Non-vitamin K antagonist oral anticoagulants (NOACs) for thromboembolic prevention, are they safe in congenital heart disease? Results of a worldwide study.

BACKGROUND: Current guidelines consider vitamin K antagonists (VKA) the oral anticoagulant agents of choice in adults with atrial arrhythmias (AA) and moderate or complex forms of congenital heart disease, significant valvular lesions, or bioprosthetic valves, pending safety data on non-VKA oral anticoagulants (NOACs). Therefore, the international NOTE registry was initiated to assess safety, change in adherence and quality of life (QoL) associated with NOACs in adults with congenital heart disease (ACHD). METHODS: An international multicenter prospective study of NOACs in ACHD was established. Follow-up occurred at 6 months and yearly thereafter. Primary endpoints were thromboembolism and major bleeding. Secondary endpoints included minor bleeding, change in therapy adherence (≥80% medication refill rate, ≥6 out of 8 on Morisky-8 questionnaire) and QoL (SF-36 questionnaire). RESULTS: In total, 530 ACHD patients (mean age 47 SD 15 years; 55% male) with predominantly moderate or complex defects (85%), significant valvular lesions (46%) and/or bioprosthetic valves (11%) using NOACs (rivaroxaban 43%; apixaban 39%; dabigatran 12%; edoxaban 7%) were enrolled. The most common indication was AA (91%). Over a median follow-up of 1.0 [IQR 0.0-2.0] year, thromboembolic event rate was 1.0% [95%CI 0.4-2.0] (n = 6) per year, with 1.1% [95%CI 0.5-2.2] (n = 7) annualized rate of major bleeding and 6.3% [95%CI 4.5-8.5] (n = 37) annualized rate of minor bleeding. Adherence was sufficient during 2 years follow-up in 80-93% of patients. At 1-year follow-up, among the subset of previous VKA-users who completed the survey (n = 33), QoL improved in 6 out of 8 domains (p ≪ 0.05). CONCLUSIONS: Initial results from our worldwide prospective study suggest that NOACs are safe and may be effective for thromboembolic prevention in adults with heterogeneous forms of congenital heart disease.

Cerebrovascular accidents in adult patients with congenital heart disease.

OBJECTIVE: To investigate the prevalence and characteristics of cerebrovascular accidents (CVA) in a large population of adults with congenital heart disease (CHD). METHODS AND RESULTS: In a retrospective analysis of aggregated European and Canadian databases a total population of 23 153 patients with CHD was followed up to the age of 16-91 years (mean 36.4 years). Among them, 458 patients (2.0%) had one or more CVA, with an estimated event rate of 0.05% per patient-year. Permanent neurological sequelae were noted in 116 patients (25.3%). The prevalence of CVA in selected diagnostic categories was as follows: open atrial septal defect 93/2351 (4.0%); closed atrial or ventricular septal defect 57/4035 (1.4%); corrected tetralogy of Fallot 52/2196 (2.4%); Eisenmenger physiology 24/467 (5.1%); other cyanotic 50/215 (23.3%); mechanical prostheses (29/882 (3.3%). Associated conditions in patients with CVA were absence of sinus rhythm (25%), transvenous pacemakers (7%), endocarditis (2%), cardiac surgery (11%) and catheter intervention (2%), but with the exception of absent sinus rhythm these were not significantly more prevalent in patients with CVA. CONCLUSION: CVA are a major contributor to morbidity in this young population despite absence of classical cardiovascular risk factors. Although the prevalence of CVA in patients with CHD appears low, it is 10-100 times higher than expected in control populations of comparable age. Residua occur in a strong minority of patients. The subjects at highest risk are those patients with CHD with cyanotic lesions, in whom the prevalence is over 10-fold above the average.

Long-term results after fluoroscopy-guided closure of patent foramen ovale for secondary prevention of paradoxical embolism.

