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Two new studies in the Journal of the American Medical Association, led by NewYork-Presbyterian Hospital/Weill Cornell Medical Center researchers, are clearing up the mystery of why some hypertensive patients continue to be at high risk for heart attack and stroke, even after drug therapy has reduced their blood pressure to safer levels.

Findings from both echocardiogram and electrocardiogram (ECG) suggest that anti-hypertensive drugs that aggressively shrink enlarged heart muscle bring added benefits to patients, lowering their risk for dangerous cardiovascular events.

"Even in the setting of aggressive blood-pressure lowering, it's the patients who had the greatest reductions in enlarged heart muscle that had the greatest improvements in prognosis," said Dr. Peter M. Okin, professor of medicine in the Greenberg Division of Cardiology at Weill Cornell Medical College, and director of Clinical Affairs at NewYork-Presbyterian/Weill Cornell.

His team's ECG-based study of more than 9,000 heart patients is published in the Nov. 17 issue of the Journal of the American Medical Association (JAMA).

A second study – based on a smaller subset of patients tracked by echocardiogram – was led by NewYork-Presbyterian/Weill Cornell researcher Dr. Richard B. Devereux and appears in the same issue of JAMA.

Additionally, a related expert commentary, plus the journal's special new "Patient Page," is published in conjunction with the two studies.

Doctors have long known that chronic high blood pressure can lead to a condition called left ventricular hypertrophy (LVH), a dangerous enlargement of muscle surrounding the heart's main pumping chamber. Experts estimate that 20 percent or more of all Americans with high blood pressure – up to 12 million people – suffer from LVH.

While enlarged hearts have long been associated with increased risks for heart attack, stroke, and heart failure, a direct cause-and-effect link has remained unclear.

"Because high blood pressure is the prime factor behind LVH, cardiovascular risk in people with enlarged hearts should decline as we successfully treat their hypertension. But we know that the rate of improvement varies between patients," said Dr. Devereux, professor of medicine in the Greenberg Division of Cardiology at Weill Cornell Medical College, and director of the Laboratory of Echocardiography at NewYork-Presbyterian/Weill Cornell.

To find out if LVH has a deleterious effect on cardiovascular health beyond its link to high blood pressure, teams led by Dr. Devereux and Dr. Okin looked at data from the ongoing Losartan Intervention For Endpoint (LIFE) study, a multicenter investigation of 9,193 European patients with high blood pressure and LVH.

In one study, Dr. Okin tracked five-year event rates for heart attack, stroke, and cardiovascular death in all 9,193 LIFE participants.

At the same time, his team monitored ongoing changes in patients' LVH via electrocardiogram – an inexpensive, widely available heart test that measures the nature and speed of electrical impulses within cardiac muscle.

In the second study, Dr. Devereux's team tracked similar changes in a smaller subset of 941 LIFE participants. Data on changes in LVH in these patients was obtained via more sophisticated (and expensive) echocardiogram, which uses sound waves to provide doctors with direct measurements of the heart's size, wall thickness, and mass (or weight) of the heart muscle.

"In both studies, we got the same result," Dr. Okin said.

"After an initial, significant decline in blood pressure due to drug therapy, improvements in hypertension tended to level out over time," he said.

"But in patients taking Losartan, we saw a steady shrinking of enlarged heart muscle that continued beyond that initial decline in high blood pressure," he said.

"It's these patients who had the best prognosis, in terms of lowered risks for heart attack and stroke."

The findings suggest that physicians may need to keep LVH reduction firmly in mind when diagnosing and treating heart patients.

"Our studies show that if one can bring down or reverse LVH, one gets an added benefit, over and above any reduction in blood pressure," Dr. Devereux said. "Ideally, you'd like to monitor the heart muscle over time, adjusting therapy accordingly."

In a previous paper published in September in Circulation, researchers led by Dr. Devereux found the angiotensin receptor antagonist drug Losartan had a decided advantage over another anti-hypertensive drug, the beta-blocker Atenolol, in reducing LVH. Other types of medications, such as ACE inhibitors or calcium channel blockers, may also be very effective, Dr. Devereux said, although more study is needed.

And what about diagnosing and monitoring patients with enlarged heart muscle? While echocardiogram gives physicians the clearest picture of the heart's changing architecture, it remains expensive and may be unavailable in many clinics.

Fortunately for heart patients, cheaper, widely available ECG remains an extremely sensitive tool, Dr. Okin said.

"Even if you use ECHO to more accurately detect the presence of hypertrophy, you can then use periodic evaluation by ECG to track changes in that risk," he said.

"That's probably the most important finding from this paper."

Funding for the LIFE study came from Merck & Co. Inc., the maker of Losartan.

Co-researchers on Dr. Devereux's study include Drs. Jens Rokkedal and Kristian Wachtell, of Glostrup University Hospital, Glostrup, Denmark; Dr. Eva Gerdts, of Haukeland University Hospital, in Bergen, Norway; Dr. Kurt Boman, of Skelleftea Lasarett and Umea University, Skelleftea, Sweden; Dr. Markku S. Niemenen, of Helsinki University Central Hospital, Helsinki, Finland; Dr. Vasilios Papademitriou, of Veterans Administration Hospital, in Washington, DC; Drs. Katherine Harris and Peter Aurup, of Merck Research Laboratories, West Point, PA; and Dr. Bjorn Dahlof, of Sahlgrenska University Hospital, Ostra, and the University of Goteborg, Sweden.

Co-researchers on Dr. Okin's study include Drs. Devereux, Nieminen, Harris, Aurup, and Dahlof; as well as Dr. Sverker Jern, of University Hospital/Ostra, Goteborg, Sweden; Dr. Sverre E. Kjeldsen, of Ullevaal University Hospital, Oslo, Norway; Dr. Stevo Julius, of the University of Michigan Medical Center, Ann Arbor; Dr. Steven Snapinn, of Amgen Inc., Thousand Oaks, Calif.; Dr. Jonathan Edelman, of Merck & Co. Inc., Whitehouse Station, NJ; Dr. Hans Wedel, of the Nordic School of Public Health, Goteborg, Sweden; and Dr. Lars H. Lindholm, of Umea University, Umea, Sweden.