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Dom Manuel de Mello Award Research Grant to Ana Catarina Fonseca
In about 30 to 40% of ischemic Cerebral Vascular Accidents (CVA) it is not possible to determine an aetiology. This happens often, even after exhaustive clinical research. It is possible that a fraction of these CVA, called cryptogenic, takes place after an episode of paroxystic atrial fibrillation (AF), which cannot be documented. The CVA related to AF are usually serious, with a mortality estimated in the first year of 50%, have a high rate of recurrence and result in morbility and significant costs. Correct identification of a cardioembolic aetiology in these patients is important given that is has been shown that oral anticoagulation, when compared to anti-aggregational therapy, reduces the risk of recurring CVA in patients with non-valvular AF, and may be associated to the lesser seriousness of the CVA in the case of recurring.
Today’s complementary means for diagnosis have a low capacity to detect paroxystic AF. Despite the Holter being superior to the electrocardiogram, in a systematic review the capacity of the Holter (24-72 hours) to detect paroxystic AF was 4.6%. Longer monitoring (4-7 days) detects AF in over 8% of patients. Prolonged recordings of events lasting 7 days, at 0, 3 and 6 months after a CVA detected AF in 14% of patients.
Thus it is necessary to equate alternative forms of detecting a possible cardioembolic aetiology in cryptogenic CVA. The importance of a correct identification of a CVA as being cardioembolic has led to the possibility of using biomarkers for its diagnosis.
Previous studies have shown an increase in seric concentrations of Brain Natriuretic Peptide (BNP) during the acute phase of ischemic CVA when compared to those of control and with the cut-off points established for heart failure. BNP is a neurohormone that has been studied and divulged as a natriuretic cardiac hormone. However, recent studies suggest that it may have an important role in the physiopathology of acute CVA. Chemically it is a peptide initially produced as a pro-hormone denominated pro-BNP. Pro-BNP is then subdivided into biologically active BNP and N-terminal-proBNP (NT-proBNP), which has no biological activity. Most tests measure NT-proBNP. Until now the production of BNP has been attributed to two places: the brain and, mainly, the heart. Here the principal stimulation for BNP synthesis and secretion is the stretching of the myocites. In a normal physiological state the auricula is the main place for cardiac production. Catecholamines, angiotensins II and endothelin may stimulate the secretion of BNP through paracrine or endocrine mechanisms. It is presumed that the NT-proBNP is eliminated from circulation through kidney excretion. The biological effects of BNP include natriuresis, diuresis, vasodilation, inhibition of the do renin-angiotensin-aldosterone axis and the sympathetic nervous system. This peptide is currently used as a marker of left ventricular and prognostic dysfunction in patients with congestive heart failure (CHF) and with acute coronary syndromes. One can observe high plasmatic levels of NT-proBNP in patients with kidney failure, essential hypertension and disrhythmias such as AF. Advanced age and low levels of haemoglobins are associated to increased plasmatic levels of BNP.
Despite BNP having been firstly identified in brain tissue, current information about this natriuretic peptide in cerebral-vascular disease is limited. Some works carried out have shown a sharp rise in NT-pro-BNP during the acute phase of ischemic CVA.
Four possibilities have been put forward for increasing of NT-proBNP during acute ischemic CVA:
- These patients often suffer from heart failure, and BNP increase might reflect ventricular dysfunction.
- A risk factor for CVA and a cause for BNP increase might be related to AF.
- As the brain is a place for the production of BNP, it might appear after lesion to the cerebral parenchyma.
- Increase in BNP, having sympathetic-inhibitive effects, may emerge as a response to an increase in sympathetic activity.
In a previous work which we carried out within the scope of an original dissertation in the Masters Course in Neurosciences at the Faculty of Medicine of the University of Lisbon (FMUL), we attempted to determine whether increase of NT-proBNP in the acute phase of ischemic CVA might have a cardiac origin. The results suggested that the increase in the seric concentration of NT-proBNP, which occurs in the context of CVA, has a cardiac origin. We noted that the patients with ischemic cardioembolic CVA had higher average concentrations of NT-proBNP, in a statistically significant form, in relation o that of the patients with non-cardioembolic ischemic CVA. No association has been found between the seric concentration of NT-proBNP and the extent or location of the CVA or the values of blood pressure. NT-proBNP had a very good capacity to diagnose cardioembolic CVA associated to atrial fibrillation in the first 72 hours after ischemic CVA, with ROC curve analysis showing that there were two cut-off points with great sensitivity and specificity. For the identification of cardioembolic aetiology CVA a value of area below the AUC curve 0.77±0.06, we established the cut-off point with the greatest specificity and sensitivity at 265.50 pg/mL (71.4% and 74% respectively). For the identification of cardioembolic aetiology CVA with AF we obtained a AUC of 0.92 ± 0.03. The NT-proBNP value established as a cut-off point was 265.50 pg/mL (sensitivity 94.4%, specificity 72.9%) and 912.0 pg/mL (sensitivity 55.5%, specificity 97.9%).
Now it is necessary to carry out a further study in a different sample, with a greater number of patients, in order to validate the cut-off points established. And it is also necessary to identify possible sources of variation in NT-proBNP, and to establish the profile for temporal evolution of NT-proBNP after an ischemic CVA. The work is orientated by Professor José Ferro and Professor Dulce Brito, with the collaboration of Dr. Sampaio Matias and the doctors from the Cerebral Vascular Accidents Unit of the Santa Maria Hospital Neurology Service.