OBJECTIVES: To carry out long-term follow-up after percutaneous closure of patent foramen ovale (PFO) in patients with cryptogenic stroke. DESIGN: Prospective cohort study. SETTING: Single tertiary care centre. PARTICIPANTS: 525 consecutive patients (mean (SD) age 51 (12) years; 56% male). INTERVENTIONS: Percutaneous PFO closure without intraprocedural echocardiography. MAIN OUTCOME MEASURES: Freedom from recurrent embolic events. RESULTS: A mean (SD) of 1.7 (1.0) clinically apparent embolic events occurred for each patient, and 186 patients (35%) had >1 event. An atrial septal aneurysm was associated with the PFO in 161 patients (31%). All patients were followed up prospectively for up to 11 years. The implantation procedure failed in two patients (0.4%). There were 13 procedural complications (2.5%) without any long-term sequelae. Contrast transoesophageal echocardiography at 6 months showed complete closure in 86% of patients, and a minimal, moderate or large residual shunt in 9%, 3% and 2%, respectively. Patients with small occluders (<30 mm; n = 429) had fewer residual shunts (small 11% vs large 27%; p<0.001). During a mean (SD) follow-up of 2.9 (2.2) years (median 2.3 years; total 1534 patient-years), six ischaemic strokes, nine transient ischaemic attacks (TIAs) and two peripheral emboli occurred. Freedom from recurrent stroke, TIA, or peripheral embolism was 98% at 1 year, 97% at 2 years and 96% at 5 and 10 years, respectively. A residual shunt (hazard ratio = 3.4; 95% CI 1.3 to 9.2) was a risk factor for recurrence. CONCLUSIONS: This study attests to the long-term safety and efficacy of percutaneous PFO closure guided by fluoroscopy only for secondary prevention of paradoxical embolism in a large cohort of consecutive patients.

Prevalence and size of directly detected patent foramen ovale in migraine with aura.

BACKGROUND: Transcranial contrast Doppler studies have shown an increased prevalence of right-to-left shunts in patients with migraine with aura compared with controls. The anatomy and size of these right-to-left shunts have never been directly assessed. METHODS: In a cross-sectional case-control study, the authors performed transesophageal contrast echocardiography in 93 consecutive patients with migraine with aura and 93 healthy controls. RESULTS: A patent foramen ovale was present in 44 (47% [95% CI 37 to 58%]) patients with migraine with aura and 16 (17% [95% CI 10 to 26%]) control subjects (OR 4.56 [95% CI 1.97 to 10.57]; p < 0.001). A small shunt was equally prevalent in migraineurs (10% [95% CI 5 to 18%]) and controls (10% [95% CI 5 to 18%]), but a moderate-sized or large shunt was found more often in the migraine group (38% [95% CI 28 to 48%] vs 8% [95% CI 2 to 13%] in controls; p < 0.001). The presence of more than a small shunt increased the odds of having migraine with aura 7.78-fold (95% CI 2.53 to 29.30; p < 0.001). Besides patent foramen ovale prevalence and shunt size, no other echocardiographic differences were found between the study groups. Headache and baseline characteristics did not differ in migraine patients with and without shunt. CONCLUSIONS: Nearly half of all patients with migraine with aura have a right-to-left shunt due to a patent foramen ovale. Shunt size is larger in migraineurs than controls. The clinical presentation of migraine is identical in patients with and without a patent foramen ovale.

Cerebrovascular response to repetitive visual stimulation in interictal migraine with aura.

