Fondation Leducq :: improving health through international efforts in cardiovascular research

Sep 08, 2010

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What's new

What's new : Pilot study in peripartum cardiomyopathy

Peripartum cardiomyopathy (PPCM) is characterized by acute heart failure late in pregnancy or early in the postpartum period. The incidence of PPCM ranges from 1 in 1000 to 2000 pregnant women in the United States to 1 in 1000 in South Africa and 1 in 300 in Haiti. Current therapy has limited effectiveness, and as many as one third to two thirds of patients may fail to recover cardiac function.

Dr. Denise Hilfiker-Kleiner, of the Adaptive and maladaptive signaling in cardiac growth and regeneration network, had previously discovered an abnormal form of the hormone prolactin in women with PPCM. Moreover, she found that bromocriptine, a blocker of prolactin release, might prevent the recurrence of PPCM with subsequent pregnancies.

Most recently, Dr. Hilfiker-Kleiner and collaborators from Beligum, South Aftrica, the United Kingdom, and the United States conducted a proof-of-concept, open-label pilot study to see whether bromocriptine could be an effective treatment for PPCM.

The study was conducted at Chris Hani Baragwanath Hospital, a public hospital in Soweto, South Africa. Twenty women were randomized into two groups, those who received standard heart failure medications, and those who, in addition to standard medications, received bromocriptine during a total of 8 weeks. The outcomes were evaluated at 6 months.

Women in the bromocriptine group had greater improvements in heart failure symptoms and cardiac function. For instance, while at the start of the study the left ventricular ejection fraction, a measure of the pumping capacity of the heart, was similar between the two groups (27% in both the standard treatment and bromocriptine groups), a much more dramatic improvement was observed in the bromocriptine group at 6 months (58%, compared to 36% in the standard treatment group). Four patients in the standard treatment group died, compared to 1 in the bromocriptine group. Bromocriptine appeared to be well tolerated, without any associated complications. Infants of mothers in both groups showed normal growth and survival.

While the study was non-blinded and included only a small number of patients in each treatment arm, it provides initial proof of concept for a role of bromocriptine in PPCM treatment. Larger, blinded studies involving multiple centers are necessary to evaluate the safety and efficacy of bromocriptine.

This study was also funded by the Medical Research Council of South Africa and the University of the Witwatersrand.

Click on the title to access the article in the April 6, 2010 issue of Circulation: Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof-of-concept pilot study.

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What's new : A closer look at cardiac muscle cells

Heart failure is defined as the inability of the heart to supply adequate blood flow to meet the body’s needs. Heart muscle cells of patients with heart failure have abnormal regulation of calcium, and the Calcium Cycling and Novel Therapeutic Approaches for Heart Failure network studies the upstream and downstream molecular pathways related to such abnormalities.

One such pathway involves the hormone adrenaline. The body increases the release of adrenaline in an attempt to stimulate the failing heart. Over the short term this stimulation helps the heart compensate, but over the long term the stimulation becomes harmful and actually worsens heart failure.

There are two types of receptors for adrenaline located on the surface of heart muscle cells, β1AR and β2AR. Both types of receptors respond to adrenaline activation by generating the same molecular signal (cyclic AMP), but the two types of receptors have different effects on the cell.

To understand how the two receptors are able to cause such distinct responses in the heart, a group of researchers, including network members Martin J. Lohse and Sian E. Harding, used a new technique called scanning ion conductance microscopy (SICM). SICM allows the analysis of specific regions of the cell surface with unprecedented detail. Using SICM and chemical probes that emit fluorescent signals when the βARs are stimulated, the investigators demonstrated that β1ARs are widely distributed throughout the membrane of healthy heart muscle cells. In contrast, β2ARs are exclusively found at the T tubules. T-tubules are specific regions of the cell membrane that contain many ion channels. The channels allow the voltage of the muscle cell to change very quickly, as occurs when the cell receives a signal to contract. In cells from animals with heart failure, β2ARs were redistributed across the cell membranes, like the β1ARs.

This work, which was reported in the March 26, 2010 issue of Science, advances our understanding of the molecular changes that occur with heart failure. The findings may lead to improved design of beta-blockers, a class of drugs that is already a mainstay of heart failure and arrhythmia treatment.

This research was also funded by the Wellcome Trust, Action Medical Research, the UK Biotechnology and Biological Sciences Research Council, and the UK Medical Research Council.

Click on the title to access the article in Science: β2-Adrenergic receptor redistribution in heart failure changes cAMP compartmentation.