No heart damage despite hereditary hypertension
German scientists have found evidence that hereditary hypertension does not necessarily lead to heart damage
For decades, scientists in Berlin have been researching a strange hereditary condition that results in half the members of certain families having unusually short fingers and extremely high blood pressure.
If left untreated, the affected patients usually die of a stroke at the age of 50 years.
Researchers at the Max Delbrück Center (MDC) in Berlin identified the cause of the disease in 2015 and were able to prove their hypothesis five years later using animal models: a mutation in the phosphodiesterase 3A gene (PDE3A) causes its encoded enzyme to become overactive, affecting bone growth and causing blood vessel hyperplasia – resulting in elevated blood pressure.
Dr Enno Klußmann is head of the Anchored Signalling Lab at the Max Delbrück Center and a scientist at the German Centre for Cardiovascular Research (DZHK).
He said: “High blood pressure almost always leads to the heart becoming weaker,” as it has to pump against a higher pressure, so the organ tries to strengthen its left ventricle.
“But ultimately, this results in the thickening of the heart muscle – known as cardiac hypertrophy – which can lead to heart failure greatly decreasing its pumping capacity.”
However, in the hypertension patients with the shortened fingers and mutated PDE3A gene, this doesn’t happen.
Klußmann advised: “For reasons that are now partly – but not yet fully – understood, their hearts appear immune to the damage that usually results from high blood pressure.”
See also: Overall disease burden of genetic risk factors estimated for first time
hypertension and brachydactyly
The scientists performed their tests on human patients with hypertension and brachydactyly (HTNB) syndrome – i.e., high blood pressure and abnormally short digits – as well as on rat models and heart muscle cells.
The cells were grown from specially engineered stem cells known as induced pluripotent stem cells. Before testing began, researchers altered the PDE3A gene in the cells and the animals to mimic HTNB mutations.
Dr Sylvia Bähring is from the Experimental and Clinical Research Center (ECRC) – a joint institution of Charité and the Max Delbrück Center.
She said: “We came across a previously unknown PDE3A gene mutation in the patients we examined.
“Previous studies had always shown the mutation in the enzyme to be located outside the catalytic domain – but we have now found a mutation right in the centre of this domain.”
Surprisingly, both mutations have the same effect in that they make the enzyme more active than usual.
This hyperactivity ramps up the degradation of one of the cell’s important signalling molecules known as cAMP (cyclic adenosine monophosphate), which is involved in the contraction of the heart muscle cells.
Bähring suggested: “It is possible that this gene modification – regardless of its location – causes two or more PDE3A molecules to cluster together and thus work more effectively.”
the proteins stay the same
The researchers used a rat model – created with CRISPR-Cas9 technology – to try to better understand the effects of the mutations.
“We treated the animals with the agent isoproterenol, a so-called beta-receptor agonist,” said Klußmann.
Such medications are sometimes used in patients with end-stage heart failure. Isoproterenol is known to induce cardiac hypertrophy.
He added: “Yet surprisingly, this occurred in the gene-modified rats in a manner similar to what we observed in the wild-type animals.
“Contrary to what we expected, the existing hypertension did not aggravate the situation.
“Their hearts were quite obviously protected from this effect of the isoproterenol.”
activating instead of inhibiting
Klußmann explained: “PDE3 inhibitors are currently in use for acute heart failure treatment to increase cAMP levels.”
Regular therapy with these drugs would rapidly sap the heart muscle’s strength.
“Our findings now suggest that not the inhibition of PDE3, but – on the contrary – the selective activation of PDE3A may be a new and vastly improved approach for preventing and treating hypertension-induced cardiac damage like hypertrophic cardiomyopathy and heart failure.”
But before that can happen, he says, more light needs to be shed on the protective effects of the mutation.
“We have observed that PDE3A not only becomes more active, but also that its concentration in heart muscle cells decreases,” the researcher reports, adding that it is possible that the former can be explained by oligomerisation – a mechanism that involves at least two enzyme molecules working together.
He concluded: “In this case, we could probably develop strategies that artificially initiate local oligomerisation – thus mimicking the protective effect for the heart.”
The study is published in Circulation.
Image: Short fingers in one family. © Sylvia Bähring.