Cerebral haemorrhage in the patient with atrial fibrillation: do we employ the direct oral anticoagulants without waiting too long?

Intracranial haemorrhage (ICH) is the most feared haemorrhagic complication of oral anticoagulant therapy (OAT), although the risk is significantly lower with direct oral anticoagulants (DOACs) compared with warfarin. Intracranial haemorrhage is generally considered, by clinicians, to be an absolute contraindication to starting or resuming OAT in patients with atrial fibrillation (AF). On the other hand, the pivotal trials with DOACs excluded patients with previous ICH. Observational studies actually indicate a net clinical benefit in favour of DOAC in patients with AF and previous ICH. This benefit is confirmed by randomized clinical trials which, however, have the limitation of the small number of cases, but larger clinical trials comparing DOACs vs. aspirin or no therapy are underway. While OAT is certainly contraindicated in patients with lobar ICH and cerebral amyloid angiopathy, in other cases, the decision must be made in the individual patient through an accurate balance between thromboembolic risk and haemorrhagic risk and a multidisciplinary cardio-neurological evaluation.

Ischaemic stroke in the absence of documented atrial fibrillation: is there who could benefit from anticoagulant therapy?

About 25% of ischaemic strokes are of cryptogenic origin and a significant proportion of them has a certain embolic nature, and for these patients the term embolic stroke of undetermined source (ESUS) has been coined. In the absence of subclinical atrial fibrillation (AF) identifiable through prolonged electrocardiogram monitoring, atrial cardiomyopathy, demonstrable through non-invasive cardiac imaging, aortic plaques and heart failure with preserved sinus rhythm, have been recognized among the potential causes of ESUS. In patients with ESUS, randomized clinical trials performed so far have failed to demonstrate a benefit of therapy with direct oral anticoagulants (DOACs). However, it is possible that in patients in whom the presence of atrial cardiomyopathy is ascertained there may be a benefit of anticoagulant therapy in secondary prevention after ESUS. In patients with aortic plaques associated with a thrombotic component and in those with heart failure and preserved sinus rhythm in the absence of AF but with a high congestive heart failure, hypertension age, diabetes, stroke, vascular disease (CHA2DS2-VASc) score, the decision on anticoagulant therapy with DOACs could be made in the individual patient even in the absence of evidence from clinical trials.

Mitral valve prolapse with ventricular arrhythmias: does it carries a worse prognosis?

The association of mitral valve prolapse (MVP) with ventricular arrhythmias has long been known and has generally been considered a benign condition. In recent years, however, a small but not negligible risk of malignant ventricular arrhythmias and sudden cardiac death has been documented in the large population of subjects with MVP. The main predictors of major arrhythmic risk identified so far include history of syncope, ventricular repolarization abnormalities in the inferior-lateral electrocardiogram leads, right bundle branch block morphology of ventricular ectopic beats, finding of areas of myocardial fibrosis on cardiac magnetic resonance, and mitral annular disjunction (MAD) on echocardiogram, as well as a possible pro-arrhythmic genetic substrate. The stratification of arrhythmic risk, with the active search for red flags and in particular of MAD, is important to identify patients with the malignant arrhythmic variant of MVP in whom to implement closer surveillance and possible therapeutic interventions.

Long-term injury after Takotsubo syndrome (stress cardiomyopathy).

Takotsubo syndrome is a clinical condition characterized by transient impairment of left ventricular contractility, in association with symptoms, increase in indices of myocardial necrosis, as well as electrocardiographic changes, but without a coronary culprit lesion, and often after a significant psychological or physical stress. Albeit very similar to acute coronary syndrome (ACS) as far as presentation and clinical course, Takotsubo syndrome was considered, up until recently, a condition with very favourable long-term prognosis, in view of the frequent complete functional recovery. More recently, several retrospective observational studies as well as registers, unexpectedly called attention to a significant incidence of major adverse cardiovascular events, not limited to the recovery period but also during the long-term follow-up, in a way very similar to the outcome of patients after ACS. Several negative prognostic factors have been isolated, such as physical stress as trigger of the condition, the presence of severe left ventricular dysfunction, and the consequent cardiogenic shock during the acute phase. These factors are able to classify better the patient's prognosis, both in the short- and long-term, and identify patients requiring a more stringent clinical follow-up, considering the higher likelihood of adverse cardiovascular events.

