Perspectives
Profile Henry Krum: resisting the pressure If there’s one man who can be said to have put Australia on the map with respect to clinical trials in cardiovascular disease, particularly in heart failure, it’s Henry Krum, Director of Monash University’s Centre of Cardiovascular Research and Education in Therapeutics. Although he established his reputation in drug therapy, his name has more recently become associated with the resurrection of a non-drug intervention, sympathetic denervation for refractory hypertension. Krum’s proof-of-concept study, published in The Lancet in 2009, was regarded by many as a breakthrough in the treatment of resistant hypertension. Like many Australians, Krum is conscious that geographically speaking his country is far from most other centres of research. However, in the globalised world of biomedicine, his contributions to cardiovascular research place him closer to its core than its periphery. But why this branch of medicine in particular? “It was the biology and the science of the system that interested me”, he says. “And the fact that it affects every organ of the body.” He wouldn’t, he adds, have been attracted by some of the more obscure backwaters of academic research. As Glasgow University Professor of Cardiology John McMurray says of Krum, “An unusual strength is the breadth and depth of his knowledge and research spanning cardiovascular disease, diabetes, and chronic kidney disease among others.” Krum trained at the University of Melbourne, graduating in 1982. 10 years on, and having completed a PhD, he spent a couple of years in the USA. The offer of a more senior academic job in Australia drew him home, initially to the University of Melbourne and more recently to Monash. During this time his main activity has been in drug development. He’s worked in the field of urotensin II pharmacology, investigated the cardiovascular safety of noncardiovascular drugs, including COX-2 inhibitors, and been on the international steering committees of a score of clinical trials. Asked what he sees as his key contribution he picks out his work on β blockers in heart failure. This brought about a fundamental change in treatment. “β blockers went from being a treatment contraindicated in heart failure to one that’s really mandated. A complete 180 degree turnaround.” Alexander Lyon, from London’s Imperial College and a consultant cardiologist at the Royal Brompton Hospital, first met Krum through their coauthorship of a chapter for a book on heart failure. Was he surprised that a man whose career had been built on drug therapy should have begun to take an interest in a non-drug intervention? Not at all, he says. “A lot of Henry’s work was on β blockers and the overactivity of the sympathetic nervous system. In using a physical as opposed to a drug technique to intervene he was still targeting a system on which he was a world expert.” www.thelancet.com Vol 383 February 15, 2014
Talking of the history of sympathectomy Krum points out that it’s far from a new idea. “Surgically it goes back to the era before there were any of the modern pharmacological agents. It was highly effective at lowering blood pressure, but it had a lot of side-effects such as postural hypotension.” In any event, the development of effective drugs killed off the interest in sympathectomy. But drug treatment isn’t always effective, and the invention of a catheter-based technique for tackling the sympathetic nerves once again made this potentially attractive for patients with treatment-resistant hypertension. The technique uses radiofrequency radiation, delivered via a catheter in the renal artery, to damage the adjacent nerve pathways. The equipment was devised in the USA “but Australia is a good place for early phase clinical work, both on devices as well as drugs”, Krum explains. “It has quite a streamlined process to register a new drug or a device and then test it, but with all of the safeguards.” Denervation for refractory hypertension is now a flourishing enterprise. “I was involved in the very first discussions of the best indication in which to begin testing denervation”, says Krum. With his established interest in heart failure he was keen to start with this condition. “But we recognised early on that ethics committees wouldn’t let us do it, so we put it into refractory hypertension patients instead.” The encouraging results of the first safety and feasibility trial have since been confirmed in a randomised controlled trial, with the results of the Symplicity HTN-1 study now published in The Lancet. Other studies, and not only its role in treating hypertension, are in the pipeline. Paul Sobotka is an American cardiologist and self-described “physician-inventor” who has collaborated extensively with Krum. Besides showing the clinical benefits of denervation, he says, the work already undertaken has generated a better understanding of the role of the sympathetic nervous system, which in turn generates new insights into conditions besides hypertension. “It opens avenues to new clinical approaches that may be of enormous value to patients with both acute and chronic conditions.” These include heart failure, chronic kidney disease, and arrhythmias. Krum says he enjoys the relative autonomy that research can offer. “At a certain level of seniority you can pursue an idea even if you’re the only one who thinks it’s going to work.” Colleagues are flattering, not only about his work. “Bright, energetic, dynamic, and always cheerful”, says McMurray. Sobotka describes him as moving gracefully between the roles of colleague, mentor, and friend. “He’s inquisitive, caring, and keen to enjoy life. His breadth of interests has allowed him to see connections that others might not.”
