A Bizarre Case of Hypertension Immunity

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human heart attack

High blood pressure almost always weakens the heart.

Surprisingly, some patients with the mutated PDE3A gene were immune to hypertension-related damage.

Scientists in Berlin have been studying for decades a strange inherited disease that causes half of people in certain families to have incredibly short fingers and abnormally high blood pressure. If left untreated, affected individuals often die of a stroke by the age of 50. Researchers at the Max Delbrück Center (MDC) in Berlin discovered the origin of the disease in 2015 and were able to verify it five years later using animal models: a mutation in the phosphodiesterase 3A (PDE3A) gene makes its encoded enzyme overactive, impairing bone growth and causing hyperplasia of blood vessels, leading to high blood pressure.

Immune to Hypertension damage

“High blood pressure almost always leads to a weakening of the heart,” says Dr. Enno Klußmann, head of the Signaling Laboratory anchored at the Max Delbrück Center and scientist at the German Center for Cardiovascular Research (DZHK). Since it has to pump against higher pressure, Klußmann explains, the organ tries to strengthen its left ventricle. “But ultimately this leads to the thickening of the heart muscle – known as cardiac hypertrophy – which can lead to heart failure significantly decreasing its pumping ability.”

Short finger hypertension family

Short fingers in a family. Credit: Sylvia Bahring

However, this does not occur in hypertensive patients with short fingers and mutant PDE3A genes. “For reasons that are now partly – but not yet fully – understood, their hearts seem immune to the damage that typically results from high blood pressure,” Klußmann says.

The research was conducted by scientists from the Max Delbrück Center, Charité – Universitätsmedizin Berlin and DZHK and was published in the journal Traffic. In addition to Klußmann, the final authors included Max Delbrück Center professors Norbert Hübner and Michael Bader, as well as Dr. Sylvia Bähring of the Center for Experimental and Clinical Research (ECRC), a joint institution of Charité and the Max Delbrück Center.

The team, which included 43 other researchers from Berlin, Bochum, Heidelberg, Kassel, Limburg, Lübeck, Canada and New Zealand, recently published their findings on the protective effects of genetic mutation – and why these findings could transform the way whose core failure is dealt with in the future. The study has four first authors, three of whom are researchers from the Max Delbrück Center and one from the ECRC.

Normal Heart vs Mutant Heart

Cross-section through a normal heart (left), through one of the mutant hearts (center), and through a severely hypertrophic heart (right). In the latter, the left ventricle is enlarged. Credit: Anastasiia Sholokh, MDC

Two mutations with the same effect

The scientists performed their tests on human patients with hypertension and brachydactyly syndrome (HTNB), i.e. high blood pressure and abnormally short digits, as well as on rat models and cells heart muscle. The cells were grown from specially engineered stem cells called induced pluripotent stem cells. Before testing began, researchers modified the PDE3A gene in cells and animals to mimic HTNB mutations.

“We discovered a previously unknown PDE3A gene mutation in the patients we examined,” Bähring reports. “Previous studies had always shown that the mutation in the enzyme was located outside the catalytic domain – but we have now found a mutation right in the center of this domain.” Surprisingly, both mutations have the same effect in that they make the enzyme more active than usual. This hyperactivity accelerates the breakdown of one of the cell’s important signaling molecules, known as cAMP (cyclic adenosine monophosphate), which is involved in the contraction of heart muscle cells. “It is possible that this genetic modification – regardless of its location – causes the clustering of two or more PDE3A molecules and therefore their effectiveness”, suspects Bähring.

Protein stays the same

The researchers used a rat model – created with CRISPR-Cas9 technology by Michael Bader’s lab at the Max Delbrück Center – to try to better understand the effects of mutations. “We treated the animals with the agent isoproterenol, a so-called beta-receptor agonist,” Klußmann explains. These drugs are sometimes used in patients with end-stage heart failure. Isoproterenol is known to induce cardiac hypertrophy. “Yet surprisingly, this happened in the genetically modified rats in a way similar to what we observed in wild-type animals. Contrary to what we expected, the existing hypertension did not make the situation worse,” reports Klußmann. “Their hearts were obviously protected from this effect of isoproterenol.”

In other experiments, the team investigated whether, and if so, which proteins in a specific heart muscle cell signaling cascade changed as a result of the mutation. Through this chain of chemical reactions, the heart reacts to adrenaline and beats faster in response to situations such as excitement. Adrenaline activates the cells’ beta receptors, causing them to produce more cAMP. PDE3A and other PDEs stop the process by chemically modifying cAMP. “However, we found little difference between the mutant and wild-type rats at both the protein and the[{” attribute=””>RNA levels,” Klußmann says.

More calcium in the cytosol

The conversion of cAMP by PDE3A does not occur just anywhere in the heart muscle cell, but near a tubular membrane system that stores calcium ions. A release of these ions into the cytosol of the cell triggers muscle contraction, thus making the heartbeat. After the contraction, the calcium is pumped back into storage by a protein complex. This process is also regulated locally by PDE.

Klußmann and his team hypothesized that because these enzymes are hyperactive in the local region around the calcium pump, there should be less cAMP – which would inhibit the pump’s activity. “In the gene-modified heart muscle cells, we actually showed that the calcium ions remain in the cytosol longer than usual,” says Dr. Maria Ercu, a member of Klußmann’s lab and one of the study’s four first authors. “This could increase the contractile force of the cells.”

Activating instead of inhibiting

“PDE3 inhibitors are currently in use for acute heart failure treatment to increase cAMP levels,” Klußmann explains. 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,” Klußmann says.

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 oligomerization – a mechanism that involves at least two enzyme molecules working together. “In this case,” says Klußmann, “we could probably develop strategies that artificially initiate local oligomerization – thus mimicking the protective effect for the heart.”

Reference: “Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage” by Maria Ercu, Michael B. Mücke, Tamara Pallien, Lajos Markó, Anastasiia Sholokh, Carolin Schächterle, Atakan Aydin, Alexa Kidd, Stephan Walter, Yasmin Esmati, Brandon J. McMurray, Daniella F. Lato, Daniele Yumi Sunaga-Franze, Philip H. Dierks, Barbara Isabel Montesinos Flores, Ryan Walker-Gray, Maolian Gong, Claudia Merticariu, Kerstin Zühlke, Michael Russwurm, Tiannan Liu, Theda U.P. Batolomaeus, Sabine Pautz, Stefanie Schelenz, Martin Taube, Hanna Napieczynska, Arnd Heuser, Jenny Eichhorst, Martin Lehmann, Duncan C. Miller, Sebastian Diecke, Fatimunnisa Qadri, Elena Popova, Reika Langanki, Matthew A. Movsesian, Friedrich W. Herberg, Sofia K. Forslund, Dominik N. Müller, Tatiana Borodina, Philipp G. Maass, Sylvia Bähring, Norbert Hübner, Michael Bader and Enno Klussmann, 19 October 2022, Circulation.
DOI: 10.1161/CIRCULATIONAHA.122.060210

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