the effects of whole-body vibration training (WBVT) on endothelial function in elderly patients with cardiovascular diseases, as well as its safety. A total of 20 elderly patients with stable cardiovascular diseases underwent WBVT, which consisted of five static resistance training exercises (squats, wide stance squats, toe-stands, squats + band, and front lunges). The parameters of WBVT included vertical vibrations, 30 Hz frequency, and a 3-mm peak-to-peak amplitude. Each vibration session lasted 30 seconds, with 120 seconds of rest between sessions. Before and after WBVT, the reactive hyperemia peripheral arterial tonometry index (RH-PAT index) and transcutaneous oxygen pressure (tcPO₂) were recorded as a measure of endothelial function and peripheral blood circulation. Systolic blood pressure, diastolic blood pressure, heart rate, and arterial oxygen saturation of pulse oximetry (SpO₂) were measured at each rest interval as well as before and after WBVT. All patients completed our WBVT protocol without adverse events. The RH-PAT index significantly increased following WBVT (1.42 to 2.06, P < 0.001). There were no significant changes in heart rate (P = 0.777), systolic blood pressure (P = 0.183), diastolic blood pressure (P = 0.925), or SpO₂ (P = 0.248) during WBVT. In conclusion, we demonstrated the acute effects of WBVT on endothelial function, with no reports of adverse events. These findings support the need for further randomized controlled studies to investigate the long-term effects of WBVT.

Coronary microvascular dysfunction and/or vasospasm are potential causes of ischaemia in patients with no obstructive coronary artery disease (INOCA). We tested the hypothesis that these patients also have functional abnormalities in peripheral small arteries.

Patients were prospectively enrolled and categorised as having microvascular angina (MVA), vasospastic angina (VSA) or normal control based on invasive coronary artery function tests incorporating probes of endothelial and endothelial-independent function (acetylcholine and adenosine). Gluteal biopsies of subcutaneous fat were performed in 81 subjects (62 years, 69% female, 59 MVA, 11 VSA, and 11 controls). Resistance arteries were dissected enabling study using wire myography. Maximum relaxation to ACh (endothelial function) was reduced in MVA vs. controls [median 77.6 vs. 98.7%; 95% confidence interval (CI) of difference 2.3-38%; P = 0.0047]. Endothelium-independent relaxation [sodium nitroprusside (SNP)] was similar between all groups. The maximum contractile response to endothelin-1 (ET-1) was greater in MVA (median 121%) vs. controls (100%; 95% CI of median difference 4.7-45%, P = 0.015). Response to the thromboxane agonist, U46619, was also greater in MVA (143%) vs. controls (109%; 95% CI of difference 13-57%, P = 0.003). Patients with VSA had similar abnormal patterns of peripheral vascular reactivity including reduced maximum relaxation to ACh (median 79.0% vs. 98.7%; P = 0.03) and increased response to constrictor agonists including ET-1 (median 125% vs. 100%; P = 0.02). In all groups, resistance arteries were ≈50-fold more sensitive to the constrictor effects of ET-1 compared with U46619.

Systemic microvascular abnormalities are common in patients with MVA and VSA. These mechanisms may involve ET-1 and were characterized by endothelial dysfunction and enhanced vasoconstriction.

ClinicalTrials.gov registration is NCT03193294.

In 2006, Takotsubo syndrome (TTC) was described as a distinct type of stress-induced cardiomyopathy (stress cardiomyopathy). However, when thinking about Takotsubo cardiomyopathy from the viewpoints of the AHA and ESC classifications, 2 possible problems may arise. The first potential problem is that a forecast of disease outcome is lacking in the ESC classification, whereas the AHA only states that 'outcome is favorable with appropriate medical therapy'. However, based on the literature data, one can make a general conclusion that occurrence of myocardial lesions in TTC (i.e., myocardial fibrosis and contraction-band necrosis) causes the same effects as in other diseases with similar levels of myocardial damage and should not be considered to have a lesser impact on mortality. To summarise, TTC can cause not only severe complications such as pulmonary oedema, cardiogenic shock, and dangerous ventricular arrhythmias, but also damage to the myocardium, which can result in the development of potentially fatal conditions even after the disappearance of LV apical ballooning. The second potential problem arises from the definition of TTC as a stress cardiomyopathy in the AHA classification. In fact, the main factors leading to TTC are stress and microvascular anginas, since, as has been already discussed, coronary spasm can cause myocardium stunning, resulting in persistent apical ballooning. Thus, based on this review, 3 distinct types of stress cardiomyopathies exist (variant angina, microvascular angina, and TTC), with poor prognosis. Adding these diseases to the classification of cardiomyopathies will facilitate diagnosis and preventive prolonged treatment, which should include intensive anti-stress therapy.

To determine if folic acid supplementation improves vascular function (brachial artery flow-mediated dilation [FMD]) in professional dancers with known endothelial dysfunction.

Prospective cross-sectional study.

Academic institution in the Midwestern United States.

Twenty-two professional ballet dancers volunteered for this study.

Subjects completed a 3-day food record to determine caloric and micronutrient intake. Menstrual status was determined by interview and questionnaire. Endothelial function was determined as flow-induced vasodilation measured by high-frequency ultrasound of the brachial artery. A change in brachial diameter of <5% to hyperemic flow stimulus was defined a priori as endothelial dysfunction. Subjects with abnormal FMD took 10 mg of folic acid daily for 4 weeks, and FMD testing was then repeated. Serum whole blood was measured for folic acid levels before and after supplementation.

