Cell Stress Response Normal Heart Failure

NH2NH2

CD45

NH2NH2

CD45

Fig. 4.8 Expression arrays are also useful to determine host stress response signaling pathways in the presence of heart failure. In this experiment, we can see that intracellular cytokine signaling path ways of Ick and fyn are both up regulated in the setting of heart failure. This is consistent with the activation of cytokine and immune signaling pathways in the setting of heart failure.

this technology to systematically identify novel ethology specific markers of disease.

This strategy has also been recently employed in prostatic cancer, where early and accurate diagnosis is particularly useful for determining course of action. Using microarray methods, an early diagnostic pattern was indeed recognized, two signaling molecules appear to be unique to early prostatic cancer - hepsin and pim-1, both are serine-threonine kinases [31].

In addition, with the increasing utilization of ventricular assist devices, there is access to tissues from heart failure patients has improved. In addition, gathering data has now become available on the potential changes and reversibility of the abnormalities observed in heart failure, and the opportunity of using this information in the future for prognosis of the patients, and in turn determining which patient may come off the assist device support, and which patient will need heart transplantation.

4.15

Application: Therapeutic Insights

How a drug acomplishes its therapeutic effect in the clinical setting has always been difficult. A drug may be developed for the purpose of targeting a specific pathway. However, in many occasions, it is the unintended effects of a drug that ultimately determine its overall biological profile in the clinical setting. An example is the recent publication of the effect of beta blockers in the setting to understand heart failure. It appears that only in patients when the beta blockade can alter the cardiac contractile protein such as the myosin isoforms that the patient will benefit with respect to reverse remodeling and improvement in clinical outcome. Therefore the availability of microarrays will now offer an unprecedented opportunity to define the diverse targets that are affected by a certain therapeutic intervention, and define the true biological impact of a certain treatment strategy. This will be particularly important in the setting of heart failure, involving a large complex of pathophysiological pathways.

4.16

Acknowledgements

The work is supported in part by grants from the Heart and Stroke Foundation of Ontario, and the Canadian Institutes of Health Research (CIHR).

4.17

References

1 Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: The Framingham Study. Journal of American College of Cardiology. 1993; 2:6A-13A.

2 O'Connell J, Bristow MR. Economic impact of heart failure in the United States: time for a different approach. Journal of Heart and Lung Transplantation. 1994; 23:107-112.

3 Haldeman GA, Rashidee A, Horswell R. Changes in mortality from heart failure - United States, 1980-1995. Mortality Morbidity Weekly Review. 1998; 47:4-7.

4 Johansen H, Strauss B, Walsh P, Moe G, Liu PP. Congestive Heart Failure: the Coming Epidemic. Canadian Medical Association Journal. 2002 (in press).

5 Institute for Clinical Evaluative Sciences (ICES). Cardiovascular health & services in Ontario: An ICES atlas. 1999; 111-122.

6 Liu P, Arnold M, Belenkie I, Howlett J, Huckell V, Ignazewski A, LeBlanc MH, McKelvie R, Niznick J, Parker JD, Rao V, Ross H, Roy D, Smith S, Sussex B, Teo KK, Tsuyuki R, White M, Beanlands D, Bernstein V, Davies R, Issac D, Johnstone D, Lee H, Moe G, Newton G, Pflugfelder P, Roth S, Rouleau J, Yusuf S. The 2001 canadian cardiovascular society consensus guideline update for the management and prevention of heart failure. Canadian Journal of Cardiology. 2001; 22:5E-48E.

7 Adams KF, Baughman K, Liu PP, et al. HFSA guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction - pharmacological approaches. Journal of Cardiac Failure. 1999; 5:357-382.

8 Cohn J. The prevention of heart failure -a new agenda. New England Journal of Medicine. 1992; 327:725-7.

9 Hunt SA, Baker DW, Chin MH, Cin-quegrani MP, Feldmanmd AM, Francis GS, Ganiats TG, Goldstein S, Gre-goratos G, Jessup ML, Noble RJ, Packer M, Silver MA, Stevenson LW, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Jacobs

AK, Hiratzka LF, Russell RO, Smith SCJ. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary. Circulation. 2001; 104:2996-3007.

