The value of a new cardiac magnetic resonance imaging protocol in Myocardial Infarction with Non-obstructive Coronary Arteries (MINOCA) - a case-control study using historical controls from a previous study with similar inclusion criteria.

BACKGROUND: Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) is common with a prevalence of 6% of all patients fulfilling the diagnosis of myocardial infarction. MINOCA should be considered a working diagnosis. Cardiac Magnetic Resonance (CMR) imaging has recently been suggested to be of great value to determine the cause behind MINOCA. The objectives of this paper are to describe the rationale behind the second Stockholm Myocardial Infarction with Normal Coronaries (SMINC-2) study and to discuss the protocol for investigation of MINOCA patients in the light of the recently published position paper from the European Society of Cardiology. METHODS: The SMINC-2 study is an open non-randomised study using historical controls for comparison. The primary aim is to prove that MINOCA patients investigated with the latest CMR imaging technique can achieve a diagnosis in 70% of all cases entirely by imaging. By including 150 patients we will have >80% chance to prove that the diagnostic accuracy can be improved by 20 absolute % with a p-value of less than 0.05 when compared with CMR imaging in the SMINC-1 study. Furthermore, in addition to invasive coronary angiography, coronary arteries are evaluated by computed tomography angiography to investigate coronary causes and questionnaires are used to describe Quality-of-Life (QoL). By January 1st 2017, 75 patients have been included. DISCUSSION: Whether CMR imaging can provide a diagnosis to an adequate proportion of MINOCA patients is unknown. Well-defined inclusion and exclusion criteria will be used to compare a MINOCA cohort from the population with an appropriate control group. Positive results are likely to influence future guidelines of the management of MINOCA. Furthermore, the study will give mechanistic insights into MINOCA in particular in patients with "true" myocardial infarction and describe QoL in this vulnerable group of patients. TRIAL REGISTRATION: Clinical Trials NCT02318498 .

Myocardial infarction with normal coronary arteries is common and associated with normal findings on cardiovascular magnetic resonance imaging: results from the Stockholm Myocardial Infarction with Normal Coronaries study.

OBJECTIVES: Myocardial infarction with angiographically normal coronary arteries (MINCA) is an important subtype of myocardial infarction; however, the prevalence, underlying pathophysiology, prognosis and optimal management of this condition are still largely unknown. Cardiovascular magnetic resonance (CMR) imaging has the potential to clarify the underlying pathology in patients with MINCA. The objective of this study was to investigate the diagnostic value of CMR imaging in this group of patients. DESIGN: The prospective, multicentre, observational Stockholm Myocardial Infarction with Normal Coronaries (SMINC) study. SETTING: Coronary care units in the Stockholm metropolitan area. SUBJECTS: Patients between 35 and 70 years of age with MINCA were consecutively included in the screening phase of the SMINC study. All patients had a typical clinical presentation, fulfilling the universal definition of myocardial infarction and had normal coronary angiography finding. Patients with known structural or coronary heart disease or other known causes of elevated troponin levels were excluded. RESULTS: In total, 176 patients with MINCA were screened from 2007 to 2011. Of these, 152 underwent CMR imaging. The investigation was performed a median of 12 (interquartile range 6-28) days after hospital admission; 67% of the findings were normal, whereas 19% of patients had signs of myocardial necrosis and 7% had signs of myocarditis. The remaining patients (7%) had either unrecognized hypertrophic cardiomyopathy or could not be classified. CONCLUSION: In this consecutive series of patients with MINCA, CMR imaging may help to differentiate between those with myocarditis, myocardial necrosis and normal myocardium. The incidence of MINCA was higher than previously reported. After excluding cases of myocarditis, MINCA consists of a large group of patients with normal CMR imaging results and a smaller group with myocardial necrosis. The aetiologies of these different imaging findings need to be explored.

Association between spironolactone added to beta-blockers and ACE inhibition and survival in heart failure patients with reduced ejection fraction: a propensity score-matched cohort study.

