β-Blockers and Progression of Coronary Atherosclerosis: Pooled Analysis of 4 Intravascular Ultrasonography Trials

To the Editor,

Sipahi and coworkers firstly reported the regressive effect of beta- blockers on the progression of coronary atherosclerosis in patients (1). As the authors discussed, reduced heart rate by beta-blockers is thought to be one of mechanisms explaining such effect of beta-blockers. Sata et al. showed that bone-marrow derived cells including hematopoietic stem cells (HSCs) differentiated into neointimal smooth-muscle cells and endothelial cells and contributed to arterial atherogenesis in experimental animal models (2). In addition, it was demonstrated that decrease of sympathetic nerve tone down-regulated HSCs mobilization from bone marrow to peripheral blood (3). From these results, it is possible that beta-blockers retard the growth of coronary atherosclerosis through diminishing of HSCs mobilization. On the other hand, statin was reported to potently augment endothelial progenitor cells and CD34-positive HSCs in peripheral blood (4). It would be helpful to determine whether anti- atherosclerotic effect of beta-blockers depends on decrease of HSCs mobilization if the authors would give information about the HSCs' number in peripheral blood of eligible patients. References

(1) Sipahi I, Tuzcu EM, Wolski KE, et al. Beta-blockers and progression of coronary atherosclerosis: Pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med 2007;147:10-18

(2) Sata M, Saiura A, Kunisato A, et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002;4:403-409

(3) Katayama Y, Battista M, Kao WM, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 2006;124:407-421.

(4) Dimmeler s, Aicher a, Vasa M, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitorcells via the PI 3-kinase/AKT pathway. J Clin Invest 2001;108:391-397.

Conflict of Interest:

None declared

Why do we not see this proposed mechanism of decreased atherosclerosis progression attributed to beta blockers as in this meta analysis when beta blockers are used in the treatment of hypertension? Prospective studies have shown no decreased incidence of MI and stroke in patients treated with beta blockers verses placebo. How can this mechanism of decreased atherosclerosis progression be active in a post MI patient treated with beta blockers and obviously not in a hypertensive patient treated with beta blocker? I think this contradiction demonstrates a fatal flaw in the conclusion reached by this meta analysis.

Conflict of Interest:

None declared

Analyzing data from four clinical trials, Sipahi et al. show that treatment with beta-adrenergic blocking agents is associated with a reduction of coronary atherosclerotic plaques, as assessed by intravascular ultrasound imaging (1). Among the possible mechanisms responsible for the antiatherosclerotic effect of beta-blockers, Sipahi et al. include an improvement of vascular function related to a reduced mechanical stress on the vessels, consequent to the reduction of heart rate and blood velocity, a reduced affinity of LDL cholesterol to vessel wall proteoglycans and blunting of the catecholamine-induced increase in endothelial permeability to lipoproteins. In recent years, however, it has become evident that inflammation is a major cause of coronary atherosclerosis. Accordingly, markers of inflammation (e.g., C-reactive protein [CRP]) are associated with an increased risk of coronary artery disease and coronary events as well as with progression of coronary atherosclerosis. Moreover, some data also suggest that statin-induced reduction of CRP levels may result in a lower progression of coronary atherosclerosis (2). Interestingly, recent experimental data have suggested that inflammatory reactions can be modulated by the activity of the autonomic nervous system (3). Specifically, vagal activation is associated with a reduction of inflammatory cell reactivity, whereas chronic adrenergic activation may favor inflammation. Accordingly, recent clinical studies in unselected subjects and in patients with various cardiac diseases, have suggested an association between sympatho-vagal imbalance toward adrenergic predominance, as assessed by heart rate variability (HRV), and increased markers of inflammation (4). Importantly, in a small randomized trial involving 21 type-1 diabetic patients with evidence of impaired cardiac autonomic function, we have recently shown that a 3-4 week treatment with atenolol (50 mg/die) was not only associated with an improvement of HRV, but also with a significant reduction of serum CRP levels (5). Thus, we would like to suggest that a further possible mechanism by which beta-blockers may exert a favorable effect on coronary atherosclerosis may consist of an anti-inflammatory action mediated by the improvement of the autonomic sympatho-vagal balance.

