Myocardial oxygen consumption during exercise in the presence of left ventricular hypertrophy secondary to supravalvular aortic stenosis

AbstractThe hypothesis that abnormally increased myocardial oxygen demands may contribute to increased vulnerability to ischemia during exercise in the chronically pressureoverloaded hypertrophied left ventricle was tested. Myocardial oxygen consumption was measured during a five stage graded treadmill exercise protocol in eight normal dogs and nine adult dogs in which a 90% increase in left ventricular mass was produced by banding the ascending aorta at 8 weeks of age. Heart rate increased progressively during exercise in both groups of dogs, but was significantly faster than normal in the group with aortic banding. Coronary blood flow increased progressively with exercise in both groups, but was significantly greater than normal in dogs with aortic banding during each exercise stage. Coronary sinus oxygen tension decreased significantly and similarly during exercise in normal and hypertrophied hearts.In dogs with hypertrophy, oxygen consumption per gram of myocardium averaged 52% greater than normal during exercise. This excess myocardial oxygen consumption in dogs with aortic banding resulted from an abnormally large increase in oxygen consumption per beat during exercise and from the faster heart rate in this group of dogs. Measurements of myocardial blood flow with microspheres demonstrated a lower subendocardial/subepicardial blood flow ratio in dogs with hypertrophy; this ratio decreased significantly during exercise in dogs with hypertrophy, but not in normal dogs.These data are consistent with the hypothesis that increased vulnerability to ischemia in the pressure-overloaded hypertrophied left ventricle is the result of both increased myocardial oxygen demands during exercise and abnormalities of myocardial perfusion

Bioenergetic Abnormalities Associated with Severe Left Ventricular Hypertrophy

Abstract Transmurally localized 31P-nuclear magnetic resonance spectroscopy (NMR) was used to study the effect of severe pressure overload left ventricular hypertrophy (LVH) on myocardial high energy phosphate content. Studies were performed on 8 normal dogs and 12 dogs with severe left ventricular hypertrophy produced by banding the ascending aorta at 8 wk of age. Spatially localized 31P-NMR spectroscopy provided measurements of the transmural distribution of myocardial ATP, phosphocreatine (CP), and inorganic phosphate (Pi); spectra were calibrated from measurements of ATP content in myocardial biopsies using HPLC. Blood flow was measured with microspheres. In hypertrophied hearts during basal conditions, ATP was decreased by 42%, CP by 58%, and the CP/ATP ratio by 32% in comparison with normal. Increasing myocardial blood flow with adenosine did not correct these abnormalities, indicating that they were not the result of persistent hypoperfusion. Atrial pacing at 200 and 240 beats per min caused no change in high energy phosphate content in normal hearts but resulted in further CP depletion with Pi accumulation in the inner left ventricular layers of the hypertrophied hearts. These changes were correlated with redistribution of blood flow away from the subendocardium in LVH hearts. These findings demonstrate that high energy phosphate levels and the CP/ATP ratio are significantly decreased in severe LVH. These abnormalities are proportional to the degree of hypertrophy but are not the result of persistent abnormalities of myocardial perfusion. In contrast, depletion of CP and accumulation of Pi during tachycardia in LVH are closely related to the pacing-induced perfusion abnormalities and likely reflect subendocardial ischemia. (J. Clin. Invest. 1993. 92:993-100

Clinical Significance of Serum Biomarkers in Pediatric Solid Mediastinal and Abdominal Tumors

Childhood cancer is the leading cause of death by disease among U.S. children between infancy and age 15. Despite successes in treating solid tumors such as Wilms tumor, disappointments in the outcomes of high-risk solid tumors like neuroblastoma have precipitated efforts towards the early and accurate detection of these malignancies. This review summarizes available solid tumor serum biomarkers with a special focus on mediastinal and abdominal cancers in children

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Measurement of the very rare K+→π+ννˉK^+ \to \pi^+ \nu \bar\nu decay

The decay K+→π+νν¯ , with a very precisely predicted branching ratio of less than 10−10 , is among the best processes to reveal indirect effects of new physics. The NA62 experiment at CERN SPS is designed to study the K+→π+νν¯ decay and to measure its branching ratio using a decay-in-flight technique. NA62 took data in 2016, 2017 and 2018, reaching the sensitivity of the Standard Model for the K+→π+νν¯ decay by the analysis of the 2016 and 2017 data, and providing the most precise measurement of the branching ratio to date by the analysis of the 2018 data. This measurement is also used to set limits on BR(K+→π+X ), where X is a scalar or pseudo-scalar particle. The final result of the BR(K+→π+νν¯ ) measurement and its interpretation in terms of the K+→π+X decay from the analysis of the full 2016-2018 data set is presented, and future plans and prospects are reviewed