10 Hwang DM, Dempsey AA, Wang RX, Rezvani M, Barrans JD, Dai KS, Wang HY, Ma H, Cukerman E, Liu YQ, Gu JR, Zhang JH, Tsui SKW, Waye MMY, Fung KP, Lee CY, Liew CC. A genome-based resource for molecular cardiovascular medicine: Toward a compendium of cardiovascular genes. Circulation. 1997; 96:4146-4203.

11 Crackower M, Oudit GY, Backx P, Penninger J. Functional analysis of a novel angiotensin converting enzyme -ACE2. Nature. 2002;250:(in press).

12 Lockhart DJ, et al. Expression monitoring of hybridization to high-density oligo-nucleotide arrays. Nature Biotechnology. 1996; 14:1675-1680.

13 Kerr MK, Churchill GA. Experimental design for gene expression microarrays. Biostatistics. 2001; 2:183-201.

14 Phillips J, Eberwine JH. Antisense RNA amplification: a linear amplification method for analyzing the mRNA population from single living cells. Methods of Enzymology. 1996; 10:283-288.

15 Collins FS. New goal for US Human Genome Project. Science. 1998; 282:682689.

16 Collins FS. Shattuck lecture - Medical and societal consequences of the Human Genome Project. New England Journal of Medicine. 1999; 341:28-37.

17 Venter JC, etc. Completion of the human genome proejct. Science. 2001; 291:1304-1351.

18 Lander ES. The new genomics: global view of biology. Science. 1996; 274:536539.

19 Brown PO, Botstein D. Exploring the new world of genome with DNA micro-arrays. Nature Genetics. 1999; 14:457-460.

20 Stears RL, Getts RC, Gullans SR. A novel, sensitive detection system for high-density microarrays using dendri-

mer technology. Physiological Genomics. 2000; 3:93-99.

21 Eberwine JH, et al. Analysis of gene expression in single live neurons. Proceedings of National Academy of Sciences USA. 1992; 89:3010-3014.

22 Luo L, et al. Gene expression profiles of laser-captured adjacent neuronal subtypes. Nature Medicine. 1999; 5:117-122.

23 Wang E, Miller LD, Ohnmacht GA, Liu ET, Marincola FM. High-fidelity mRNA amplification for gene profiling. Nature Biotechnology. 2000; 28:457-459.

24 Lipshutz RJ, Fodor SP, Gingeras TR, Lockhart D. High density synthetic oligonucleotide arrays. Nature Genetics. 1999; 22:20-24.

25 Schena M, Shalon D, R.W. D, Brown PO. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science. 1995; 270:467470.

26 Wodicka L, Dong H, Mittmann M, Ho M, Lockhart D. Genome-wide expression monitoring in Saccharomyces cere-visiae. Nature Biotechnology. 1997; 25:1359-1367.

27 Bowtell DD. Options available-from start to finish-for obtaining expression data by microarray. Nature Genetics. 1999; 21:25-32.

28 Liu P. The path to cardiomyopathy: cycles of injury, repair and maladaptation. Current Opinion in Cardiology. 1996;

29 Taylor LA, Carthy CM, Yang D, Saad K, Wong D, Schreiner G, Stanton LW, McManus BM. Host gene regulation during coxsackievirus B3 infection in mice: assessment by microarrays. Circulation Research. 2000; 87:328-334.

30 Aronow BJ, Toyokawa T, Canning A, Haghighi K, Delling U, Kranias EG, Molkentin JD, Dorn III GW. Divergent transcriptional responses to independent genetic causes ofcardiac hypertrophy. Physiological Genomics. 2001; 6:19-28.

31 Dhanasekaran SM, Barrette TR, Ghosh D, Shah R, Varambally S, Kur-achi K, Pientak KJ, Rubin MA, Chin-naiyan AM. Delineation of prognostic biomarkers in prostate cancer. Nature. 2001; 422:822-826.

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