Sodium-glucose co-transporter-2 drugs: are we sure they are useful only in the treatment of diabetes?

The sodium-glucose co-transporter-2 (SGLT2) inhibitors are a new class of oral anti-diabetic drugs acting through the inhibition of renal reabsorbtion of glucose. Three important randomized clinical trial in diabetic patients receiving SGLT2 inhibitors (vs. placebo), demonstrated a significant reduction of major adverse cardiovascular events, but only in patients with known atherosclerotic disease, and a clear-cut and early reduction in hospital admissions for heart failure in patients in primary as well as secondary prevention settings. This latter information prompted the design of a recent study the DAPA-HF (Dapagliflozin And Prevention Of Adverse-outcomes In Heart Failure) trial, comparing dapagliflozin vs. placebo, and showing a significant reduction of clinical relevant episodes of heart failure in patients with reduced left ventricular ejection fraction, regardless the presence of diabetes mellitus. The mechanism by which the SGLT2 inhibitors exert their anti-heart failure action is not well understood but appears to be independent from its hypoglycaemic action. These results, along with the scarcity of adverse side effects of the drug, render dapagliflozin a new tool in the treatment of heart failure.

[Influenza infection and risk of myocardial infarction: the protective effect of influenza vaccination. One more reason to vaccinate]. / Influenza e rischio di infarto miocardico acuto: ruolo protettivo della vaccinazione anti-influenzale. Un motivo in più per vaccinare.

Influenza infection, although considered a relatively benign pathology, is associated with a high number of hospital admissions and significant mortality, especially for the most vulnerable subjects. There is a great deal of evidence regarding the existence of an association between influenza and occurrence of cardiovascular events. Influenza vaccination by reducing the transmission of infection aims to reduce its complications, including cardiovascular events. The available studies have confirmed the safety of influenza vaccination in patients at high cardiovascular risk, even if performed during acute coronary syndrome hospitalization, and its efficacy in reducing coronary events. The cardiac benefit of influenza vaccination has been acknowledged by the cardiological scientific societies in the drafting of guidelines for both stable coronary artery disease and heart failure.

Severe low-gradient aortic stenosis, with preserved ventricular function: should it be treated?

Exists a group of patients with small AVA (<0,6 cm/m), and normal LVEF (≥50%) who display a low transvalvular flow (LF) [index stroke volume (SVi)<35 ml/m2] and/or low transvalvular gradient (LG). This condition is called severe paradoxical aortic stenosis (SAO) LFLG. In many studies this condition was associated to increased mortality both with medical therapy and with surgical intervention. Crucial is define correctly the diagnostical criteria of this condition. Indeed there are several specific anatomical and functional characteristics useful in differentiating paradoxical severe aortic stenosis from the other forms of aortic stenosis. In case of doubt in the diagnostical process, the Multidetector Computed Tomography (MDCT) could be useful in quantifying calcificazions of the aortic valve. The guidelines European Society of Cardiology (ESC) and American College of Cardiology (ACC) recomended aortic valve replacement for symptomatic patients with paradoxical LFLG severe aortic stenosis, recommending to accurately measure the flow in these patients as to differentiate them from those with NFLG and better prognosis.

[Inflammation and lipids in the coronary pathology. Risk factors, causes or therapeutic target?]. / Infiammazione e lipidi nella patologia coronarica. Fattori di rischio, cause scatenanti o target terapeutici?

The search for new risk markers of cardiovascular (CV) risk is continuous, aimed to improve its estimate. Among them, the measurement of C-reactive protein (CRP) levels seems the most promising one. CV risk evaluation systems as Reynolds score, integrating CPR dosage to classic risk factors, were shown to improve the detection of subjects at higher risk, who deserve a more effective CV prevention. The use of CRP as a guide in primary prevention was tested for the first time in the JUPITER study, a large randomized trial comparing rosuvastatin 20 mg and placebo. Admission criteria were based on the presence of an inflammatory status only (CRP >2 mg/l), aside from CV risk factors (LDL <130 mg/dl). Rosuvastatin 20 mg, compared to placebo, significantly reduced composite primary endpoint (CV mortality, myocardial infarction, ischemic stroke, hospitalization for unstable angina and myocardial revascularization). These results confirmed the continuous relationship between decreased cholesterol level and clinical benefit also in primary prevention. The high prevalence of metabolic syndrome in this study population confirmed the link between this condition and the presence of an inflammatory status, and the high incidence of events occurred in the placebo group suggests an important role of CRP in the detection of subjects at higher CV risk. The greatest reduction of CV events was seen in the subgroup of patient who achieved the "double target" of both decreased lipids and inflammation marker, similarly to PROVE IT-TIMI 22 in secondary prevention. The presence of an inflammatory status may allow the detection of more vulnerable patients, where statin treatment may result in a greater benefit, as both LDL cholesterol and inflammatory status are reduced, and clinical CV events are consequently decreased.

