Student survey after ten years of continuous blended teaching of echocardiography.

OBJECTIVE: To analyse the impact of 10 years of blended echocardiography teaching. METHODS AND RESULTS: A questionnaire was emailed to all medical doctors who graduated from the blended learning diploma in echocardiography developed by the University of Chile and taught by a team from Chile and Spain. One hundred and forty of the 210 students who graduated from the program between 2011 and 2020 completed the questionnaire: 53.57% were anaesthesiologists, and 26.42% were intensivists. More than 85% of respondents indicated that the online teaching met their expectations, and 70.2% indicated that the hands-on practice fulfilled the stated objectives. In a retrospective analysis using self-reported data, graduates reported that their use of transthoracic and transoesophageal echocardiography has increased from 24.29% to 40.71% and from 13.57% to 27.86%, repectively, after the programme compared to before the programme. They used echocardiography mainly in the perioperative period (56.7%) and during intensive care (32.3%), while only 11% of respondents used it in emergency care units. Nearly all (92.4%) respondents reported that the skills learned was very useful in their professional practice. CONCLUSIONS: Ten years after its launch, the blended learning diploma in echocardiography was well rated by graduate specialists, and is associated with a significant increase in the use of echocardiography in the perioperative period and during intensive care. The main challenges are to establish a longer period of practice and achieve greater implantation in emergency medicine.

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.

[The uncertainties of statistical "significance"]. / Artículo de Revisión.

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.

[Ventricular contractility: Physiology and clinical projection]. / Contractilidad ventricular: Fisiología y proyección clínica.

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.

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.

Exercise preconditioning of myocardial infarct size in dogs is triggered by calcium.

We showed that exercise induces early and late myocardial preconditioning in dogs and that these effects are mediated through nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase activation. As the intracoronary administration of calcium induces preconditioning and exercise enhances the calcium inflow to the cell, we studied if this effect of exercise triggers exercise preconditioning independently of its hemodynamic effects. We analyzed in 81 dogs the effect of blocking sarcolemmal L-type Ca channels with a low dose of verapamil on early and late preconditioning by exercise, and in other 50 dogs, we studied the effect of verapamil on NADPH oxidase activation in early exercise preconditioning. Exercise reduced myocardial infarct size by 76% and 52% (early and late windows respectively; P < 0.001 both), and these effects were abolished by a single low dose of verapamil given before exercise. This dose of verapamil did not modify the effect of exercise on metabolic and hemodynamic parameters. In addition, verapamil blocked the activation of NADPH oxidase during early preconditioning. The protective effect of exercise preconditioning on myocardial infarct size is triggered, at least in part, by calcium inflow increase to the cell during exercise and, during the early window, is mediated by NADPH oxidase activation.

Preconditioning tachycardia decreases the activity of the mitochondrial permeability transition pore in the dog heart.

Cardioprotection by preconditioning is a central issue of current research on heart function. Several reports indicate that preventing the assembly and opening of the mitochondrial permeability transition pore (mPTP) protects the heart against ischemia-reperfusion injury. We have previously reported that brief episodes of tachycardia decrease the infarct size produced by subsequent prolonged occlusion of a coronary artery, indicating that controlled tachycardia is an effective preconditioning manoeuvre. The effects of preconditioning tachycardia on mPTP activity have not been reported. Therefore, in this work we investigated if preconditioning tachycardia protects against calcium-induced mitochondrial swelling, a measure of mPTP activity. We found that tachycardia decreased by 2.5-fold the rate of mitochondrial calcium-induced swelling, a factor that presumably contributes to the cardioprotective effects of tachycardia. The oxidative status of the cell increased after tachycardia, as evidenced by the decrease in the cellular and mitochondrial GSH/GSSG ratio. We also observed increased S-glutathionylation of cyclophilin-D, an essential mPTP component, after tachycardia. This reversible redox modification of cyclophilin-D may account, al least in part, for the decreased mPTP activity produced by preconditioning tachycardia.

Late cardiac preconditioning by exercise in dogs is mediated by mitochondrial potassium channels.