For the Symplicity HTN-1 study see Articles page 622 For more on Centre of Cardiovascular Research and Education in Therapeutics see http://www.ccretherapeutics. org.au/
For Krum et al’s 2009 study see Articles Lancet 2009; 373: 1275–81
Geoff Watts 591
Profile Henry Krum: resisting the pressure If there’s one man who can be said to have put Australia on the map with respect to clinical trials in cardiovascular disease, particularly in heart failure, it’s Henry Krum, Director of Monash University’s Centre of Cardiovascular Research and Education in Therapeutics. Although he established his reputation in drug therapy, his name has more recently become associated with the resurrection of a non-drug intervention, sympathetic denervation for refractory hypertension. Krum’s proof-of-concept study, published in The Lancet in 2009, was regarded by many as a breakthrough in the treatment of resistant hypertension. Like many Australians, Krum is conscious that geographically speaking his country is far from most other centres of research. However, in the globalised world of biomedicine, his contributions to cardiovascular research place him closer to its core than its periphery. But why this branch of medicine in particular? “It was the biology and the science of the system that interested me”, he says. “And the fact that it affects every organ of the body.” He wouldn’t, he adds, have been attracted by some of the more obscure backwaters of academic research. As Glasgow University Professor of Cardiology John McMurray says of Krum, “An unusual strength is the breadth and depth of his knowledge and research spanning cardiovascular disease, diabetes, and chronic kidney disease among others.” Krum trained at the University of Melbourne, graduating in 1982. 10 years on, and having completed a PhD, he spent a couple of years in the USA. The offer of a more senior academic job in Australia drew him home, initially to the University of Melbourne and more recently to Monash. During this time his main activity has been in drug development. He’s worked in the field of urotensin II pharmacology, investigated the cardiovascular safety of noncardiovascular drugs, including COX-2 inhibitors, and been on the international steering committees of a score of clinical trials. Asked what he sees as his key contribution he picks out his work on β blockers in heart failure. This brought about a fundamental change in treatment. “β blockers went from being a treatment contraindicated in heart failure to one that’s really mandated. A complete 180 degree turnaround.” Alexander Lyon, from London’s Imperial College and a consultant cardiologist at the Royal Brompton Hospital, first met Krum through their coauthorship of a chapter for a book on heart failure. Was he surprised that a man whose career had been built on drug therapy should have begun to take an interest in a non-drug intervention? Not at all, he says. “A lot of Henry’s work was on β blockers and the overactivity of the sympathetic nervous system. In using a physical as opposed to a drug technique to intervene he was still targeting a system on which he was a world expert.” www.thelancet.com Vol 383 February 15, 2014
Talking of the history of sympathectomy Krum points out that it’s far from a new idea. “Surgically it goes back to the era before there were any of the modern pharmacological agents. It was highly effective at lowering blood pressure, but it had a lot of side-effects such as postural hypotension.” In any event, the development of effective drugs killed off the interest in sympathectomy. But drug treatment isn’t always effective, and the invention of a catheter-based technique for tackling the sympathetic nerves once again made this potentially attractive for patients with treatment-resistant hypertension. The technique uses radiofrequency radiation, delivered via a catheter in the renal artery, to damage the adjacent nerve pathways. The equipment was devised in the USA “but Australia is a good place for early phase clinical work, both on devices as well as drugs”, Krum explains. “It has quite a streamlined process to register a new drug or a device and then test it, but with all of the safeguards.” Denervation for refractory hypertension is now a flourishing enterprise. “I was involved in the very first discussions of the best indication in which to begin testing denervation”, says Krum. With his established interest in heart failure he was keen to start with this condition. “But we recognised early on that ethics committees wouldn’t let us do it, so we put it into refractory hypertension patients instead.” The encouraging results of the first safety and feasibility trial have since been confirmed in a randomised controlled trial, with the results of the Symplicity HTN-1 study now published in The Lancet. Other studies, and not only its role in treating hypertension, are in the pipeline. Paul Sobotka is an American cardiologist and self-described “physician-inventor” who has collaborated extensively with Krum. Besides showing the clinical benefits of denervation, he says, the work already undertaken has generated a better understanding of the role of the sympathetic nervous system, which in turn generates new insights into conditions besides hypertension. “It opens avenues to new clinical approaches that may be of enormous value to patients with both acute and chronic conditions.” These include heart failure, chronic kidney disease, and arrhythmias. Krum says he enjoys the relative autonomy that research can offer. “At a certain level of seniority you can pursue an idea even if you’re the only one who thinks it’s going to work.” Colleagues are flattering, not only about his work. “Bright, energetic, dynamic, and always cheerful”, says McMurray. Sobotka describes him as moving gracefully between the roles of colleague, mentor, and friend. “He’s inquisitive, caring, and keen to enjoy life. His breadth of interests has allowed him to see connections that others might not.”
For the Symplicity HTN-1 study see Articles page 622 For more on Centre of Cardiovascular Research and Education in Therapeutics see http://www.ccretherapeutics. org.au/
For Krum et al’s 2009 study see Articles Lancet 2009; 373: 1275–81
Geoff Watts 591
