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Heart therapies may come from genetic studies
SCIENCE AND MEDICINE
Heart therapies may come from genetic studies ew therapies for heart failure may come from studying the genetics of cardiovascular disease, delegates heard at a recent meeting (Jan 10–12; Orlando, FL, USA). Several speakers focused on the role of the -adrenergic pathway in heart failure. Howard Rockman (University of North Carolina, Chapel Hill, NC, USA) reported that in cardiac failure -adrenergic receptors are desensitised by phosphorylation, a process mediated by -adrenergic-receptor kinase (-ARK) and -arrestin. Animal studies threw more light on the pathway. For example, mice lacking -arrestin died in utero but heterozygous animals were viable and had increased responsiveness to isoproterenol stimulation. Transgenic mice over-expressing a dominant negative -ARK were also more responsive to isoproterenol. When these latter mice were crossed with a mouse strain lacking muscle LIM protein which develops pump failure, left ventricular function was conserved in the offspring even though their hearts were structurally abnormal. These results indicate that targeting the -adrenergic signalling pathway may be therapeutically useful. Steven Liggett (University of
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Cincinatti, OH, USA) analysed the clinical relevance of 1 and 2adrenergic-receptor polymorphisms in patients with heart failure. Polymorphisms were evenly distributed between patients and controls, but those patients with congestive heart failure with isoleucine rather than threonine at position 164 of the 2-adrenergic receptor had a poorer prognosis. 1year survival was 42% for patients with the Ile/Ile genotype compared with 80% in patients with Ile/Thr or Thr/Thr. Pharmacogenomics —genetics-based drug tailoring—is starting to look feasible in the cardiovascular field. According to Vince Stanton (Variagenics, Cambridge MA, USA), heritability is more important for drug metabolism than for disease. For example, the genotype of thiopurine-s-methyl transferase distinguishes between slow and fast metabolisers and should be used to determine the individual dosage for thiopurine-derived drugs, he explained. A similar genotypedependent drug response was described for cholesterol-ester transferase, where regression of atherosclerotic plaques after treatment with pravastatin is genotype dependent. Pieter A Doevendans
US FDA advisers back new myopia aid
N
earsighted Americans may soon have another reason to throw away their glasses: a surgical implant that in clinical trials restored vision to 20/40 or better in most patients. On Jan 13, US FDA advisers gave their backing to the technology, KeraVision’s Intacs. Also known as an intrastromal corneal ring, each Intacs lens reshapes a cornea’s curvature, says KeraVision (Fremont, CA, USA). Myopia is corrected by adding material, not by physically cutting, as in the laser procedures already approved by the FDA. Thus, unlike laser surgery, the procedure can be reversed if patients are dissatisfied. In clinical trials, after 1 year of follow-up in 410 eyes, 98% of eyes had 20/40 vision or better, 78% had
300
20/20 or better, and 56% had 20/16 or better. In phase II and III trials, about 5% of patients chose to have the corneal ring removed. Most had them taken out because of disappointment with vision correction or because of side-effects. The latter were similar to those caused by laser surgery: glare, problems with night vision, and some haloing. The corneal ring implant procedure will also probably cost the same as laser treatment—about US$2000 per eye. KeraVision was seeking approval to treat patients with −1·0 to −3·5 diopters of myopia. Intacs are already approved in Canada and several European countries.
News in brief TTV in Brazil A survey done in research institutes in the Brazilian states of São Paulo and Para has identified transfusion-transmitted virus (TTV) in 30 of 125 patients with chronic liver disease, including some positive for hepatitis B or C (Rev Inst Med Trop São Paulo 1998; 40: 335–6). Two cases in São Paulo could not be classified as one of the two known TTV genotypes, suggesting that there may be other new genotypes in Brazil, says one of the authors, Joao Renato Rebello Pinho (Adolfo Lutz Institute, São Paulo). Since its first identification in Japan in 1997, TTV been detected in several countries, including the UK (Lancet 1998; 352: 195–97). Test for human BSE Following on from the publication of a study on variant Creutztfeld-Jakob disease and other human prion diseases in last week’s Lancet, (p 183–89), the Daily Telegraph reported (Jan 16) that: “Thousands will face tests for BSE in humans.” Samples taken from tonsils and appendices removed in routine operations over the past 10 years will be investigated in three centres, the article said. HIV vaccines solved? Vaccines based on recombinant gp120 envelope protein have so far been disappointing but a new study may indicate a way forward. Rachel LaCasse (University of Montana, Missoula, MT, USA) and colleagues report that, in a mouse model, formaldehyde-fixed wholecell vaccines elicited antibodies able to neutralise 23 of 24 primary HIV isolates. In these vaccines it is proposed that transient immunogens produced during the interaction of envelope proteins with cell receptors are fixed and available to the host’s immune system (Science 1999; 283: 357–62). Dog bite infections In a study done at 18 US emergency departments, the microbes present in infected dog (50 patients) and infected cat (57 patients) bite wounds were analysed. A complex mix of microbes was found, including Pasturella spp but also many other organisms not previously recognised as wound pathogens (N Engl J Med 1999; 340: 85–92).