[Imaging of atherosclerosis]. / L'imaging dell'aterosclerosi.

Atherosclerosis is a chronic disease potentially involving the whole arterial system that causes a spectrum of clinical manifestations ranging from acute myocardial infarction to stable angina or stroke. The continuous accumulation of lipids, fibrous and inflammatory elements in the arterial wall leads to progressive lumen narrowing with subsequent ischemia. Acute coronary syndromes (unstable angina, acute myocardial infarction) have a more complex and dynamic pathogenesis with coronary plaque rupture and thrombosis as the final common pathway. As only some plaques lead to clinical events whereas many others remain asymptomatic life-long, different imaging modalities have been applied to define the atherosclerotic burden and/or the anatomical characteristics of unstable or vulnerable lesions. Carotid ultrasound, multislice computed tomography (MSCT) or nuclear magnetic resonance (NMR) have been applied to assess the atherosclerotic burden in asymptomatic subjects, while coronary angiography has been mainly used to assess unstable plaques at the time of coronary events. Today intravascular ultrasound (IVUS) offers qualitative details on plaque composition, like hard and soft components, that are helpful to assess unstable lesions, but other important details (lipid pool areas or fibrous cap thickness, ulcerations, thrombotic apposition or erosion) are either below the resolution of IVUS or not easily visualized. In the last years novel techniques have been developed to overcome these limitations. Optical coherence tomography and the combination of anatomical and biological imaging using hybrid techniques (like virtual histology or the combination of positron emission tomography and MSCT or NMR) appear to be particularly attractive. These approaches will likely provide new insights into the pathophysiology of acute coronary events and into the effects of aggressive preventive therapies.

Strong and independent prognostic value of peak circulatory power in adults with congenital heart disease.

BACKGROUND: The identification of patients with adult congenital heart disease (ACHD) who are at higher risk of death is challenging. Peak circulatory power (CircP; expressed as peak exercise oxygen uptake multiplied for peak mean arterial blood pressure) is a strong predictor of death in adults with acquired heart disease. We sought to establish the distribution and the prognostic value of peak CircP across a wide spectrum of patients with ACHD. METHODS: Four hundred thirty-two consecutive patients with ACHD of varying diagnosis underwent cardiopulmonary exercise testing at a single laboratory between 1996 and 2005. Patient age was 32 +/- 10 years. RESULTS: A gradual variation in peak CircP was found across the spectrum of congenital heart defects (P < .0001 at analysis of variance). Reduced peak CircP values were associated with the presence of heart failure symptoms (P < .0001), absence of sinus rhythm (P = .010), and use of antiarrhythmic medications (P = .0013). At a follow-up of 4.4 +/- 2.4 years, 23 patients (5.3%) had died. Peak CircP was a strong predictor of mortality when univariate analysis was used and the strongest independent predictor of mortality among exercise parameters. A peak CircP < or = 1476 mm Hg mlO2 min(-1) kg(-2) was associated with a 15.4-fold increase in the 4-year risk of death. CONCLUSIONS: Peak CircP is abnormal across the spectrum of ACHD. Peak CircP appears as the strongest predictor of adverse outcome in ACHD.

Usefulness of cardiopulmonary exercise to predict long-term prognosis in adults with repaired tetralogy of Fallot.

