Brain natriuretic peptide

A Heart-Failure Prevention Strategy Put to the Test.

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An intervention based on biomarker screening yields improved rates of left ventricular dysfunction but uncertain clinical benefit.
The prevalence of heart failure (HF) is rising, despite progress in understanding and treating risk factors. In a nonblinded trial, 1374 adults (average age, 65; 45% men) with ≥1 risk factor for HF (≥3, 27%) underwent annual B-type natriuretic peptide (BNP) screening and were randomized to either BNP-guided intervention or usual care, in which BNP results were unavailable to providers. Intervention-group participants with elevated BNP levels (≥50 pg/mL) were referred for echocardiography and collaborative specialist–primary care. The primary endpoint was the composite of new-onset HF and left ventricular (LV) systolic dysfunction, with or without symptoms; because of slower-than-anticipated enrollment, LV diastolic dysfunction was added to the composite endpoint after trial inception.

During mean follow-up of 4.2 years, the revised primary endpoint occurred significantly less frequently in the intervention group than in the usual-care group (5.3% vs. 8.7%; odds ratio, 0.55). The rate of asymptomatic LV dysfunction was also lower in the intervention group (4.3% vs. 6.6%; OR, 0.57; P=0.01). The risk for symptomatic HF did not differ significantly between the two groups (1.0% vs. 2.1%; OR, 0.48; P=0.12), but the risk for emergency cardiovascular hospitalization was significantly lower in the intervention group (22.3 vs. 40.4 per 1000 patient-years). Of note, renin-angiotensin-aldosterone–inhibitor use was more common in the intervention group than in the usual-care group (56.5% vs. 49.6%).

COMMENT

This study is important as a relatively rigorous attempt to assess a preventive strategy for heart failure, but the results should not change practice. The lack of blinding could explain some of the outcome differences; the importance of asymptomatic left ventricular dysfunction — especially echocardiographic diastolic abnormalities — is of questionable importance to patients; and the feasibility of implementing the intervention in large populations remains unclear. Nonetheless, these findings should initiate a robust discussion about HF prevention, including the value of biomarkers for this purpose.

 

Source: NEJM

 

Making sense of chromogranin A in heart disease.

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Chromogranin A is an acidic protein present in secretory granules of neuroendocrine cells. In plasma, chromogranin A is an important marker of neuroendocrine tumours. Chromogranin A measurement has gained interest in cardiovascular disease, because increased plasma concentrations are associated with risk of clinical deterioration and death in patients with acute coronary syndromes or chronic heart failure. Cardiac chromogranin A is stored in atrial granules with cardiac natriuretic peptides—the principal cardiac hormones associated with systemic homoeostasis of water and blood pressure. Expression of cardiac chromogranin A is decreased in patients treated with mechanical assist device therapy, which parallels findings on B-type natriuretic peptide mRNA expression and concomitant plasma concentrations.1

Support for a cardiovascular role for chromogranin A comes from mice deficient in chromogranin A gene expression, because they display a hypertensive phenotype that can be fully reversed by infusion with the chromogranin A fragment catestatin.2One proposed explanation for this is that mice deficient in chromogranin A have increased catecholamine release, which is a known mechanism in essential hypertension. The first observation of chromogranin A in myocardial infarction was reported by Omland and colleagues in 2003.3 Plasma concentrations of chromogranin A were measured in 119 patients 3 days after onset of symptoms. Increased plasma chromogranin A concentrations were associated with an increased risk of death, but the association disappeared when the results were adjusted for patient age. In a later study from the same researchers,4plasma chromogranin A concentrations were found to be predictive of patient outcomes following myocardial infarction after multivariable analyses that included patient age, diabetes, and sex. The largest study so far on chromogranin A in acute coronary syndromes included 1268 patients with a follow-up of 7·5 years.5 Basal chromogranin A concentrations in plasma were strongly associated with long-term mortality, admissions to hospital for heart failure, and recurrent myocardial infarction, with hazard ratios between 1·27 (95% CI 1·10—1·47) and 1·57 (95% CI 1·44—1·70). The association was maintained even after the results were adjusted for conventional risk markers.

Chronic heart failure is characterised by pronounced activation of the neuroendocrine system and adrenal noradrenaline release; chromogranin A could be a useful clinical marker in this syndrome.6 So far, the largest study of plasma chromogranin A measurement in chronic heart failure is the GISSI-Heart Failure trial.7 The study included 1233 patients with stable heart failure and followed them up for 4 years. In univariable analysis, increased chromogranin A plasma concentrations were associated with all-cause mortality, with hazard ratios between 1·58 (95% CI 1·17—2·11) and 2·35 (95% CI 1·78—3·10). However, after adjustment for known risk factors of mortality the association was lost. Thus, this clinically well characterised study concluded that chromogranin A measurement does not seem to be useful in the assessment of mortality risk in stable chronic heart failure beyond what physical examination, routine biochemical analyses, and cardiac natriuretic peptide measurement already offer. Since this study, two small investigations have been reported on chromogranin A as a biomarker in heart failure.8, 9 Both suggest that chromogranin A measurement adds independent prognostic information beyond B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide measurement.

Measurement of plasma chromogranin A is a complex matter. Chromogranin A is a protein that contains many dibasic aminoacid motifs prone to endoproteolytical cleavage. The cellular processing of chromogranin A encompasses a plethora of fragments from the primary precursor, some of which are proposed to have independent hormonal activity (figure). However, no specific receptor-mediated mechanisms have been identified for the fragments. The primary structure of the peptide fragments also challenges the idea that they act as soluble hormones in plasma. One way around the troublesome processing of chromogranin A could be to use a processing-independent assay for measurement. By production of a uniform peptide fragment for standard measurement by epitope-specific radioimmunoassay (or other types of immunoassays), the assay can be correctly calibrated and can measure the total sum of chromogranin A translational products irrespective of its variable and poorly characterised cellular processing.10 A processing-independent assay has the general advantage of storage stability of plasma samples, since they need treatment with trypsin or another suitable endoprotease to release the measured ligand. For now, we conclude that the present studies should be interpreted with caution, because plasma chromogranin A is not a uniform analyte, and the assays used so far measure different—and often unknown—epitopes within the primary protein structure.