We previously showed that exercise induces myocardial preconditioning in dogs and that early preconditioning is mediated through mitochondrial adenosine triphosphate-sensitive potassium channels. We decided to study if late preconditioning by exercise is also mediated through these channels. Forty-eight dogs, surgically instrumented and trained to run daily, were randomly assigned to 4 groups: (1) Nonpreconditioned dogs: under anesthesia, the coronary artery was occluded during 1 hour and then reperfused during 4.5 hours. (2) Late preconditioned dogs: similar to group 1, but the dogs run on the treadmill for 5 periods of 5 minutes each, 24 hours before the coronary occlusion. (3) Late preconditioned dogs plus 5-hydroxydecanoate (5HD): similar to group 2, but 5HD was administered before the coronary occlusion. (4) Nonpreconditioned dogs plus 5HD: similar to group 1, but 5HD was administered before the coronary occlusion. Infarct size (percent of the risk region) decreased by effect of exercise by 56% (P < 0.05), and this effect was abolished with 5HD. 5HD by itself did not modify infarct size. Exercise did not induce myocardial ischemia, and the hemodynamics during ischemia-reperfusion period did not differ among groups. These effects were independent of changes in collateral flow to the ischemic region. We concluded that late cardiac preconditioning by exercise is mediated through mitochondrial adenosine triphosphate-sensitive potassium channels.

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.

[Cardiovascular aging]. / Envejecimiento cardiovascular.

Aging produces its own cardiovascular changes, mainly remodelling of arteries, heart and the microcirculation. These progressive changes, detected since adolescence, represent a major risk 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 ventricular 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. At present 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.

Tachycardia increases NADPH oxidase activity and RyR2 S-glutathionylation in ventricular muscle.

We have shown previously that electrically induced tachycardia effectively produces myocardial preconditioning. Among other effects, tachycardia increases calcium release rates in microsomal fractions enriched in sarcoplasmic reticulum (SR) isolated from dog cardiac ventricular muscle. Here, we report that preconditioning tachycardia increased twofold the NADPH oxidase activity of isolated SR-enriched microsomal fractions, measured as NADPH-dependent generation of superoxide anion and hydrogen peroxide. Tachycardia also augmented the association of rac1 and the NADPH oxidase cytosolic subunit p47(phox) to the microsomal fraction, without modifying the content of the membrane integral subunit gp91(phox). Microsomes from control animals displayed endogenous S-glutathionylation of cardiac ryanodine receptors (RyR2); in microsomal fractions isolated after tachycardia RyR2 S-glutathionylation levels were 1.7-fold higher than in controls. Parallel in vitro experiments showed that NADPH produced a transient increase in calcium release rates and enhanced 1.6-fold RyR2 S-glutathionylation in control microsomes but had marginal or no effects on microsomes isolated after tachycardia. Catalase plus superoxide dismutase, and the NADPH oxidase inhibitors apocynin and diphenyleneiodonium prevented the in vitro stimulation of calcium release rates and RyR2 S-glutathionylation induced by NADPH, suggesting NADPH oxidase involvement. Conversely, addition of reducing agents to vesicles incubated with NADPH markedly inhibited calcium release and prevented RyR2 S-glutathionylation. We propose that tachycardia stimulates NADPH oxidase activity, which by enhancing RyR2 redox modifications such as S-glutathionylation, would contribute to sustain faster calcium release rates during conditions of increased cardiac activity. This response may be an important component of tachycardia-induced preconditioning.

Effect of tachycardia on myocardial sarcoplasmic reticulum and Ca2+ dynamics: a mechanism for preconditioning?

We have previously demonstrated that brief episodes of tachycardia prior to a prolonged occlusion of a coronary artery, followed by reperfusion, substantially reduce the infarct size. Adenosine receptors and mitochondrial ATP-dependent K(+) channels mediate this effect. Since preconditioning can be induced or reverted by maneuvers that increase or decrease [Ca(2+)](i), respectively, and tachycardia increases [Ca(2+)](i), we studied the participation of sarcoplasmic reticulum and Ca(2+) in the preconditioning effect of tachycardia. We measured the effect of ischemia and tachycardia on Ca(2+) uptake and release by sarcoplasmic reticulum vesicles isolated from left ventricular canine myocardium. Myocardial ischemia increased Ca(2+)-release rate constants and decreased both the initial rates of Ca(2+) uptake and [(3)H]-ryanodine binding by sarcoplasmic reticulum. In addition, ischemia induced a decrease in the pentameric form of phospholamban and in the content of ryanodine-receptor Ca(2+)-release channel protein. All these effects were reverted in hearts preconditioned with tachycardia. Furthermore, tachycardia by itself increased [(3)H]-ryanodine binding, Ca(2+)-release rate constants and the protein levels of ryanodine-receptor Ca(2+)-release channels and the ATP-dependent Ca(2+) pump. These results suggest that tachycardia preserves the integrity of the sarcoplasmic reticulum preventing the excess of release and the decrease of uptake of Ca(2+) produced by ischemia, thereby avoiding cytosolic Ca(2+) overload. This sarcoplasmic reticulum protection could partly explain the preconditioning effect of tachycardia.

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 (AU)

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