Regulation of Coronary Blood Flow During Exercise

Exercise is the most important physiological stimulus for increased myocardial oxygen demand. The requirement of exercising muscle for increased blood flow necessitates an increase in cardiac output that results in increases in the three main determinants of myocardial oxygen demand: heart rate, myocardial contractility, and ventricular work. The approximately sixfold increase in oxygen demands of the left ventricle during heavy exercise is met principally by augmenting coronary blood flow (similar to 5-fold), as hemoglobin concentration and oxygen extraction ( which is already 70-80% at rest) increase only modestly in most species. In contrast, in the right ventricle, oxygen extraction is lower at rest and increases substantially during exercise, similar to skeletal muscle, suggesting fundamental differences in blood flow regulation between these two cardiac chambers. The increase in heart rate also increases the relative time spent in systole, thereby increasing the net extravascular compressive forces acting on the microvasculature within the wall of the left ventricle, in particular in its subendocardial layers. Hence, appropriate adjustment of coronary vascular resistance is critical for the cardiac response to exercise. Coronary resistance vessel tone results from the culmination of myriad vasodilator and vasoconstrictors influences, including neurohormones and endothelial and myocardial factors. Unraveling of the integrative mechanisms controlling coronary vasodilation in response to exercise has been difficult, in part due to the redundancies in coronary vasomotor control and differences between animal species. Exercise training is associated with adaptations in the coronary microvasculature including increased arteriolar densities and/or diameters, which provide a morphometric basis for the observed increase in peak coronary blood flow rates in exercise-trained animals. In larger animals trained by treadmill exercise, the formation of new capillaries maintains capillary density at a level commensurate with the degree of exercise-induced physiological myocardial hypertrophy. Nevertheless, training alters the distribution of coronary vascular resistance so that more capillaries are recruited, resulting in an increase in the permeability-surface area product without a change in capillary numerical density. Maintenance of alpha- and beta-adrenergic tone in the presence of lower circulating catecholamine levels appears to be due to increased receptor responsiveness to adrenergic stimulation. Exercise training also alters local control of coronary resistance vessels. Thus arterioles exhibit increased myogenic tone, likely due to a calcium-dependent protein kinase C signaling-mediated alteration in voltage-gated calcium channel activity in response to stretch. Conversely, training augments endothelium-dependent vasodilation throughout the coronary microcirculation. This enhanced responsiveness appears to result principally from an increased expression of nitric oxide ( NO) synthase. Finally, physical conditioning decreases extravascular compressive forces at rest and at comparable levels of exercise, mainly because of a decrease in heart rate. Impedance to coronary inflow due to an epicardial coronary artery stenosis results in marked redistribution of myocardial blood flow during exercise away from the subendocardium towards the subepicardium. However, in contrast to the traditional view that myocardial ischemia causes maximal microvascular dilation, more recent studies have shown that the coronary microvessels retain some degree of asodilator reserve during exercise-induced ischemia and remain responsive to vasoconstrictor stimuli. These observations have required reassessment of the principal sites of resistance to blood flow in the microcirculation. A significant fraction of resistance is located in small arteries that are outside the metabolic control of the myocardium but are sensitive to shear and nitrovasodilators. The coronary collateral system embodies a dynamic network of interarterial vessels that can undergo both long- and short-term adjustments that can modulate blood flow to the dependent myocardium. Long-term adjustments including recruitment and growth of collateral vessels in response to arterial occlusion are time dependent and determine the maximum blood flow rates available to the collateral-dependent vascular bed during exercise. Rapid short-term adjustments result from active vasomotor activity of the collateral vessels. Mature coronary collateral vessels are responsive to vasodilators such as nitroglycerin and atrial natriuretic peptide, and to vasoconstrictors such as vasopressin, angiotensin II, and the platelet products serotonin and thromboxane A(2). During exercise, beta-adrenergic activity and endothelium-derived NO and prostanoids exert vasodilator influences on coronary collateral vessels. Importantly, alterations in collateral vasomotor tone, e. g., by exogenous vasopressin, inhibition of endogenous NO or prostanoid production, or increasing local adenosine production can modify collateral conductance, thereby influencing the blood supply to the dependent myocardium. In addition, vasomotor activity in the resistance vessels of the collateral perfused vascular bed can influence the volume and distribution of blood flow within the collateral zone. Finally, there is evidence that vasomotor control of resistance vessels in the normally perfused regions of collateralized hearts is altered, indicating that the vascular adaptations in hearts with a flow-limiting coronary obstruction occur at a global as well as a regional level. Exercise training does not stimulate growth of coronary collateral vessels in the normal heart. However, if exercise produces ischemia, which would be absent or minimal under resting conditions, there is evidence that collateral growth can be enhanced. In addition to ischemia, the pressure gradient between vascular beds, which is a determinant of the flow rate and therefore the shear stress on the collateral vessel endothelium, may also be important in stimulating growth of collateral vessels