References

1 Wohlschlaeger J, von Winterfeld M, Milting H, et al. Decreased myocardial chromogranin A expression and colocalization with brain natriuretic peptide during reverse cardiac remodeling after ventricular unloading. J Heart Lung Transplant 2008;27: 442-449. CrossRef | PubMed

2 Mahapatra NR, O’Connor DT, Vaingankar SM, et al. Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J Clin Invest 2005; 115: 1942-1952. CrossRef | PubMed

3 Omland T, Dickstein K, Syversen U. Association between plasma chromogranin A concentration and long-term mortality after myocardial infarction. Am J Med 2003; 114: 25-30. CrossRef | PubMed

4 Estensen ME, Hognestad A, Syversen U, et al. Prognostic value of plasma chromogranin A levels in patients with complicated myocardial infarction. Am Heart J 2006; 152: 927e1-927e6. PubMed

5 Jansson AM, Røsjø H, Omland T, et al. Prognostic value of circulating chromogranin A levels in acute coronary syndromes.Eur Heart J 2009; 30: 25-32. CrossRef | PubMed

6 Braunwald E. Biomarkers in heart failure. N Engl J Med 2008; 358: 2148-2159. CrossRef | PubMed

7 Røsjø H, Masson S, Latini Rfor the GISSI-HF Investigators. Prognostic value of chromogranin A in chronic heart failure: data from the GISSI-Heart Failure trial. Eur J Heart Fail 2010; 12: 549-556. CrossRef | PubMed

8 Dieplinger B, Gegenhuber A, Kaar G, Poelz W, Haltmayer M, Mueller T. Prognostic value of established and novel biomarkers in patients with shortness of breath attending an emergency department. Clin Biochem 2010; 43: 714-719.CrossRef | PubMed

9 Zhu D, Wang F, Yu H, Mi L, Gao W. Catestatin is useful in detecting patients with stage B heart failure. Biomarkers 2011;16: 691-697. CrossRef | PubMed

10 Goetze JP, Hunter I, Lippert SK, Bardram L, Rehfeld JF. Processing-independent analysis of peptide hormones and prohormones in plasma. Front Biosci 2012; 17: 1804-1815. CrossRef | PubMed

Source: Lancet

Itching study ‘finds chemical that makes us scratch’.

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itch

Researchers have found a chemical that is necessary in order to feel the urge to scratch an itch.

They were able to turn off the urge in mice while leaving the animals’ other senses, such as touch and temperature, intact.

It is hoped that a deeper understanding of itching could eventually lead to therapies for patients with debilitating, chronic itch.

The study was published in the journal Science.

The team at the National Institute of Dental and Craniofacial Research, part of the US National Institutes of Health, bred mice that were unable to produce a chemical called Nppb.

It is a small signalling chemical that allows brain cells to communicate with each other.

Mice without the chemical looked and acted like other mice, said Dr Santosh Mishra, except “when we exposed the mice to several itch-inducing substances, it was amazing to watch, nothing happened, the mice wouldn’t scratch”.

Injections of Nppb into a mouse’s spinal cord made them scratch.

‘Landline to the brain’

The group of researchers said the chemical was involved in taking itching sensations in the skin and passing them up the spinal cord and into the brain.

Dr Mark Hood said: “Our work shows that itch, once thought to be a low-level form of pain, is a distinct sensation that is uniquely hardwired into the nervous system with the biochemical equivalent of its own dedicated landline to the brain.”

He told the BBC: “I’d be extremely surprised if it didn’t work the same way in people.”

Insect bites, psoriasis and eczema can all result in a strong itch. Some people develop a profound urge to itch with no obvious cause.

Dr Hood said this could be “devastating” and lead to a “poor quality of life when people just keep scratching”. The only treatment is to sever the nerves in the affected region, but this also damages other sensations.

Researchers are keen to find a way to selectively turn off the need to itch in people with these conditions.

However, Nppb looks unlikely to be the immediate answer as it also has an important role in the heart so any drug could have serious side effects.

Prof Malcolm Rustin, from the British Association of Dermatologists, said it was “desperately important” that drugs to combat itch were developed.

“In patients with eczema, the first symptom is itch. There is debate if you have itch, damage the skin barrier and let allergens in, it becomes a vicious circle.”

He said this was an “interesting study” and that developing blockers for the chemical pathway in which Nppb was involved might treat itch.

Source: BBC line-�Nh:8(� �� ckground:white’>Continue reading the main story

 

“Start Quote

What we know about habit formation is that you want to make the behaviour easy to perform, so that people repeat it often and it becomes part of their daily routine”

Prof Wendy WoodUniversity of Southern California

“Habits persist even when we’re tired and don’t have the energy to exert self-control.”

She added: “Everybody gets stressed. The whole focus on controlling your behaviour may not actually be the best way to get people to meet goals.

“If you are somebody who doesn’t have a lot of willpower, our study showed that habits are much more important.”

Prof Wood said the findings had implications for those seeking to affect people’s behaviour.

“The central question for behaviour-change efforts should be, how can you form healthy, productive habits?

“What we know about habit formation is that you want to make the behaviour easy to perform, so that people repeat it often and it becomes part of their daily routine.”

Source: BBC