Cortical hypersensitivity and absent habituation to different stimuli have been observed in migraine patients. These features might also be transmitted to the cerebral vasoreactivity, but results are conflicting so far. Transcranial Doppler ultrasound (TCD) was used to assess cerebral blood flow velocity (CBFV) changes in the middle (MCA) and posterior cerebral arteries (PCA) in relation to repetitive checkerboard visual stimulation. Stimulation consisted of 10 consecutive cycles, each comprising 10 s stimulation and 10 s rest. TCD recordings were analysed using stimulus-related averaging algorithm. Data of 19 interictal migraineurs with aura were compared to those of 19 headache-free healthy volunteers. The CBFV increase in PCA and in MCA during visual stimulation was significantly larger and steeper in migraineurs than in controls (P = 0.017 and P = 0.005). The response in PCA remained stable over the 10 stimulation cycles, both in migraineurs and in controls. The response in MCA was stable only in migraineurs. In controls it decreased over the last 5 stimulation cycles compared with the first 5 cycles (P = 0.04). Migraineurs with aura exhibit a larger cerebrovascular response to repetitive visual stimulation compared to headache-free subjects. A reduced adaptation to environmental stimuli in migraine is suggested, since there was no habituation in migraineurs in contrast to healthy controls.

Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks.

Among 215 patients referred for percutaneous closure of patent foramen ovale (PFO) after presumed paradoxical embolism, we assessed the prevalence of migraine. In the year prior to PFO closure, 48 (22%) patients had migraine, twice the expected prevalence of 10 to 12% in the general European population. In patients with migraine with aura, percutaneous PFO closure reduced the frequency of migraine attacks by 54% (1.2 +/- 0.8 vs 0.6 +/- 0.8 per month; p = 0.001) and in patients with migraine without aura by 62% (1.2 +/- 0.7 vs 0.4 +/- 0.4 per month; p = 0.006). PFO closure did not have an effect on headache frequency in patients with nonmigraine headaches (1.4 +/- 0.9 vs 1.0 +/- 0.9 per month; p = NS).

Percutaneous closure of patent foramen ovale: impact of device design on safety and efficacy.

OBJECTIVE: To compare the safety and efficacy of percutaneous closure of patent foramen ovale (PFO) with the Amplatzer PFO occluder (Amplatzer) or the PFO STAR device (STAR) in patients with presumed paradoxical embolism. METHODS: Implantation characteristics, procedural complications, residual shunt, and recurrence of thromboembolic events were recorded prospectively in 100 consecutive patients undergoing percutaneous PFO closure with the STAR (n = 50) or Amplatzer (n = 50) devices between 1998 and 2001. The study was not randomised. Device implantation was successful in all cases. RESULTS: There were more procedural complications in the STAR than in the Amplatzer group (8/50 v 1/50, p = 0.01). More than one device placement attempt was an independent predictor of procedural complications (odds ratio (OR) 8.5, 95% confidence interval (CI) 1.3 to 55.8; p = 0.03). A residual shunt six months after PFO closure, assessed by transoesophageal contrast echocardiography, occurred more often in the STAR than the Amplatzer group (17/50 v 3/50, p = 0.004), and was predicted in the STAR group by the use of a device with a 5 mm as opposed to a 3 mm disc connector (OR 6.1, 95% CI 1.1 to 34.0; p = 0.04). The actuarial risk of recurrent thromboembolic events after 3.5 years was 16.8% (95% CI 7.6% to 34.6%) in the STAR and 2.7% (95% CI 0.4% to 17.7%) in the Amplatzer group after three years (p = 0.08). CONCLUSIONS: Percutaneous PFO closure with the Amplatzer PFO occluder had fewer procedural complications and was more likely to be complete than with the STAR device. These findings underline the importance of device design for successful percutaneous PFO closure.

[Atrial fibrillation and stroke]. / Vorhofflimmern und Hirninfarkt.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. The prevalence of AF is 0.4% in the general population and increases with age up to 6-8% in octogenarians. In Switzerland, approximately 68,000 persons are in atrial fibrillation, and in the EU countries 3.5 millions. Atrial fibrillation disturbs synchronous mechanical atrial activity and impairs the haemodynamics. This can give rise to thrombus formation, mostly in the left atrial appendage, and embolism to the systemic circulation. Clinical manifestations are most often neurological such as transient ischaemic attacks or ischaemic strokes, on average 5% per year. Of all strokes, one in every six occurs in patients with AF. Antiarrhythmic therapy is useful to improve cardiac rate and function in AF. However, to reduce first or recurrent emboli, antithrombotic therapy is of paramount importance. Adjusted-dose warfarin reduces first or recurrent strokes by about 60%. When patients with non-valvular AF are anticoagulated, the odds against ischaemic stroke and intracranial bleeding favour an INR between 2.0 and 3.0. Acetylsalicylic acid is less efficacious than warfarin in AF patients, reducing the risk of stroke by about 20%. Therefore, anticoagulation is the current treatment modality in AF patients at high or intermediate risk, i.e. patients with history of transient ischaemic attack or stroke, those aged > 65 years, those with a history of hypertension, diabetes, heart failure or structural heart disease, valvular disease or significant systolic dysfunction. Antiplatelet agents should be used only for young (< 65 years) AF patients at low risk.