PURPOSE: Heart failure (CHF) guidelines recommend mineralocorticoid receptor antagonists for all symptomatic patients treated with a combination of ACE inhibitors/angiotensin receptor blockers (ARBs) and beta-blockers. As opposed to both eplerenone trials, patients in RALES (spironolactone) received almost no beta-blockers. Since pharmacological properties differ between eplerenone and spironolactone, the prognostic benefit of spironolactone added to this baseline combination therapy needs clarification. METHODS: We included 4,832 CHF patients with chronic systolic dysfunction from the Norwegian Heart Failure Registry and the heart failure outpatients' clinic of the University of Heidelberg. Propensity scores for spironolactone receipt were calculated for each patient and used for matching to patients without spironolactone. RESULTS: During a total follow-up of 17,869 patient-years, 881 patients (27.0 %) died in the non-spironolactone group and 445 (28.4 %) in the spironolactone group. Spironolactone was not associated with improved survival, neither in the complete sample (HR 0.82; 95 % CI 0.64-1.07; HR 1.03; 95 % CI 0.88-1.20; multivariate and propensity score adjusted respectively), nor in the propensity-matched cohort (HR 0.98; 95 % CI 0.82-1.18). CONCLUSION: In CHF outpatients we were unable to observe an association between the use of spironolactone and improved survival when administered in addition to a combination of ACE/ARB and beta-blockers.

Troponin elevation in coronary vs. non-coronary disease.

Acute myocardial infarction is defined as myocardial cell death due to prolonged myocardial ischaemia. Cardiac troponins (cTn) are the most sensitive and specific biochemical markers of myocardial injury and with the new high-sensitivity troponin methods very minor damages on the heart muscle can be detected. However, elevated cTn levels indicate cardiac injury, but do not define the cause of the injury. Thus, cTn elevations are common in many disease states and do not necessarily indicate the presence of a thrombotic acute coronary syndrome (ACS). In the clinical work it may be difficult to interpret dynamic changes of troponin in conditions such as stroke, pulmonary embolism, sepsis, acute perimyocarditis, Tako-tsubo, acute heart failure, and tachycardia. There are no guidelines to treat patients with elevated cTn levels and no coronary disease. The current strategy of treatment of patients with elevated troponin and non-acute coronary syndrome involves treating the underlying causes. The aim of this paper is to review data from studies of non-ACS patients with acutely elevated troponin who in clinical practice may be difficult to discriminate from ACS patients.

Anti-CCP and RF IgM: predictors of impaired endothelial function in rheumatoid arthritis patients.

OBJECTIVE: To determine whether the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor immunoglobulin M (RF IgM) is associated with endothelial dysfunction in patients with rheumatoid arthritis (RA). METHODS: We studied the presence of anti-CCP antibodies and RF IgM and endothelial function in terms of the reactive hyperaemic index (RHI) in 53 consecutive RA patients. Endothelial function was measured by using a finger plethysmograph. RESULTS: RHI was significantly lower in anti-CCP-positive RA patients (n = 33, RHI = 1.78, SD = 0.30) than in anti-CCP-negative RA patients (n = 20, RHI = 2.19, SD = 0.59; p = 0.008). A similar result was found in RF IgM-positive patients (n = 34, RHI = 1.77, SD = 0.30) vs. RF IgM-negative patients (n = 19, RHI = 2.23, SD = 0.58; p = 0.003). There were no significant differences between the groups regarding age, gender, traditional cardiovascular risk markers, Disease Activity Score using 28 joint counts (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), extra-articular manifestations (EAMs), use of glucocorticosteroids, statins, angiotensin-converting enzyme (ACE) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs). CONCLUSION: The presence of anti-CCP antibodies and RF IgM was related to impaired endothelial function independent of other cardiovascular risk factors in RA patients. Thus, these autoantibodies might reflect an early reversible stage of the atherosclerotic process, and may indicate increased risk of cardiovascular disease (CVD). Further studies are needed to explore whether anti-CCP antibodies and RF IgM may act directly or indirectly to cause endothelial dysfunction, or merely reflect endothelial dysfunction in RA patients.