This is the work that will be carried out, having originated in a Masters thesis in the Masters in Neurosciences at the FMUL and which received the Manuel de Mello Grant awarded by the Amélia da Silva de Mello Foundation.
Ana Catarina Fonseca
Neurology Service
catarinagfonseca@gmail.com
Today’s complementary means for diagnosis have a low capacity to detect paroxystic AF. Despite the Holter being superior to the electrocardiogram, in a systematic review the capacity of the Holter (24-72 hours) to detect paroxystic AF was 4.6%. Longer monitoring (4-7 days) detects AF in over 8% of patients. Prolonged recordings of events lasting 7 days, at 0, 3 and 6 months after a CVA detected AF in 14% of patients.
Thus it is necessary to equate alternative forms of detecting a possible cardioembolic aetiology in cryptogenic CVA. The importance of a correct identification of a CVA as being cardioembolic has led to the possibility of using biomarkers for its diagnosis.
Previous studies have shown an increase in seric concentrations of Brain Natriuretic Peptide (BNP) during the acute phase of ischemic CVA when compared to those of control and with the cut-off points established for heart failure. BNP is a neurohormone that has been studied and divulged as a natriuretic cardiac hormone. However, recent studies suggest that it may have an important role in the physiopathology of acute CVA. Chemically it is a peptide initially produced as a pro-hormone denominated pro-BNP. Pro-BNP is then subdivided into biologically active BNP and N-terminal-proBNP (NT-proBNP), which has no biological activity. Most tests measure NT-proBNP. Until now the production of BNP has been attributed to two places: the brain and, mainly, the heart. Here the principal stimulation for BNP synthesis and secretion is the stretching of the myocites. In a normal physiological state the auricula is the main place for cardiac production. Catecholamines, angiotensins II and endothelin may stimulate the secretion of BNP through paracrine or endocrine mechanisms. It is presumed that the NT-proBNP is eliminated from circulation through kidney excretion. The biological effects of BNP include natriuresis, diuresis, vasodilation, inhibition of the do renin-angiotensin-aldosterone axis and the sympathetic nervous system. This peptide is currently used as a marker of left ventricular and prognostic dysfunction in patients with congestive heart failure (CHF) and with acute coronary syndromes. One can observe high plasmatic levels of NT-proBNP in patients with kidney failure, essential hypertension and disrhythmias such as AF. Advanced age and low levels of haemoglobins are associated to increased plasmatic levels of BNP.
Despite BNP having been firstly identified in brain tissue, current information about this natriuretic peptide in cerebral-vascular disease is limited. Some works carried out have shown a sharp rise in NT-pro-BNP during the acute phase of ischemic CVA.
Four possibilities have been put forward for increasing of NT-proBNP during acute ischemic CVA:
- These patients often suffer from heart failure, and BNP increase might reflect ventricular dysfunction.
- A risk factor for CVA and a cause for BNP increase might be related to AF.
- As the brain is a place for the production of BNP, it might appear after lesion to the cerebral parenchyma.
- Increase in BNP, having sympathetic-inhibitive effects, may emerge as a response to an increase in sympathetic activity.
In a previous work which we carried out within the scope of an original dissertation in the Masters Course in Neurosciences at the Faculty of Medicine of the University of Lisbon (FMUL), we attempted to determine whether increase of NT-proBNP in the acute phase of ischemic CVA might have a cardiac origin. The results suggested that the increase in the seric concentration of NT-proBNP, which occurs in the context of CVA, has a cardiac origin. We noted that the patients with ischemic cardioembolic CVA had higher average concentrations of NT-proBNP, in a statistically significant form, in relation o that of the patients with non-cardioembolic ischemic CVA. No association has been found between the seric concentration of NT-proBNP and the extent or location of the CVA or the values of blood pressure. NT-proBNP had a very good capacity to diagnose cardioembolic CVA associated to atrial fibrillation in the first 72 hours after ischemic CVA, with ROC curve analysis showing that there were two cut-off points with great sensitivity and specificity. For the identification of cardioembolic aetiology CVA a value of area below the AUC curve 0.77±0.06, we established the cut-off point with the greatest specificity and sensitivity at 265.50 pg/mL (71.4% and 74% respectively). For the identification of cardioembolic aetiology CVA with AF we obtained a AUC of 0.92 ± 0.03. The NT-proBNP value established as a cut-off point was 265.50 pg/mL (sensitivity 94.4%, specificity 72.9%) and 912.0 pg/mL (sensitivity 55.5%, specificity 97.9%).
Now it is necessary to carry out a further study in a different sample, with a greater number of patients, in order to validate the cut-off points established. And it is also necessary to identify possible sources of variation in NT-proBNP, and to establish the profile for temporal evolution of NT-proBNP after an ischemic CVA. The work is orientated by Professor José Ferro and Professor Dulce Brito, with the collaboration of Dr. Sampaio Matias and the doctors from the Cerebral Vascular Accidents Unit of the Santa Maria Hospital Neurology Service.
This is the work that will be carried out, having originated in a Masters thesis in the Masters in Neurosciences at the FMUL and which received the Manuel de Mello Grant awarded by the Amélia da Silva de Mello Foundation.
Ana Catarina Fonseca
Neurology Service
catarinagfonseca@gmail.com
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