References

1. Sipahi I, Tuzcu EM, Wolski KE, Nicholls SJ, Schoenhagen P, Hu B, Balog C, Shishehbor M, Magyar WA, Crowe TD, Kapadia S, Nissen SE. Beta-blockers and progression of coronary atherosclerosis: pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med 2007;147:10-8.

2. Schoenhagen P, Tuzcu EM, Apperson-Hansen C, Wang C, Wolski K, Lin S, Sipahi I, Nicholls SJ, Magyar WA, Loyd A, Churchill T, Crowe T, Nissen SE. Determinants of arterial wall remodeling during lipid-lowering therapy: serial intravascular ultrasound observations from the Reversal of Atherosclerosis with Aggressive Lipid Lowering Therapy (REVERSAL) trial. Circulation 2006 ;113(24):2826-34.

3. Tracey KJ. The inflammatory reflex. Nature 2002;420:853-9.

4. Lanza GA, Sgueglia GA, Cianflone D, Rebuzzi AG, Angeloni G, Sestito A, Infusino F, Crea F, Maseri A; SPAI (Stratificazione Prognostica dell'Angina Instabile) Investigators. Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris. Am J Cardiol 2006;97:1702-6.

5. Lanza GA, Pitocco D, Navarese EP, Sestito A, Sgueglia GA, Manto A, Infusino F, Musella T, Ghirlanda G, Crea F. Association between cardiac autonomic dysfunction and inflammation in type 1 diabetic patients: effect of beta-blockade. Eur Heart J 2007;28:814-20.

Conflict of Interest:

None declared

We thank Dr.Kida for suggesting an additional mechanism for the anti- atherosclerotic effects of beta-blockers. Because information on hematopoietic stem cells was not collected in the trials, we are not able to provide an insight into this mechanism using our dataset.

Conflict of Interest:

None declared

Dr. Dunaway's statement "Prospective studies have shown no decreased incidence of myocardial infarction (MI) and stroke in patients treated with beta blockers verses placebo" is not true. The meta-analyses by Lindholm et al. (1) and Bradley et al. (2) involving more than 20.000 patients with hypertension showed that beta-blockers significantly reduce the incidence of stroke by 19% as compared to placebo (95% confidence interval for relative risk 0.71-0.93). While there was only a statistical trend for reduced incidence of MI in these meta-analyses (relative risk 0.83-1.05), beta-blockers reduce the incidence of MI significantly by 28- 41% in patients with history of MI (3, 4). Recently, it has been recommended that in primary prevention patients beta-blockers should not be preferred over other antihypertensives as a first line agent. However, in our article (5) we have stated ""¦ our analysis involved only patients with established coronary artery disease. Therefore, no conclusion about the effects of ß-blocker use can be drawn for primary prevention (for example, hypertensive patients without coronary artery disease)." in order to limit the implications of our study to secondary prevention patients.

REFERENCES

1. Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005;366(9496):1545-53.

2.Bradley HA, Wiysonge CS, Volmink JA, Mayosi BM, Opie LH. How strong is the evidence for use of beta-blockers as first-line therapy for hypertension? Systematic review and meta-analysis. J Hypertens. 2006;24(11):2131-41.

3.Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med. 1981;304(14):801-7.

4.Julian DG, Prescott RJ, Jackson FS, Szekely P. Controlled trial of sotalol for one year after myocardial infarction. Lancet. 1982;1(8282):1142-7.

5.Sipahi I, Tuzcu EM, Wolski KE, et al. Beta-blockers and progression of coronary atherosclerosis: pooled analysis of 4 intravascular ultrasonography trials. Ann Intern Med. 2007;147(1):10-8.

Conflict of Interest:

Dr. Sipahi has received an educational grant from Pfizer and lecture honoraria from AstraZeneca. Dr. Nissen has received research support from AstraZeneca, Eli Lilly, Pfizer, Takeda, Sankyo, and Sanofi-Aventis. He has also consulted for a number of pharmaceutical companies without financial compensation. All honoraria, consulting fees, or other payments from any for-profit entity are paid directly to charity so that neither income nor any tax deduction is received.