The course of D-dimer, high-sensitivity C-reactive protein and pro-B-type natriuretic peptide in patients with non-ST-elevation myocardial infarction.

BACKGROUND: Elevated levels of high-sensitivity C-reactive protein (hs-CRP), B-type natriuretic peptide (BNP), and D-dimer each are associated with higher rates of death and recurrent ischemic events in patients with acute myocardial infarction (AMI). The aim of this study was to examine the dynamic course of D-dimer, hs-CRP, and pro-BNP in patients with Non-ST-Elevation Myocardial Infarction (NSTEMI). METHODS: The study group consisted of 82 patients presenting with symptoms suggestive of acute coronary syndrome (ACS). 40 of the patients were diagnosed as NSTEMI and for the rest AMI was ruled out. Blood was drawn at the time of admission, 6 and 12 hours after that. The samples were tested for hs-CRP, pro-BNP and fibrin D-dimer by a quantitative, point-of-care instrument system (Stratus CS). RESULTS: D-dimer and pro-BNP did not change between admission and 6 and 12 hours after admission in patients with acute NSTEMI, whereas hs-CRP went down 12 hours after admission compared to the admission value (14.9 +/- 19.4 (mg/mL) v 10.1 +/- 13.5 (mg/mL), p = 0.04). CONCLUSIONS: There was no dynamic change of D-dimer or pro-BNP during the first 12 hours after admission in patients with acute NSTEMI, whereas hs-CRP decreased 12 hours after admission in these patients.

Gender differences in the effects of cardiovascular drugs.

Although sex-specific differences in cardiovascular medicine are well known, the exact influences of sex on the effect of cardiovascular drugs remain unclear. Women and men differ in body composition and physiology (hormonal influences during the menstrual cycle, menopause, and pregnancy) and they present differences in drug pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics, so that is not rare that they may respond differently to cardiovascular drugs. Furthermore, women are also less often treated with evidence-based drugs thereby preventing optimization of therapeutics for women of all ages, experience more relevant adverse drug reactions than men, and remain underrepresented in most clinical trials. Thus, current guidelines for prevention, diagnosis, and medical treatment for cardiovascular diseases are based on trials conducted predominantly in middle-aged men. A better understanding of these sex-related differences is fundamental to improve the safety and efficacy of cardiovascular drugs and for developing proper individualized cardiovascular therapeutic strategies both in men and women. This review briefly summarizes gender differences in the pharmacokinetics and pharmacodynamics of cardiovascular drugs and provides recommendations to close the gaps in our understanding of sex-specific differences in drug efficacy and safety.

Troponin and exercise.

Cardiac troponins are the preferred biomarkers in diagnostic of myocardial infarction, but these markers also can rise in response to exercise. Multiple studies have assessed troponins post-exercise, but the results have varied and there have been disagreements about the mechanism of troponin release. The aim of this paper was to review the literature, and to consider factors and mechanisms regarding exercise-induced increase of troponin. 145 studies were found after a search in pubmed and inclusion of additional articles found in the reference list of the first articles. Results showed that troponin rises in 0-100% of subjects after prolonged heavy exercise like marathon, but also after short-term and intermittent exercise like 30min of running and basketball. The variation can be due to factors like intensity, age, training experience, variation in sample size, blood sample timing and troponin assay. The pattern of troponin level post-exercise corresponds to release from the cytosolic compartment of cardiomyocytes. Increased membrane permeability might be caused by production of reactive oxygen species or alterations in calcium, pH, glucose/fat metabolism or in communication between integrins. Other suggested mechanisms are increased cardiovascular stress, inflammation, vasculitis, release of troponin degradation products in "blebs", dehydration, impaired renal clearance and expression of cardiac troponin in skeletal muscle. It can be concluded that both heavy and light exercise may cause elevated troponin, which have to be considered when patient are suspected to have a myocardial infarction. Several factors probably influence post-exercise levels of troponin, but the mechanism of release is most likely physiologic.