Quantitative contrast echocardiographic assessment of collateral derived myocardial perfusion during elective coronary angioplasty.

OBJECTIVE: To determine whether myocardial contrast echocardiography can be used to quantify collateral derived myocardial flow in humans. METHODS: In 25 patients undergoing coronary angioplasty, a collateral flow index (CFI) was determined using intracoronary wedge pressure distal to the stenosis to be dilated, with simultaneous mean aortic pressure measurements. During balloon occlusion, echo contrast was injected into both main coronary arteries simultaneously. Echocardiography of the collateral receiving myocardial area was performed. The time course of myocardial contrast enhancement in images acquired at end diastole was quantified by measuring pixel intensities (256 grey units) within a region of interest. Perfusion variables, such as background subtracted peak pixel intensity and contrast transit rate, were obtained from a fitted gamma variate curve. RESULTS: 16 patients had a left anterior descending coronary artery stenosis, four had a left circumflex coronary artery stenosis, and five had a right coronary artery stenosis. The mean (SD) CFI was 19 (12)% (range 0-47%). Mean contrast transit rate was 11 (8) seconds. In 17 patients, a significant collateral contrast effect was observed (defined as peak pixel intensity more than the mean + 2 SD of background). Peak pixel intensity was linearly related to CFI in patients with a significant contrast effect (p = 0.002, r = 0.69) as well as in all patients (p = 0.0003, r = 0.66). CONCLUSIONS: Collateral derived perfusion of myocardial areas at risk can be demonstrated using intracoronary echo contrast injections. The peak echo contrast effect is directly related to the magnitude of collateral flow.

Recreational scuba diving, patent foramen ovale and their associated risks.

Scuba diving has become a popular leisure time activity with distinct risks to health owing to its physical characteristics. Knowledge of the behaviour of any mixture of breathable gases under increased ambient pressure is crucial for safe diving and gives clues as to the pathophysiology of compression or decompression related disorders. Immersion in cold water augments cardiac pre- and afterload due to an increase of intrathoracic blood volume and peripheral vasoconstriction. In very rare cases, the vasoconstrictor response can lead to pulmonary oedema. Immersion of the face in cold water is associated with bradycardia mediated by increased vagal tone. In icy water, the bradycardia can be so pronounced, that syncope results. For recreational dives, compressed air (i.e., 4 parts nitrogen and 1 part oxygen) is the preferred breathing gas. Its use is limited for diving to 40 to 50 m, otherwise nitrogen narcosis ("rapture of the deep") reduces a diver's cognitive function and increases the risk of inadequate reactions. At depths of 60 to 70 m oxygen toxicity impairs respiration and at higher partial pressures also functioning of the central nervous system. The use of special nitrogen-oxygen mixtures ("nitrox", 60% nitrogen and 40% oxygen as the typical example) decreases the probability of nitrogen narcosis and probably bubble formation, at the cost of increased risk of oxygen toxicity. Most of the health hazards during dives are consequences of changes in gas volume and formation of gas bubbles due to reduction of ambient pressure during a diver's ascent. The term barotrauma encompasses disorders related to over expansion of gas filled body cavities (mainly the lung and the inner ear). Decompression sickness results from the growth of gas nuclei in predominantly fatty tissue. Arterial gas embolism describes the penetration of such gas bubbles into the systemic circulation, either due to pulmonary barotrauma, transpulmonary passage after massive bubble formation ("chokes") or cardiac shunting. In recreational divers, neurological decompression events comprise 80% of reported cases of major decompression problems, most of the time due to pathological effects of intravascular bubbles. In divers with a history of major neurological decompression symptoms without evident cause, transoesophageal echocardiography must be performed to exclude a patent foramen ovale. If a cardiac right-to-left shunt is present, we advise divers with a history of severe decompression illness to stop diving. If they refuse to do so, it is crucial that they change their diving habits, minimising the amount of nitrogen load on the tissue. There is ongoing debate about the long term risk of scuba diving. Neuro-imaging studies revealed an increased frequency of ischaemic brain lesions in divers, which do not correlate well with subtle functional neurological deficits in experienced divers. In the light of the high prevalence of venous gas bubbles even after dives in shallow water and the presence of a cardiac right-to-left shunt in a quarter of the population (i.e., patent foramen ovale), arterialisation of gas bubbles might be more frequent than usually presumed.

