Artículo de Revisión / The uncertainties of statistical "significance"

Statistical inference was introduced by Fisher and Neyman-Pearson more than 90 years ago to define the probability that the difference in results between several groups is due to randomness or is a real, "significant" difference. The usual procedure is to test the probability (P) against the null hypothesis that there is no real difference except because of the inevitable sampling variability. If this probability is high we accept the null hypothesis and infer that there is no real difference, but if P is low (P < 0.05) we reject the null hypothesis and infer that there is, a "significant" difference. However, a large amount of discoveries using this method are not reproducible. Statisticians have defined the deficiencies of the method and warned the researchers that P is a very unreliable measure. Two uncertainties of the "significance" concept are described in this review: a) The inefficacy of a P value to discard the null hypothesis; b) The low probability to reproduce a P value after an exact replication of the experiment. Due to the discredit of "significance" the American Statistical Association recently stated that P values do not provide a good measure of evidence for a hypothesis. Statisticians recommend to never use the word "significant" because it is misleading. Instead, the exact P value should be stated along with the effect size and confidence intervals. Nothing greater than P = 0.001 should be considered as a demonstration that something was discovered. Currently, several alternatives are being studied to replace the classical concepts.

Contractilidad ventricular: fisiología y proyección clínica / Ventricular contractility: physiology and clinical projection

The contractile state of the heart is the result of myocardial contractility, the intrinsic mechanism that regulates the force and the shortening of the ventricle and determines the ventricular ejection volume. However, the ejection volume is also modulated by ventricular preload (diastolic ventricular volume) and afterload (resistance to ejection). Accordingly, a decrease in contractility may be masked by changes in preload or afterload, maintaining a normal ejection volume and delaying the diagnosis of myocardial damage. Thus, it is necessary to develop a non-invasive method to measure contractility in the clinical practice. We review in this article the basic principles of cardiac contraction, the concept of contractility and its measurement with the ventricular pressure-volume loop, an experimental method that also measures most of the hemodynamic variables of the cardiac cycle including preload, afterload, ventricular work, ventricular lusitropy and arterial elastance. This method has been recently validated in cardiac patients and allows to evaluate the evolution of contractility in heart failure in a non invasive way. Although some modifications are still necessary, it will probably have an extensive use in practical cardiology in the near future.

Envejecimiento cardiovascular: [revisión] / Cardiovascular aging: [review]

Aging produces its own cardiovascular changes, mainly remodelling of arteries, heart and the microcirculation. These progressive changes, detected since adolescence, represent a major rísk factor for the development of cardiovascular diseases. Remodelling of arteries produces a thickening of the intima-media with fracture of elastic fibers and their replacement by collagen. These alterations induce an increase of the pulse wave and aortic impedance, with greater resistance to ventrícular ejection, that in turns induces the remodelling of the left ventricle. Ventricular remodelling leads to systolic, diastolic and chronotropic dysfunctions that explain the reduced capacity of old people to increase cardiac output during exercise. These alterations together with oxidative endothelial dysfunction and somatic mitochondrial mutations in the skeletal muscle decrease aerobic capacity, especially in adults aged >70 years. On the other hand, the transmission of an increased pulse wave to microvessels, mainly of the brain and kidneys, damage these organs. There is a search for candidate genes associated to this phenotype, especially those associated with arterial structure. Atpresent no specific treatment is available for cardiovascular aging. Exercise preserves a better aerobic capacity but does not prevent its decline with age. Vasodilator drugs may decrease aortic impedance and perhaps delay remodelling. However there is no clinical evidence available to recommend these drugs in young healthy people. Finally new drugs that modify aortic molecular structure are been investigated.

Participación de Ca2+ en el precondicionamiento del miocardio por ejercicio / Role of Ca2+ in exercise induced myocardial preconditioning

Antecedentes: Episodios breves de ejercicio previos a la oclusión prolongada de una arteria coronaria disminuyen el tamaño del infarto inducido por ésta. Objetivo: Dado que la administración intracoronaria de Ca2+ induce precondicionamiento, y el ejercicio probablemente aumenta el calcio citosólico, decidimos estudiar si el precondicionamiento por ejercicio está mediado por Ca2+. Material y método: Para ello analizamos el efecto del bloqueo de los canales de calcio del sarcolema, con verapamilo, sobre la acción precondicionante del ejercicio. Se midió tamaño del infarto en perros entrenados a correr en cinta sin finasignados aleatoriamente a los siguientes grupos. I: Isquemia inducida por oclusión coronaria durante 1 hora seguida de reperfusión por 4 hrs. E+I: Similar al grupo I, pero los perros hicieron ejercicio antes de inducir la isquemia. V+I: Similar al grupo I, pero se administró verapamilo antes de inducir la isquemia. V+E+I : Similar al grupo E+I, pero se administró verapamilo antes del ejercicio. Para estudiar el posible rol mediador del retículo sarcoplasmático (RS) en los efectos de la isquemia y de verapamilo, se midió la captación y la liberación de calcio en vesículas de RS de la pared del ventrículo izquierdo sometida a isquemia con o sin verapamilo en perros con y sin precondicionamiento con ejercicio. Los resultados, expresados como promedio +/- ES, se analizaron mediante ANOVA seguido del test de Holm para comparaciones múltiples. Resultados: Verapamilo revirtió el efecto protector del ejercicio sobre el tamaño del infarto (E+I: 6,0 +/- 9,4; N=12 vs V+E+I: 27,7+/-9,6; N=15; P<0.05), pero no modificó el efecto protector del ejercicio precondicionante sobre los trastornos de transporte de calcio en el RS inducidos por la isquemia. Conclusiones: Nuestros resultados sugieren que el precondicionamiento inducido por ejercicio está mediado por la entrada de calcio a la célula...

