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system, which was my own research focus," says Dr. Husain, who credits former Directors of Research, cardi- ologist Bernadine Healy, MD, and F. Merlin Bumpus, PhD, with pointing their attention to the importance of this system in the heart. "I wondered if there could be another enzyme, besides ACE, that was responsible for the conversion of angiotensin I into angiotensin II." Using cardiomyopathic hamsters and working in collaboration with the clinical/research physiology team, Dr. Husain's biochemistry group eventu- ally identified chymase as the hidden key to converting angiotensin I into the biologically active angiotensin II, even when ACE is blocked. "This was different from the blood ves- sel, where angiotensin generation, and hence hypertension, could be blocked by ACE inhibitors," Dr. Husain explains. "This understanding provided the early promise of a new class of anti-heart failure drugs to more effectively treat post-heart attack patients by blocking angiotensin in the heart." Since the 1990s, when this research was conducted, it has been discovered that chymase has many biologically important targets in addition to angio- tensin. As a result, many pharmaceutical companies have now developed specific human chymase inhibitors. Preclinical studies in the U.S. and Japan show that these chymase inhibitors are highly effective in animals with myocardial i n f a rc t ion , a nd t hei r ef fe c t s a re protective even on top of ACE inhibi- tor treatment. "Surprisingly these drugs also reduce infarct size, suggesting that chymase inhibition actually protects the heart muscle from dying," says Dr. Husain. The Syncope Clinic On the opposite end of the spectrum from hypertension (though still closely related) is syncope and orthostatic intolerance, which includes a spectrum from lightheadedness to fainting that can occur in some people, usually when they stand up. Although it is typically associated with hypotension, and was once dismissed by clinicians as being "in patients' minds," Cleveland Clinic researchers wanted to understand why it happens only in some people and only in certain circumstances. With the aid of a tilt table provided by the Radiology Department, the clinical hypertension research team conducted physiologic studies on hemodynamics, blood volume, autonomic reflexes and circulating humoral factors, defining ways to determine the mechanisms underlying the all-too-common problem of syncope. Dr. Fouad-Tarazi and clinical cardiac elec- trophysiologist Freddy Abi-Samra, MD, who is now affiliated with Ochsner Health System in New Orleans, Louisiana, were part of that team. They published a paper in 1988 on the use of head-up tilt testing in the workup of syncope of unknown origin and established a clinical model that is now used to study syncope around the world. "We induced vasovagal and vasode- pressor reactions in patients w ith recurrent syncope using a tilt table and, after following up with pathophysi- ological studies, were able to identify autonomic dysfunction, venous pooling, and hypovolemia as etiology factors, or more accurately, underpinning predis- posing factors," explains Dr. Abi-Samra. "What we also discovered is that top and bottom blood pressure can drop together, or just the top, or just the bot- tom," adds Dr. Fouad-Tarazi. "Just as important are changes in heart rate and the electrocardiogram during the test." The research led to a range of treat- ment options tailored to each syncope sufferer's unique situation for better responses and outcomes. "If someone has hypovolemia, we pre- scribe a specific medication and we pay attention to dietary salt intake. If venous pooling is the problem, we prescribe lower body exercises designed to enhance venous return and perhaps support stockings. If it is postural orthostatic tachycardia syndrome (POTS) of the beta-hyperadrenergic type, we prescribe beta blockers," says Dr. Abi-Samra. "If it is POTS with inability to vasoconstrict ('partial efferent autonomic dysfunction' type), we prescribe a vasoconstrictor. At the same time, we aim at reversal of other associated circulatory/cardiovas- cular culprits." Dr. Fouad-Tarazi explains that special combinations of therapy apply to special situations such as supine hypertension associated with orthostatic hypotension. "We have always kept our options open for acquiring and developing new approaches to fit the needs of our patients as well as to embrace advancements in science and technology applicable to this field," she says. The Role of Collaboration A ll t h ree phy sicia ns a g ree t hat Cleveland Clinic could not have become the research leader it is in the field of cardiovascular disorders without the structure that encouraged constant col- laboration, not only among the various cardiovascular research groups, but also between researchers and clinicians. "When people work together, big things can happen," says Dr. Fouad- Tarazi, who adds that she hopes her forthcoming book (the working title is "Your Heart is at the Center of it All") will not only shine a spotlight on Cleveland Clinic's contributions to cardiovascular research, but also raise awareness among both clinicians and basic scientists to work together 'as a unit.' She also hopes her book will highlight the need to recognize and manage all types of blood pres- sure dysregulation. "Sometimes, guidelines or recom- mendations are published that are based on clinical experience," she says. "But being able to establish the mechanisms through research can actually make the guidelines or recommendations stronger and more effective. This helps us recognize the basis of changes and understand why people respond in a certain way. And that helps in the choice of a specific line of treatment for a specific patient." ■ COV ER FE AT UR E 1 0 | Cleveland/Akron/Canton MD NEWS ■ M D N E W S . CO M ■ S E P T E M B E R /O C T O B E R 2 0 1 5