The body of De Villota, who was 33, was discovered at the Hotel Sevilla Congresos in Seville early on Friday morning.
Dr Joaquin Lucena Romero, head of forensic services at the Institute for Legal Medicine, later confirmed De Villota's death "was due to natural causes".
But the HSE will now be ramping up its investigation that began immediately after De Villota's accident at Duxford Aerodrome on July 3 last year.
On that occasion, with De Villota conducting straightline aerodynamic testing for Marussia, the Spaniard was involved in a freak accident when she ran into a stationary service vehicle.
De Villota lost her right eye, and almost her life, but following a month's recuperation in hospital she eventually made a remarkable recovery, showing strength of character and a pioneering spirit.
Although no fault was found with the car, the HSE has been looking into the circumstances surrounding the incident.
In light of her death, a HSE spokeswoman said: "We don't know if there is a link between her injuries and her subsequent death, but we would expect to be kept informed of any new evidence."
News of De Villota's death filtered through just as the second practice session for the Japanese Grand Prix was drawing to a close on Friday, and was greeted with deep shock and sadness.
Williams development driver Susie Wolff told Press Association Sport: "What she came through was a testament to her strength of character and her positive outlook on life.
"She was just an incredible lady, no matter what she did on the race track. She was just an incredible character."
Jenson Button said: "This is a real shock to the whole Formula One family and the world of motorsport.
"She had been through so much - much more than most people will ever have to go through in their lives - and it's been so tough for her."
Fernando Alonso spoke on behalf of all in Spain as he said of De Villota that "a great fighter with a big smile has left us".
The daughter of two-time grand prix starter Emilio, De Villota competed in a variety of open-wheel and hard-top categories over the years.
After a test with Lotus Renault in August 2011, De Villota was given her big break in March last year when she was appointed test driver with Marussia.
An ambassadorial role followed in June with the FIA's newly-founded Women & Motorsport Commission, and after her accident she also served on the FIA's Action for Road Safety campaign and FIA Drivers' Commission.