Background: Brief episodes of exercise prior to a prolonged occlusion of a coronary artery substantially reduce infarct size. Aim: Since the intracoronary administration of Ca2+ induces preconditioning and exercise most likely increases cytosolic calcium we put forward the hypothesis that preconditioning by exercise is mediated by calcium. Methods: For this purpose we analyzed the effect of verapamil, a sarcolemmal calcium channel blocker, on preconditioning by exercise. We measured infarct size in dogs randomly assigned to one of the following groups. I: Ischemia induced by coronary occlusion during 1 hour followed by reperfusion during 4 hours. E+I: Similar to group I, but the dogs run on a treadmill prior to ischemia. V+I: Similar to group I but verapamil was administered before the coronary occlusion. V+E+I: Similar to group E+I but verapamil was administered before exercise. SR vesicles from ventricular tissue were isolated from dogs subjected to the same experimental protocols and calcium release and active calcium uptake were measured. Results were expressed as Mean +/- SE and analyzed by ANOVA followed by Holm test for multiple comparisons. Results: Verapamil reverted the protective effect of exercise on infarct size (E+I: 6,0 +/- 9,4; N=12 vs V+E+I: 27,7 +/- 9,6;N=15; P<0.05) however it did not modify the protective effect of exercise on the alterations produced by ischemia on calcium transport in the RS. Conclusions: These results suggest that the preconditioning effect of exercise is mediated by calcium entering the cell through the sarcolemma but not by exercise effects on SR calcium transport.

Efecto de la activación y el bloqueo beta adrenérgico sobre la distensibilidad ventricular del miocardio isquémico / Effects of activation and beta adrenergic block on the ventricular distensibility during miocardial ischemia

La isquemia cardíaca disminuye la distensibilidad y velocidad de relajación ventricular. Debido al uso frecuente de fármacos beta adrenérgicos en pacientes con isquemia cardíaca, nosotros estudiamos el efecto de la activación y del bloqueo beta adrenérgico sobre la distensibilidad y la velocidad de relajación del ventrículo izquierdo del perro mediante las curvas de presión ventricular diastólica-longitud de segmento (PVD-LS) y la constante de tiempo de relajación (T), respectivamente. La isquemia miocárdica desplazó la curva PVD-LS por aumento de PVD sin cambio de LS. La presión ventricular de fin de diástole (PVFD) aumentó de 7 ñ 0.6 a 15.2 ñ 1.4 mm Hg (p <0.001) y T aumentó de 25 ñ 5.5 a 36.7 ñ 7.5 m. s. (p<0.02). Propranolol, en presencia de isquemia, desplazó aun más la curva PVD-LS y aumentó PVFD 22.4 ñ 4.4 mm Hg (p<0.02) y T a 54.7 ñ 9.6 m.s. (p<0.02). Isoproterenol, en cambio, revirtió el efecto de la isquemia; desplazó la curva PVD-LS hacia la posición control y disminuyó PVFD a 6.8 ñ 0.8 mm Hg (p<0.001) y T a 19.8 ñ 4.3 m.s. (p<0.05). Estos resultados demuestran que la disminución de distensibilidad y velocidad de relajación miocárdica producida por la isquemia son exacerbadas o contrarrestadas por el bloqueo o activación beta adrenérgica, respectivamente

Effects of alpha-1 adrenergic blockade on regional flow in the ischemic heart

Aunque la isquemia induce una poderosa vasodilatación coronaria, persiste un tono vasoconstrictor alfa en el miocardio isquémico. Con el fin de determinar si este tono vasoconstrictor es mediado por receptores alfa, nosotros medimos el flujo coronario con microesferas radiactivas en el ventrículo izquierdo normal e isquémico del perro, antes y durante el bloqueo alfa-1 adrenérgico con trimazosin. La isquemia se produjo disminuyendo la presión de perfusión coronaria a 22 ñ 1.4 mmHg. La frecuencia cardíaca y la presión arterial se mantuvieron constantes en cada experimento. Trimazosin aumentó el flujo significativamente en la pared ventricular normal, en mayor proporción en el subepicardio que en el subendocardio produciendo una disminución del cociente del flujo subendocárdico/subepicárdico de 1.38 ñ 0.12 a 1.20 ñ 0.11 (p < 0.05). En la región isquémica Trimazosin no modificó el flujo transmural, pero disminuyó el flujo en el subendocardio y lo aumentó en el subepicardio con la consiguiente disminución del cociente de flujo subendocárdico/subepicárdico de 0.63 ñ 0.09 a 0.38 ñ 0.06 (p < 0.01). Estos resultados muestran que en el miocardio isquémico persiste un tono vasoconstrictor mediado por receptores alfa-1 adrenérgicos, y el bloqueo de éstos deteriora la perfusión del subendocardio