Sympathetic stimulation using the cold pressor test increases coronary collateral flow.

BACKGROUND: Little is known about the vasomotor function of human coronary collateral vessels. The purpose of this study was to examine collateral flow under a strong sympathetic stimulus (cold pressor test, CPT). METHODS: In 30 patients (62 +/- 12 years) with coronary artery disease, two subsequent coronary artery occlusions were performed with random CPT during one of them. Two minutes before and during the 1 minute-occlusion, the patient's hand was immerged in ice water. For the calculation of a perfusion pressure-independent collateral flow index (CFI), the aortic (Pao), the central venous (CVP) and the coronary wedge pressure (Poccl) were measured: CFI = (Poccl - CVP)/(Pao - CVP). RESULTS: CPT lead to an increase in Pao from 98 +/- 14 to 105 +/- 15 mm Hg (p = 0.002). Without and with CPT, CFI increased during occlusion from 14% +/- 10% to 16% +/- 10% (p = 0.03) and from 17% +/- 9% to 19% +/- 9% (p = 0.006), respectively, relative to normal flow. During CPT, CFI was significantly higher at the beginning as well as at the end of the occlusion compared to identical instants without CPT. CFI at the end of the control occlusion did not differ significantly from the CFI at the beginning of occlusion with CPT. CONCLUSIONS: During balloon occlusion, collateral flow increased due to collateral recruitment independent of external sympathetic stimulation. Sympathetic stimulation using CPT additionally augmented collateral flow. The collateral-flow-increasing effect of CPT is comparable to the recruitment effect of the occlusion itself. This may reflect a coronary collateral vasodilation mediated by the sympathetic nervous system.

Relation between directly detected patent foramen ovale and ischemic brain lesions in sport divers.

BACKGROUND: In divers, the significance of a patent foramen ovale and its potential relation to paradoxical gas emboli remain uncertain. OBJECTIVE: To assess the prevalence of symptoms of decompression illness and ischemic brain lesions in divers with regard to the presence of a patent foramen ovale. DESIGN: Retrospective cohort study. SETTING: University hospital and three diving clubs in Switzerland. PARTICIPANTS: 52 sport divers and 52 nondiving controls. MEASUREMENTS: Prevalence of self-reported decompression events, patent foramen ovale on contrast transesophageal echocardiography, and ischemic brain lesions on magnetic resonance imaging. RESULTS: The risk for decompression illness events was 4.5-fold greater in divers with patent foramen ovale than in divers without patent foramen ovale (risk ratio, 4.5 [95% CI, 1.2 to 18.0]; P = 0.03). Among divers, 1.23 +/- 2.0 and 0.64 +/- 1.22 ischemic brain lesions per person (mean +/- SD) were detected in those with and those without patent foramen ovale, respectively. Among controls, 0.22 +/- 0.44 and 0.12 +/- 0.63 lesion per person were detected (P < 0.001 for all groups). CONCLUSIONS: Regardless of whether a diver has a patent foramen ovale, diving is associated with ischemic brain lesions.