Alicia Ault
THE LANCET • Vol 353 • January 23, 1998
Heart therapies may come from genetic studies ew therapies for heart failure may come from studying the genetics of cardiovascular disease, delegates heard at a recent meeting (Jan 10–12; Orlando, FL, USA). Several speakers focused on the role of the -adrenergic pathway in heart failure. Howard Rockman (University of North Carolina, Chapel Hill, NC, USA) reported that in cardiac failure -adrenergic receptors are desensitised by phosphorylation, a process mediated by -adrenergic-receptor kinase (-ARK) and -arrestin. Animal studies threw more light on the pathway. For example, mice lacking -arrestin died in utero but heterozygous animals were viable and had increased responsiveness to isoproterenol stimulation. Transgenic mice over-expressing a dominant negative -ARK were also more responsive to isoproterenol. When these latter mice were crossed with a mouse strain lacking muscle LIM protein which develops pump failure, left ventricular function was conserved in the offspring even though their hearts were structurally abnormal. These results indicate that targeting the -adrenergic signalling pathway may be therapeutically useful. Steven Liggett (University of
N
Cincinatti, OH, USA) analysed the clinical relevance of 1 and 2adrenergic-receptor polymorphisms in patients with heart failure. Polymorphisms were evenly distributed between patients and controls, but those patients with congestive heart failure with isoleucine rather than threonine at position 164 of the 2-adrenergic receptor had a poorer prognosis. 1year survival was 42% for patients with the Ile/Ile genotype compared with 80% in patients with Ile/Thr or Thr/Thr. Pharmacogenomics —genetics-based drug tailoring—is starting to look feasible in the cardiovascular field. According to Vince Stanton (Variagenics, Cambridge MA, USA), heritability is more important for drug metabolism than for disease. For example, the genotype of thiopurine-s-methyl transferase distinguishes between slow and fast metabolisers and should be used to determine the individual dosage for thiopurine-derived drugs, he explained. A similar genotypedependent drug response was described for cholesterol-ester transferase, where regression of atherosclerotic plaques after treatment with pravastatin is genotype dependent. Pieter A Doevendans
US FDA advisers back new myopia aid
N
earsighted Americans may soon have another reason to throw away their glasses: a surgical implant that in clinical trials restored vision to 20/40 or better in most patients. On Jan 13, US FDA advisers gave their backing to the technology, KeraVision’s Intacs. Also known as an intrastromal corneal ring, each Intacs lens reshapes a cornea’s curvature, says KeraVision (Fremont, CA, USA). Myopia is corrected by adding material, not by physically cutting, as in the laser procedures already approved by the FDA. Thus, unlike laser surgery, the procedure can be reversed if patients are dissatisfied. In clinical trials, after 1 year of follow-up in 410 eyes, 98% of eyes had 20/40 vision or better, 78% had
300
20/20 or better, and 56% had 20/16 or better. In phase II and III trials, about 5% of patients chose to have the corneal ring removed. Most had them taken out because of disappointment with vision correction or because of side-effects. The latter were similar to those caused by laser surgery: glare, problems with night vision, and some haloing. The corneal ring implant procedure will also probably cost the same as laser treatment—about US$2000 per eye. KeraVision was seeking approval to treat patients with −1·0 to −3·5 diopters of myopia. Intacs are already approved in Canada and several European countries.
News in brief TTV in Brazil A survey done in research institutes in the Brazilian states of São Paulo and Para has identified transfusion-transmitted virus (TTV) in 30 of 125 patients with chronic liver disease, including some positive for hepatitis B or C (Rev Inst Med Trop São Paulo 1998; 40: 335–6). Two cases in São Paulo could not be classified as one of the two known TTV genotypes, suggesting that there may be other new genotypes in Brazil, says one of the authors, Joao Renato Rebello Pinho (Adolfo Lutz Institute, São Paulo). Since its first identification in Japan in 1997, TTV been detected in several countries, including the UK (Lancet 1998; 352: 195–97). Test for human BSE Following on from the publication of a study on variant Creutztfeld-Jakob disease and other human prion diseases in last week’s Lancet, (p 183–89), the Daily Telegraph reported (Jan 16) that: “Thousands will face tests for BSE in humans.” Samples taken from tonsils and appendices removed in routine operations over the past 10 years will be investigated in three centres, the article said. HIV vaccines solved? Vaccines based on recombinant gp120 envelope protein have so far been disappointing but a new study may indicate a way forward. Rachel LaCasse (University of Montana, Missoula, MT, USA) and colleagues report that, in a mouse model, formaldehyde-fixed wholecell vaccines elicited antibodies able to neutralise 23 of 24 primary HIV isolates. In these vaccines it is proposed that transient immunogens produced during the interaction of envelope proteins with cell receptors are fixed and available to the host’s immune system (Science 1999; 283: 357–62). Dog bite infections In a study done at 18 US emergency departments, the microbes present in infected dog (50 patients) and infected cat (57 patients) bite wounds were analysed. A complex mix of microbes was found, including Pasturella spp but also many other organisms not previously recognised as wound pathogens (N Engl J Med 1999; 340: 85–92).
Alicia Ault
THE LANCET • Vol 353 • January 23, 1998