Adults with tetralogy of Fallot (TOF) have increased long-term mortality. The identification of patients at greater risk for death or cardiac-related morbidity is challenging. This study was conducted to assess the prognostic value of cardiopulmonary exercise testing in adults with repaired TOF. One hundred eighteen consecutive adults with repaired TOF (mean age at repair 4.8 +/- 4.2 years) underwent cardiopulmonary exercise testing at a mean age of 24 +/- 8 years (range 16 to 59). The degree of pulmonary regurgitation, right ventricular function, and right ventricular systolic pressure were determined by transthoracic echocardiography. After the exercise tests, patients were regularly followed up for cardiac-related events. During a mean follow-up of 5.8 +/- 2.3 years (range 0.6 to 9.7), 9 patients died and 18 underwent hospitalization. Peak oxygen uptake (hazard ratio 0.974, 95% confidence interval 0.950 to 0.994), the slope of ventilation (VE) per unit of carbon dioxide production (VCO(2)) (hazard ratio 1.076, 95% confidence interval 1.038 to 1.115), and New York Heart Association functional class (hazard ratio 2.118, 95% confidence interval 1.344 to 3.542) were independent predictors of death or hospitalization. Patients with peak oxygen uptake < or =36% of predicted value and those with VE/VCO(2) slopes >39 were at greater risk for cardiac-related death (5-year mortality 48% vs 0%, p <0.0001, and 31% vs 0%, p <0.0001, respectively). In conclusion, the measurement of peak oxygen uptake and VE/VCO(2) slope in adults with repaired TOF can be prognostically important and could become a powerful tool to rationalize decisions regarding the prevention of premature sudden death and the need for reintervention.

Impact of pulmonary regurgitation and right ventricular dysfunction on oxygen uptake recovery kinetics in repaired tetralogy of Fallot.

BACKGROUND: Patients with repaired tetralogy of Fallot (ToF) featuring severe pulmonary regurgitation (PR) and/or right ventricular (RV) dysfunction have reduced exercise tolerance. AIMS: To assess the impact of PR and of RV function on the ability to recover from exercise in ToF patients. METHODS: 61 consecutive patients aged 23.1+/-12.1 years underwent maximal cardiopulmonary exercise test (CPX), transthoracic echocardiography and magnetic resonance imaging. This data was compared to those of 153 matched healthy subjects. RESULTS: 19 patients (31%) had severe PR. RV dysfunction was noted in 19 patients (31%). Nine patients (15%) had both severe PR and RV dysfunction. Patients had lower peak oxygen uptake (VO2), VO2 slope, carbon dioxide production (VCO2) slope and O2 pulse slope (p < 0.0001), especially those with severe PR and RV dysfunction (p < 0.0001). Heart rate slope was similar between groups. No patient with severe PR and RV dysfunction had a predicted peak VO2 > 40%. CPX had a high sensitivity and specificity to identify patients with severe PR and RV dysfunction. CONCLUSIONS: In ToF patients, severe PR and RV dysfunction lead to delayed recovery from exercise. CPX can identify patients with severe PR and RV dysfunction and may be useful to guide the pulmonary valve replacement decision-making process.

Recovery kinetics of oxygen uptake is prolonged in adults with an atrial septal defect and improves after transcatheter closure.

BACKGROUND: In adults with an atrial septal defect (ASD) transcatheter closure leads to an improvement of peak oxygen uptake (VO2), but the kinetics of recovery of VO2 after maximal exercise in this patient population and the impact of transcatheter ASD closure have never been investigated. METHODS: Twenty consecutive patients underwent a maximal cardiopulmonary exercise test both the day before and 6 months after transcatheter ASD closure. For comparison, an age- and sex-matched group consisting of 53 healthy adults was built. The constant decay of VO2, CO2 production (VCO2), minute ventilation (VE), and heart rate (HR), expressed as the first-degree slope of a single linear relation, were calculated for the first minute of recovery. RESULTS: Patients with an ASD had a prolonged VO2 slope (P =.0012), VCO2 slope (P =.0003), and VE slope (0.013) when compared with control subjects. Six months after transcatheter ASD closure, significant improvements of VO2 slope (P =.0043) and of VCO2 slope (P =.0022) were recorded, so that no difference was found when compared with those of the control group (P =.1 and P =.06, respectively). The VE slope and HR slope did not change after closure. A significant association between VO2 slope and peak VO2 in the group of patients with ASD was shown by the Spearman correlation, both before (r = 0.67, P =.0012) and after ASD closure (r = 0.71, P =.0004). CONCLUSIONS: A limited cardiopulmonary reserve in adults with no symptom who have an ASD appears to affect not only maximal exercise responses but also the recovery phase. Transcatheter ASD closure induces a significant improvement of the ability of recovering from maximal exercise and eliminates the difference with a healthy population.