Sixty-four percent of dancers (n = 14) had abnormal brachial artery FMD (<5%) (mean ± standard deviation, 2.9% ± 1.5%). After 4 weeks of folic acid supplementation (10 mg/day), FMD improved in all the subjects (7.1% ± 2.3%; P < .0001).

This study reveals that vascular endothelial function improves in dancers after supplementation with folic acid (10 mg/day) for at least 4 weeks. This finding may have clinically important implications for future cardiovascular disease risk prevention.

Police officers were hypothesized to have decreased endothelial function, measured by brachial artery flow-mediated dilation (FMD).

We compared FMD in police officers (n = 261) and a population sample of men and women (n = 229), all from the same geographical region and free of clinical cardiovascular disease (CVD).

Compared with the population sample, police officers had significantly increased age-adjusted CVD risk factors (systolic and diastolic blood pressure, total cholesterol, smoking prevalence, and alcohol consumption). Police officers exhibited lower mean FMD after adjustment for age, gender, and traditional CVD risk factors among those aged 55 years or younger (%dilation: police = 5.49%, population = 6.49%; P = 0.04).

Police officers exhibited decreased endothelial function (lower FMD) compared with the civilian sample, which was not fully explained by traditional CVD risk factors, suggesting that other pathways may contribute to increased CVD risk in law enforcement work.

The role of endothelial dysfunction in coronary vasospasm is controversial. We hypothesized that reactive oxygen species (ROS) and endothelin-1 (ET-1) are plausible candidates as the mediator of vasospasm is linked to endothelial dysfunction. In a pig model with repetitive endothelial injury in coronary arteries, intracoronary administration of serotonin induced a vasospasm at the endothelial injury site. The level of endothelin-converting enzyme was upregulated at that site where, upon exposure to serotonin, there were also increases in p47(phox), ROS, and ET-1 fluorescence intensities, and myosin light chain phosphorylation and RhoA activation were detected. The nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin, had the effect of extinguishing not only ROS but also the appearance of ET-1. The chronic blockade of endothelin type-A receptor prevented a serotonin-triggered vasospasm along with the inhibition of ROS generation and myosin light chain phosphorylation. Under the coronary artery endothelial dysfunction, ET-1 is essential for an ROS-dependent coronary vasospasm. Our findings suggest that endothelial dysfunction plays a critical role in clinically defined human Prinzmetal angina.

An 11-year-old boy received stent implantation for peripheral pulmonary stenosis through the left modified Blalock-Taussig shunt from the left brachial approach because of the hairpin-shaped route from a femoral or carotid approach. A temporary bypass between the left radial and the femoral arteries was established to prevent ischemic complication of the left forearm. There was no ischemic change of the left forearm in the physiological monitoring despite the long procedure (more than 4 hr) and brachial arterial spasms. No complications occurred after the procedure. The temporary bypass will support fewer complications in various catheter interventions through a brachial arterial approach in children.

The ability to assess endothelial function non-invasively with B-mode ultrasound has lead to its widespread application in a variety of studies. However, the absolute values obtained using this approach vary considerably across studies. We studied whether technical aspects of the methodology can explain the wide variety in absolute values across studies.

A literature search was performed to identify published reports on flow-mediated vasodilatation (FMD) of the brachial artery published between 1992 and 2001. Information on type of equipment (wall track/B-mode), location of the measurement (antecubital fossa/upper arm), occlusion site (lower/upper arm), occlusion duration (min), and occlusion pressure was extracted. Patient characteristics were also extracted. For the healthy populations, mean FMD varied from 0.20 to 19.2%; for the coronary heart disease (CHD) patients FMD varied from -1.3 to 14%; for subjects with diabetes mellitus FMD varied from 0.75 to 12%. Compared with occlusion at the upper arm, lower arm occlusion was related to decreased FMD (mean difference in FMD -2.47%; 95% CI 0.55-4.39). An occlusion duration of > or =4.5 min was related to an increased FMD compared with an occlusion time of < or =4 min (mean difference 1.30%; 95% CI 0.35-2.46). These findings were adjusted for other technical aspects of the methodology and for differences in risk factors between populations.

Mean FMD differs widely between studies. There is a great overlap between populations (healthy, CHD, diabetics). Our findings suggest that the technical aspects of the measurements, the location, and the duration of the occlusion may explain some of these differences, whereas type of equipment, location of the measurement, and occlusion pressure do not.

Under physiologic conditions, epicardial arteries contribute minimally to coronary vascular resistance. However, in the presence of endothelial dysfunction, stimuli that normally produce vasodilation may instead cause constriction. Examples include neural release of acetylcholine or norepinephrine, platelet activation and production of serotonin and thrombin, and release of local factors such as bradykinin. This shift from a primary endothelial-mediated vasodilator influence to one of endothelial dysfunction and unchecked vasoconstriction is precisely the milieu in which coronary vasospasm is observed. This condition, which typically occurs during periods of relatively sedentary activity, is associated with focal and transient obstruction of an epicardial arterial segment resulting in characteristic echocardiographic changes and symptoms of myocardial ischemia. This review highlights the current understanding of mechanisms regulating the coronary circulation during health and examines the pathophysiologic changes that occur with coronary spasm. Genetic and other predisposing conditions are addressed, as well as novel therapies based on recent mechanistic insights of the coronary contractile dysfunction associated with coronary spasm.