Morphine in the treatment of acute pulmonary oedema--Why?

Morphine has for a long time, been used in patients with acute pulmonary oedema due to its anticipated anxiolytic and vasodilatory properties, however a discussion about the benefits and risks has been raised recently. A literature search in Medline and Embase using the keywords "pulmonary oedema" OR "lung oedema" OR "acute heart failure" AND "morphine" was performed. A certain vasodilation has been described after morphine administration, but the evidence for this mechanism is relatively poor and morphine-induced anxiolysis may possibly be the most important factor of morphine in pulmonary oedema and therefore some authors have suggested benzodiazepines as an alternative treatment. Respiratory depression seems to be a less relevant clinical problem according to the literature, whereas vomiting is common, which may cause aspiration. In the largest outcome study, based on the ADHERE registry, morphine given in acute decompensated heart failure was an independent predictor of increased hospital mortality, with an odds ratio of 4.8 (95% CI: 4.52-5.18, p<0.001). Other, smaller studies have shown a significant association between morphine administration and mortality, which was lost after adjusting for confounding factors. Morphine is still used for pulmonary oedema in spite of poor scientific background data. A randomised, controlled study is necessary in order to determine the effect--and especially the risk--when using morphine for pulmonary oedema. Since the positive effects are not sufficiently documented, and since the risk for increased mortality cannot be ruled out, one can advocate that the use should be avoided.

Troponins in heart failure.

The signs and symptoms of heart failure are frequently unspecific and correlate poorly with objective indices of cardiac function. Objective assessment of cardiac function by echocardiography or other imaging modalities also correlate poorly with symptomatic status and functional capacity. Accordingly, there is a need for circulating biomarkers that can provide incremental diagnostic and prognostic information to the existing armamentarium of tests. The introduction of more sensitive assays that allow determination of very low circulating concentrations of the myofibrillar proteins cardiac troponin I and T has not only resulted in improved diagnostic accuracy in the setting of acute coronary syndromes. The high sensitivity assays have also shown that cardiac troponins are frequently found chronically circulating in a variety of acute and chronic, cardiac and non-cardiac disease conditions, including acute heart failure and chronic symptomatic and asymptomatic left ventricular dysfunction. Cardiac troponin I and T provide may provide clinically useful prognostic information both concerning the future risk of developing heart failure in asymptomatic subjects and the risk of fatal events and hospital admissions in those with already established heart failure This review summarizes current literature on the clinical performance and utility of cardiac troponin measurements as diagnostic and prognostic tools in patients with symptomatic heart failure, as well as in those with asymptomatic left ventricular dysfunction, and clinical phenotypes at high risk for developing heart failure, including stable coronary artery disease, left ventricular hypertrophy, and aortic stenosis.

Myocarditis or "true" infarction by cardiac magnetic resonance in patients with a clinical diagnosis of myocardial infarction without obstructive coronary disease: A meta-analysis of individual patient data.

