"Early heart disease ran in Rick Del Sontros family and every time he went for a run he was scared his heart would betray him. So he did all he could to improve his odds. He kept himself lean stayed away from red meat spurned cigarettes and exercised intensely even completing an Ironman Triathlon. I had bought the dream if you just do the right things and eat the right things you will be O.K. said Mr. Del Sontro whose cholesterol and blood pressure are reassuringly low. But after his sister just  years old found out she had advanced heart disease Mr. Del Sontro then  and the president of Zippy Shell a selfstorage company went to a cardiologist.  An Xray of his arteries revealed the truth. Like his grandfather his mother his four brothers and two sisters he had heart disease. One brother Michael has not received a diagnosis of the disease. Now he and his extended family have joined an extraordinary federal research project that is using genetic sequencing to find factors that increase the risk of heart disease beyond the usual suspects  high cholesterol high blood pressure smoking and diabetes. The aim is to see if genetics can explain why heart disease strikes apparently healthy people. The hope is that a family like Mr. Del Sontros could be a Rosetta stone for heart disease  that their arteries profound but mysterious propensity to clog could reveal forces that do the same in millions of others. We dont know yet how many pathways there are to heart disease said Dr. Leslie Biesecker who directs the study Mr. Del Sontro joined. Thats the power of genetics. To try and dissect that. Researchers have long known that a family history of early death from heart disease doubles a persons risk independently of any other factors. Family history is defined as having a father or a brother who were given a diagnosis of heart disease before age  or a mother or sister before age . Scientists are studying the genetic makeup of each member of the Del Sontro family searching for telltale mutations or aberrations in the long sequence of three billion chemicals that make up human DNA.  Until very recently such a project almost certainly would have been futile. Picking through DNA for tiny aberrations was so costly and timeconsuming that it was impractical to take on for an entire family.  Analyzing the deluge of data would have been overwhelming. But costs have plunged and data analysis has advanced. Rick Del Sontro keeps himself lean and watches his diet but despite his efforts he has heart disease like many in his family.CreditBrendan Hoffman for The New York Times  With the right family you may need only one family said Dr. Robert C. Green httppcpgm.partners.orgaboutusleadershipfaculty of Harvard Medical School who studies genetics and medicine and is not involved in the study. Beyond Risk Factors Control of cardiovascular disease is one of medicines great success stories. Over the past  years heart disease death rates have steadily dropped  percent from their peak in the s. But doctors still rely mostly on risk factors discovered decades ago  cholesterol levels blood pressure diabetes smoking obesity and a sedentary lifestyle.  Risk factors are part of the canon now in medicine said Dr. Gary H. Gibbons the director of the National Heart Lung and Blood Institute http We use them every day. Still people arrive at the hospital every day with heart attacks. And heart disease is still the leading killer of men and women. Each year nearly  people in the United States die of heart disease. Though the average age for a first heart attack has steadily risen  it is now  for men and  for women  many die much younger. And many had no obvious risk factors. What researchers ask are they missing The old method of inquiry into heart disease was to start with basic laboratory research test a hypothesis in animals develop a drug and then test it in humans. That approach led to some expensive failures. Researchers now want to use human genetics. We need to understand disease biology in humans said Dr. Elias Zerhouni a former director of the National Institutes of Health and now president for global research and development at Sanofi. The tools are here. But the greatest challenge is to figure out how to prevent heart disease in the first place. And that is where the Del Sontro family comes in. A Familys Grim Secret Mr. Del Sontro had been more or less in denial about his familys heart disease problem until one of his sisters Robin Ashwood found out she had it. One Saturday morning about six years ago she was running on a treadmill when her arms began to feel sore as if she had done a tough workout with weights. She ended her workout and the pain went away. But it came back later that day while she was shopping with her younger sister Tina Del Sontro. Ms. Del Sontro pressed her sister to go to an emergency room asking Do you really want to die on the floor of Sams Club The family history of heart disease is dire. Their grandfather had a severe heart attack when he was . Their mother started having severe chest pains at . And toward the end of their mothers life she was popping nitroglycerin pills like Tic Tacs Mr. Del Sontro said. She had openheart surgery three times and died on the operating table at . Robin Ashwood one of Mr. Del Sontros sisters found out she had extensive heart disease even though her electrocardiograms had come back normal. Six of her seven siblings also have heart disease despite not having any of the traditional risk factors.CreditBrendan Hoffman for The New York Times So Ms. Ashwood went to a nearby emergency room. Doctors took her blood pressure. It was elevated she says and she was terrified. They did an electrocardiogram. It was normal. They told her she was fine. Advertisement But she recalled that her mothers electrocardiogram had been fine too and she died of the disease. She called her cardiologist the next day. But he blew me off she said. He told me it was probably a stomach problem. Still fearful she coldcalled cardiologists offering to pay for a consultation if a doctor would just look at her medical record and family history. Dr. Leslie R. Fleischer in Pensacola Fla. where Ms. Ashwood was living at the time took her on. He threaded a catheter through