TO: Journal of American Medical Association

JAMA, To the Editor: In the JAMA issue of August 25 1999, Dr. Psaty et.al. and Dr. Temple did an excellent and well fundamented analysis of the concerns vs. possible advantages for the use of surrogate end points in the approval of drugs for cardiovascular risk factors (CRF). [1]

While the optimal solutions are found, We propose the use of the PULSE×MASS INDEX (PMI), beside the chosen end points, as a help for a more complete evaluation of a drug's safety. The PMI reflects overweight, sympathetic stimulation, oxidative metabolic rate, hyperinsulinemia, physical fitness and side effects of drugs like water retention, potent vasodilation, tachycardia, cardiotoxicity, etc. PMI can predict mortality in overweight vs. fitness; correlates closely with the calculations of risk according to the Framingham Heart Study and can explain the results of drugs for CRF beside there primary actions. [2]

Ideal is a PULSE×MASS INDEX 1.0. [Resting Heart Rate (RHR)×Body Mass Index (BMI)1730, or 72×24]. The investigated drugs should improve the treated CRF without increasing, or better reducing PMI.

For instance, Betablockers are well known to reduce mortality [3], and PMI. Similarly, physical fitness reduces mortality and PMI, in longterm studies. [4] In the less fit patients of this Norwegian Study, who have increased RHR (10.1bpm) and BMI (2.7kg/m2), the combined observed mortality is 1.28. The calculated PMI is almost identical: 1.27. [(72+10.1)×(24+2.7)1730]. This highlights the practical use of PMI.

In Type 2 Diabetes, Metformin reduces mortality.[5] If we apply the PMI as a pharmacological principle, we can reason that Metformin improves the Glucose metabolism without promoting hyperinsulinism, weight gain, hypoglycemia or sympathetic (pulse) stimulation, contrary to sulphonylurea or insulin. Like for Betablockers, this fact reinforces the utility of PMI as a marker for the study of cardiovascular or metabolic drugs.

In the daily practice we manage the risk factors to prevent the major end points. The PULSE×MASS INDEX, a widely accessible index of physical signs, can contribute to evaluate the safety and benefits of treatments for cardiovascular risk factors.

Enrique Sánchez-Delgado, MD Heinz Liechti, M.Sc. Laboratorios Solka, Managua, Nicaragua

e-mail: solka@ibw.com.ni

1. Psaty B, et. al. Surrogate End Points, Health Outcomes, and the Drug-Approval Process for the Treatment of Risk Factors for Cardiovascular Disease. JAMA. 1999;282:719-720
2. Sánchez-Delgado E, Liechti H. Lifetime risk of developing coronary heart disease. Lancet. 1999;353:924-25.
3. Gottlieb S, et. al. Effects of Beta-Blockade on Mortality among High-Risk and Low-Risk Patients after Myocardial Infarction. N Engl J Med. 1998;339:489-97
4. Erikssen G, et. al. Changes in physical fitness and changes in mortality. Lancet. 1998;352:759-62
5. U.K. Prospective Diabetes Study Group (UKPDS 34). Effects of Intensive Blood Glucose Control with Metformin on Complications in Overweight Patients with Type II Diabetes. Lancet. 1998;352:854-65

To: New England Journal of Medicine

Dear Sir,

In your issue of October 28 (1), Christopher Cole and colleagues demonstrate that a delayed heart rate recovery immediately after exercise is a predictor of mortality. Clinicians have now several useful, simple and inexpensive tools for diagnose and prognose of cardiovascular risk. Besides the known risk factors (CVSRF): diabetes, hypertension, smoking and hyperlipidaemia, and the calculation of the absolute and relative risk according to the Framingham Heart Study, we propose the use of the pulse×mass index, the chronotropic incompetence (CI) or a failure to achieve at least 85% of a patient's age-predicted maximal heart rate, and the heart rate recovery (HRR), for a more complete clinical evaluation.

Based on our own investigations, a pulse×mass index (PMI ) of 0.7 - 1.0 [Resting Heart Rate (RHR)×Body Mass Index (BMI)1730, or 72×24] would be ideal. The PMI reflects overweight, stress, sympathetic stimulation, oxidative metabolic rate, hyperinsulinemia, physical fitness and side effects of drugs like water retention, potent vasodilation and tachycardia.

The therapeutic interventions should improve the treated CVSRF without increasing, or better reducing PMI, while improving CI and HRR.

We have observed that the pulse×mass index has a highly significant correlation with the

calculation of the absolute cardiovascular risk according to Framingham (FHS) and we invite other investigators to confirm this observations.

Moreover we have also observed, that if there is a relation of three to one between pulse and BMI (e.g., 72 to 24) and this relation was maintained proportional as BMI increases, then the enlarged mortality becomes predictable -e.g., for a BMI of 33 and a theoretically corresponding pulse of 99 (1/3), the pulse×mass index (33×99÷1730) is 1·9 or almost two-fold, corresponding with the known doubling of mortality with this BMI. The same tendency is found for every increase of BMI and pulse. (2)

Analyzing the data of other recent studies like the ones from Calle et al. in USA (3), Bender et al. in Germany (4), and Erikssen et al. in Norway (5), you can observe that in the cases where both BMI and RHR are given (5), the real calculated pulse×mass index corresponds very closely to the real, empirically observed mortality. In the other cases where only BMI is given, if you assume a theoretical relation of three to one between RHR and BMI, you can also observe that the calculated theoretical PMI, has also an overall very close correlation with the real mortality in the different subgroups.

Enrique Sánchez-Delgado, MD, Heinz Liechti, M.Sc.; Laboratorios Solka, Managua, Nicaragua

e-mail: solka@ibw.com.ni

1. Cole C R, et al., Heart-Rate Recovery Immediately after Exercise as a Predictor of Mortality. N Engl J Med 1999; 341:1351-7
2. Stevens J, et al., The effects of age on the association between body-mass index and mortality. N Engl J Med 1998; 338:1-7
3. Calle E E, et al., Body-mass index and mortality in a Prospective Cohorte of U.S. Adults. N Engl J Med 1999; 341:1097-105
4. Bender R, et al., Effect of Age on Excess Mortality in Obesity. JAMA. 1999; 281:1498-1504
5. Erikssen G, et. al., Changes in physical fitness and changes in mortality. Lancet. 1998;352:759-62

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