OBJECTIVE: Myocardial Infarction with Non-Obstructed Coronary Arteries (MINOCA) is common, but the causes are to a large extent unknown. Thus, we aimed to study the prevalence of myocarditis and "true" myocardial infarction determined by cardiac magnetic resonance (CMR) imaging in MINOCA patients, and risk markers for these two conditions in this population. METHODS: A search was made in the PubMed and Cochrane databases using the search terms "Myocardial infarction", "Coronary angiography", "Normal coronary arteries" and "MRI". All relevant abstracts were read and seven of the studies fulfilled the inclusion criteria; studies describing case series of patients fulfilling the diagnosis of acute myocardial infarction with normal or non-obstructive coronary arteries on coronary angiography that were investigated with CMR imaging. Data from five of these studies are presented. RESULTS: A total of 556 patients from 5 different sites were included. Fifty-one percent were men with a mean age of 52 ± 16 years. Thirty-three per cent of the patients had myocarditis (n = 183), whereas 21% of the patients had infarction on CMR (n = 115). Young age and a high CRP were associated with myocarditis whereas male sex, treated hyperlipidemia, high troponin ratio and low CRP were associated with "true" myocardial infarction. CONCLUSION AND RELEVANCE: The results of this meta-analysis of individual data showed that myocarditis and "true" myocardial infarction are common in MINOCA when determined by CMR imaging. This information emphasizes the importance of performing CMR imaging in MINOCA patients and can be used clinically to guide diagnostics and treatment of MINOCA patients.

Prevention of cardiovascular disease in rheumatoid arthritis.

The increased risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA) has been recognized for many years. However, although the characteristics of CVD and its burden resemble those in diabetes, the focus on cardiovascular (CV) prevention in RA has lagged behind, both in the clinical and research settings. Similar to diabetes, the clinical picture of CVD in RA may be atypical, even asymptomatic. Therefore, a proactive screening for subclinical CVD in RA is warranted. Because of the lack of clinical trials, the ideal CVD prevention (CVP) in RA has not yet been defined. In this article, we focus on challenges and controversies in the CVP in RA (such as thresholds for statin therapy), and propose recommendations based on the current evidence. Due to the significant contribution of non-traditional, RA-related CV risk factors, the CV risk calculators developed for the general population underestimate the true risk in RA. Thus, there is an enormous need to develop adequate CV risk stratification tools and to identify the optimal CVP strategies in RA. While awaiting results from randomized controlled trials in RA, clinicians are largely dependent on the use of common sense, and extrapolation of data from studies on other patient populations. The CVP in RA should be based on an individualized evaluation of a broad spectrum of risk factors, and include: 1) reduction of inflammation, preferably with drugs decreasing CV risk, 2) management of factors associated with increased CV risk (e.g., smoking, hypertension, hyperglycemia, dyslipidemia, kidney disease, depression, periodontitis, hypothyroidism, vitamin D deficiency and sleep apnea), and promotion of healthy life style (smoking cessation, healthy diet, adjusted physical activity, stress management, weight control), 3) aspirin and influenza and pneumococcus vaccines according to current guidelines, and 4) limiting use of drugs that increase CV risk. Rheumatologists should take responsibility for the education of health care providers and RA patients regarding CVP in RA. It is immensely important to incorporate CV outcomes in testing of anti-rheumatic drugs.

Carbohydrate-deficient transferrin is associated with insulin sensitivity in hypertensive men.

An elevated concentration of carbohydrate-deficient transferrin in serum (CDT) has been reported to indicate excessive ethanol consumption. However, in hypertensive men, we found low values for diagnostic sensitivity and specificity. Furthermore, in the individuals with high CDT values, the concentrations of serum triglycerides and blood glucose were low rather than high, indicating that factors related to insulin/glucose metabolism may be operative. The current study addresses this issue by examining 48 patients with treated hypertension and at least 1 of following: hypercholesterolemia, history of smoking, and diabetes mellitus. We determined serum CDT, fasting plasma insulin, and glucose disposal rate during hyperinsulinemic euglycemic clamp. Seven patients had elevated CDT concentrations. This group of patients had higher glucose disposal rates than the others (mean difference, 19 mumol/min.kg lean body mass; 95% confidence interval, 5-33 mumol/min.kg lean body mass; P = 0.0096), but did not differ in body mass index or alcohol intake. Serum CDT correlated positively with glucose disposal rate (r = 0.55; P = 0.0004) and negatively with fasting plasma insulin (r = -0.43; P = 0.0039). These relationships remained after exclusion of 8 patients with diabetes mellitus and adjustment for potentially confounding factors. We conclude that the serum CDT concentrations in our patients were associated with insulin sensitivity.