Accurate determination of mitral regurgitation by assessing its influence on the combined diastolic mitral and pulmonary venous flow: just 'looking twice'.

AIMS: To assess the diagnostic accuracy of combined transmitral E wave velocity and reversed systolic pulmonary venous flow for the quantification of mitral regurgitation severity. METHODS AND RESULTS: Measuring forward and total left ventricular stroke volume, mitral regurgitation severity was assessed quantitatively by calculating the regurgitant fraction in 106 consecutive patients with pure mitral regurgitation. According to the regurgitant fraction, the optimal E wave velocity for accurate distinction of mild to moderate and more than moderate mitral regurgitation was chosen by calculating the receiver-operating characteristic plot. Severe mitral regurgitation was defined by reversed systolic pulmonary venous flow. Combining transmitral E wave velocity and reversed systolic pulmonary venous flow had an overall accuracy of 78% (95% CI 70--86%) for classification of mitral regurgitation severity. E wave velocity >1.0ms(-1) predicted more than moderate mitral regurgitation with 78% sensitivity (95% CI 69-86%) and 90% specificity (95% CI 82--95%), resulting in a positive likelihood ratio of 8.1 (95% CI 5--15) and negative likelihood ratio of 0.25 (95% CI 0.18--0.35). For reversed systolic pulmonary venous flow in the presence of increased E wave velocity, the sensitivity and specificity to detect severe mitral regurgitation was 78% (95% CI 69--86%) and 97% (95% CI 92--99%) with the corresponding positive and negative likelihood ratio of 29 (95% CI 11--96) and 0.22 (95% CI 0.14--0.31). Test accuracy was independent of systolic function in a multivariate regression analysis. CONCLUSIONS: 'Looking twice', once at the transmitral E wave velocity and once at pulmonary venous flow in patients with mitral regurgitation, allows accurate determination of moderately severe and severe mitral regurgitation.

Gender differences in coronary artery size per 100 g of left ventricular mass in a population without cardiac disease.

OBJECTIVES: To determine whether there is a gender difference in coronary artery size normalised for left ventricular (LV) mass. BACKGROUND: Small coronary artery caliber may play a role as a risk factor for coronary artery disease in women. However, the existence of a gender difference in coronary artery size is controversial. Furthermore, coronary artery size ought to be normalised for LV mass, since there is a theoretical relation of coronary artery size to LV mass according to the law of minimum viscous energy loss for the transport of blood in the coronary circulation. METHODS: In 200 individuals (100 women) without cardiac disease and with normal Doppler echocardiography, left main (LCA) and right coronary artery (RCA) size were determined using transoesophageal echocardiography. LV mass was assessed by transgastric M-mode echocardiography. RESULTS: Age (44 +/- 15 years in women; 41 +/- 16 years in men), the presence of non-cardiac diseases, cardiovascular risk factors and medication were similar in women and men. LV mass in women was lower than in men (148 +/- 36 g, 189 +/- 45 g; p < 0.0001). LCA and RCA cross-sectional areas in women were smaller than those in men (LCA: 10 +/- 3 and 16 +/- 5 mm2, p < 0.0001; RCA: 4 +/- 2 and 7 +/- 3 mm2, p < 0.0001, respectively). LCA and RCA cross-sectional areas of women were smaller even after normalisation for LV mass (LCA: 7 +/- 3 and 9 +/- 3 mm2/100 g LV mass, p < 0.0001; RCA: 3 +/- 1 and 4 +/- 1 mm2/100 g LV mass, p = 0.002, respectively). LCA caliber of women ranged below the theoretically expected size according to the law of minimum viscous energy loss for the transport of blood in the coronary circulation, whereas those of men tended to be above it. CONCLUSIONS: In a population without cardiac disease, women have smaller coronary artery size even after normalisation for left ventricular mass.