After 20 years of research, a study recently published in Nature Genetics has revealed the genetic causes of a rare and curious syndrome that is similar to hypertension and accompanied by patients with short fingers (brachydactyly type E). There are only 6 unrelated families in the world who have this syndrome; they are from the United States, France, Turkey, South America, and two from Canada. All these individuals share a mutation in a tiny region of phosphodiesterase 3A (PDE3A), which modifies the resistance of blood vessels and the mechanism through which blood pressure is regulated. The researchers believe that the rare syndrome could provide insight into how and why people develop hypertension and suffer heart failure.
“Insights from this study could also lead to a new therapeutic strategy for heart failure – even in the overwhelming majority of patients with hypertension who don’t have these mutations,” said Matthew Movsesian, a cardiologist expert in PDE3 from the Department of Internal Medicine at the University of Utah School of Medicine who collaborated with researchers from the Experimental and Clinical Research Center (ECRC) of the Charité Medical Faculty in Berlin.
Hypertension is the most frequent cause of death in the world. Genetics play a major role in hypertension, and to date, only genes involved in salt intake by the kidney have actually been linked to the condition, despite the fact that most people with hypertension do not present sensitivity to salt in their diet. This suggests that other unknown genes might influence hypertension.
The German team was focused on one extended Turkish family with this syndrome, observing that affected individuals died of stroke before the age of 50 if their hypertension went untreated. In addition, each of the 6 families had a different mutation clustering within a small, 5 amino acid stretch of the PDE3A enzyme, which seems to increase this enzyme’s activity.
“This finding is too crazy to be made up,” noted Friedrich Luft, corresponding author on the study. “The mutations are astounding and that is what makes genetics fun.”
As part of the study, researchers isolated mesenchymal stem cells from those individuals suffering with this condition and prompted them to become vascular smooth muscle cells (VSMCs) (cells that line blood vessels). Apparently, the mutated VSMCs grew much more quickly than normal ones. “If VSMCs are more dense, they would thicken the vessel walls and impair relaxation. This could mean that PDE3A influences blood pressure by changing the resistance of blood vessels,” Luft explained.
The hypothesis still has to be verified, but higher activity of PDE3 might be the cause of high blood pressure. Researchers now believe that improved PDE3 inhibitors can be designed, positively impacting heart conditions. “If we can understand how these more active forms of PDE3A protect the heart against the development of hypertrophy, we may gain an understanding how the reverse of that – PDE3 inhibition — increases sudden cardiac death,” noted Movsesian.