a blood vessel from her groin to her heart and shot dye into the coronary arteries to make them visible on Xrays. He saw extensive heart disease. One coronary artery was almost completely blocked and the others were partly blocked. I have been doing this for  years Dr. Fleischer said. So I am not surprised. I am just sad. He inserted a stent  a small wire cage  into an artery that was  percent blocked. And he warned Ms. Ashwood that all her siblings should get tested. Tina Del Sontro went first. She was  but tests showed she had heart disease too. Her doctor told her a heart attack was in her future saying she recalls Its not if it is going to happen  its when. So Rick went to a general practitioner who told him he had nothing to worry about. Then his brother Peter  at the time saw a cardiologist and days later had emergency double bypass surgery. Shaken Rick decided he too should see a cardiologist. Dr. Edward Bodurian in Chevy Chase Md. first suggested a heart scan to look for calcification in his arteries  a sign of blockages. The scan showed potential problems so Dr. Bodurian performed the same catherization test that had detected Ms. Ashwoods disease. It revealed the grim news about his blocked arteries. Most people who have this test can leave the hospital quickly. Doctors insert a plug in the hole in the groin where the catheter is inserted to stop the bleeding. But Mr. Del Sontro had so little body fat that a plug would not stay in place. So he had to lie flat on his back for hours in Suburban Hospital which happened to be across the street from the National Institutes of Health. While Mr. Del Sontro was lying there someone came by  he never got the persons name  and told him there was a study starting at the National Institutes of Health that you might find relevant. It was the one Dr. Biesecker was directing to find new causes of heart disease. I keep waiting for the day when I have shortness of breath Mr. Del Sontro said while at home in Washington with his yearold son Nico and his yearold daughter Siena.CreditGreg Kahn for The New York Times This serendipitous encounter led to his familys participation in the study. Seeking the Mutation Dr. Bieseckers project had a specific goal to recruit  people a quarter with no heart disease and a quarter each with mild moderate and severe forms of the disease. The hope was that by comparing the genes of people with varying degrees of severity the researchers might discover genetic alterations that would reveal why heart disease occurs. They made some interesting observations about gene mutations that were already known to cause heart diseases but the Del Sontros offered the possibility of discovering an entirely new genetic pathway to heart disease. Now eight family members have joined the study and Dr. Biesecker is searching for more. Even so finding the tiny troublemaking genetic glitches in the familys genes is an intimidating task. There are  genes in each persons DNA and each gene is can be made up of a string of hundreds of DNA letters and can harbor variations. Most of the variations are meaningless. In the entire DNA  which contains genes and regions that control genes  there are six billion DNA letters to check. To figure out what DNA changes might be important the researchers are comparing the DNA sequences of Rick Del Sontro and his family with those of others in the study looking for genetic changes that occur in every member of the Del Sontro family who has heart disease but that are not generally found in healthy people. Dr. Biesecker acknowledged that there was no guarantee of success. He and his colleagues know the gene mutation in the Del Sontro family must be rare. Otherwise lots of people would have early heart disease but no obvious risk factors. To keep the focus on truly rare mutations the researchers are excluding those that are present in both members of the Del Sontro family and  percent or more of the other study participants. That strategy alone Dr. Biesecker said has eliminated the vast majority of candidate genes. The researchers are now searching for culprits among genes that remain  a search that could take years. Or the change might be in a poorly understood region of DNA that controls genes rather than in a gene itself. Researchers ignorance of these control regions and what many of them do might doom the effort. So the researchers are hoping the Del Sontro familys heart disease is caused by a mutated gene. Our main job is to find the gene Dr. Biesecker said. Still Mr. Del Sontro is preparing for the worst. He has life insurance and longterm care insurance. I keep waiting for the day when I have shortness of breath he said. When his heart disease was first diagnosed four and a half years ago Mr. Del Sontro now  told his cardiologist he wanted to run one more Bay to Breakers race a centuryold kilometer race in San Francisco. His doctor told him absolutely not saying You are the kind of guy we will read about who dies during the race of a massive heart attack. Mr. Del Sontro could still exercise his cardiologist said but no more than  minutes a day. Mr. Del Sontro is all too aware that the cause of his heart disease is a mystery but he worries that if he fails to eat right and exercise he might make his illness even worse. So he left for the gym before dawn on a recent chilly morning. He lifted weights using dumbbells and bars moving quickly from exercise to exercise. Fortyfive minutes later sweating he was done. His disease casts a dark shadow not just on him but on his entire family. At dinner one recent evening at their yellow brick townhouse in the Georgetown neighborhood in Washington his wife Pura admitted to worrying but said We dont talk about it a lot. She served Indian takeout  saffron rice tandoori chicken eggplant. Tall slender and elegant in skinny jeans and a long beige sweater she ate sparingly and drank a Coke Zero. Mr. Del Sontro drank only water and took small portions.  Their yearold daughter Siena said she was afraid she had inherited her fathers heart problems. He reassured her that scientists would surely have found a treatment by the time she grew up. I hope it doesnt hurt she told him. Her shy yearold brother Nico slipped away from the dinner table."