Independent relationship between microalbuminuria and plasminogen activator inhibitor-1 activity (PAI-1) activity in clinically healthy 58-year-old men.

The aim of this cross-sectional study was to investigate the relationship between low-grade albuminuria (microalbuminuria) and factors of the coagulation- and fibrinolysis systems in 104 clinically healthy 58-year-old men recruited from the general population. Urinary albumin excretion was significantly associated with body mass index, systolic and diastolic blood pressure, plasminogen activator inhibitor (PAI)-1 activity, tissue plasminogen activator (tPA) antigen, tPA activity (negatively) and protein S (P<0.05). There were no associations between urinary albumin excretion and antithrombin III, fibrinogen, protein C, thrombin/antithrombin factor or von Willebrand factor. In multiple regression analysis urinary albumin excretion was independently and significantly associated with PAI-1 activity and systolic blood pressure (P<0.05). In conclusion we report that urinary albumin excretion was independently and significantly associated with PAI-1 activity in clinically healthy 58-year-old men. This relationship may contribute to the previously reported increased cardiovascular morbidity in subjects with microalbuminuria.

Prothrombin fragment 1+2 is a risk factor for myocardial infarction in treated hypertensive men.

BACKGROUND: Haemostatic factors may play a part in the development of acute coronary heart disease. OBJECTIVE: To evaluate as predictors of major coronary events (fatal and non-fatal myocardial infarctions and sudden death) levels of fibrinogen, von Willebrand factor, prothrombin fragment 1+2, thrombin-antithrombin complex, plasminogen activator inhibitor activity and C-reactive protein. METHODS: We studied 131 men, aged 56-77 years, with treated hypertension and at least one additional cardiovascular risk factor (hypercholesterolaemia, diabetes mellitus or smoking). These patients were recruited from a continuing risk factor intervention study. The mean observation time was 3.0 years. RESULTS: Fourteen patients died and 16 had a major coronary event during the follow-up period. After adjustments for other risk factors, levels of prothrombin fragment 1+2 and C-reactive protein were independent predictors of major coronary events. The other measured haemostatic variables were not significantly associated with major coronary events during follow-up. Fibrinogen and prothrombin fragment 1+2 levels were independent predictors for mortality. CONCLUSIONS: Among treated hypertensive men, levels of prothrombin fragment 1+2 and C-reactive protein were independent predictors of major coronary events.

Urinary albumin excretion is associated with the intima-media thickness of the carotid artery in hypertensive males with non-insulin-dependent diabetes mellitus.

OBJECTIVE: To examine the relationship between urinary albumin excretion and ultrasonographically assessed morphology of the common carotid artery in hypertensive men with and without non-insulin-dependent diabetes mellitus. DESIGN: Cross-sectional study. SETTING: An outpatient clinic in a city hospital. PATIENTS: Hypertensive male patients (n = 25) with non-insulin-dependent diabetes mellitus and non-diabetic hypertensive male patients (n = 94) aged 50-72 years, randomly selected from a larger study group. MAIN OUTCOME MEASURES: Overnight urinary albumin excretion and B-mode ultrasound examinations of the carotid artery. RESULTS: Among the diabetic patients the logarithm of the overnight urinary albumin excretion was independently and significantly associated with the common carotid artery intima-media thickness, which was also true after adjustment for concomitant cardiovascular disease. In the non-diabetic group there was no association between intima-media thickness and urinary albumin excretion. No relationship between the occurrence of plaque and urinary albumin excretion was observed in any of the study groups. The results were reproducible at a re-examination after 3 years using the same methods. CONCLUSION: Among the hypertensive men with non-insulin-dependent diabetes mellitus, an independent and significant relationship, reproducible after 3 years, was found between urinary albumin excretion and the intima-media thickness of the common carotid artery. No such relationship was found in the group of non-diabetic hypertensive males.