CARDIOKIN1: Computational Assessment of Myocardial Metabolic Capability in Healthy Controls and Patients With Valve Diseases.

BACKGROUND: Many heart diseases can result in reduced pumping capacity of the heart muscle. A mismatch between ATP demand and ATP production of cardiomyocytes is one of the possible causes. Assessment of the relation between myocardial ATP production (MVATP) and cardiac workload is important for better understanding disease development and choice of nutritional or pharmacologic treatment strategies. Because there is no method for measuring MVATP in vivo, the use of physiology-based metabolic models in conjunction with protein abundance data is an attractive approach. METHOD: We developed a comprehensive kinetic model of cardiac energy metabolism (CARDIOKIN1) that recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts, and in vivo studies with humans. We used the model to assess the energy status of the left ventricle of healthy participants and patients with aortic stenosis and mitral valve insufficiency. Maximal enzyme activities were individually scaled by means of protein abundances in left ventricle tissue samples. The energy status of the left ventricle was quantified by the ATP consumption at rest (MVATP[rest]), at maximal workload (MVATP[max]), and by the myocardial ATP production reserve, representing the span between MVATP(rest) and MVATP(max). RESULTS: Compared with controls, in both groups of patients, MVATP(rest) was increased and MVATP(max) was decreased, resulting in a decreased myocardial ATP production reserve, although all patients had preserved ejection fraction. The variance of the energetic status was high, ranging from decreased to normal values. In both patient groups, the energetic status was tightly associated with mechanic energy demand. A decrease of MVATP(max) was associated with a decrease of the cardiac output, indicating that cardiac functionality and energetic performance of the ventricle are closely coupled. CONCLUSIONS: Our analysis suggests that the ATP-producing capacity of the left ventricle of patients with valvular dysfunction is generally diminished and correlates positively with mechanical energy demand and cardiac output. However, large differences exist in the energetic state of the myocardium even in patients with similar clinical or image-based markers of hypertrophy and pump function. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03172338 and NCT04068740.

Clinical Applications of Natriuretic Peptides in Assessment of Valvular Heart Disease.

Biomarkers such as natriuretic peptides (NPs) have evolving clinical utility beyond the scope of heart failure. The role of NPs in the management of valvular heart disease is a growing area of investigation. NPs have much potential in the assessment of asymptomatic patients with hemodynamically significant valvular lesions who have traditionally been excluded from consideration of surgical intervention. NPs also have a role in the risk stratification of these patients as well as in routine surveillance and monitoring. Together with echocardiographic data and functional status, NPs are being incorporated into the management of valvular heart disease. In this review we examine the evidence for the role of natriuretic peptides in assessment of VHD.

Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy.

INTRODUCTION: The rhythmic opening and tightly closing of cardiac valve leaflets are cardiac cyclic events imposing to blood a unidirectional course along the vascular tree. Drugs with 5-HT2B agonism properties can seriously compromise this biological function critical for hemodynamic efficiency as their intrinsic pro-fibrotic effects can, with time, make valvular coaptation blood regurgitant. TOPICS COVERED: Cardiac valve anatomy, physiology and pathology as well as 5-HT2B receptor properties (coupling, effects mediated, biased agonism) are briefly exposed. Approaches to unveil 5-HT2B receptor liability of drug candidates are detailed. In silico computational models can rapidly probe molecules for chemical signatures associated with 5-HT2B receptor affinity. In vitro radioligand competition assays allow quantifying receptor binding capacity (Ki, IC50), the pharmacological nature (agonism, antagonism) of which can be ascertained from cytosolic second messenger (inositol phosphates, Ca(++), MAPK2) changes. Potencies calculated from the latter data may exhibit variability as they are dependent upon the readout measured and the experimental conditions (e.g., receptor density level of cell material expressing human 5-HT2B receptors). The in vivo valvulopathy effects of 5-HT2B receptor agonists can be assessed by echocardiographic measurements and valve histology in rats chronically treated with the candidate drug. Finally, safety margins derived from from nonclinical and clinical data are evaluated in terms of the readout, usefulness and scientific reliability. DISCUSSION: The Safety Pharmacology toolbox for detecting possible 5-HT2B receptor agonism liabilities of candidate drugs requires meticulous optimization and validation of all its (in silico, in vitro and in vivo) components to perfect its human predictability power. In particular, since 5-HT2B receptor agonism is biased in nature, the most predictive readout(s) of valvular liability should be identified and prioritized in keeping with best scientific practice teachings.

Assessment of right ventricular oxidative metabolism by positron emission tomography with C-11 acetate in aortic valve disease.

Evaluation of right ventricular (RV) oxidative metabolism is limited by the inability to easily determine oxygen extraction by the RV myocardium and the complex morphology of this ventricle. Because left ventricular C-11 clearance rate constants closely correlate with myocardial oxygen consumption, it was postulated that C-11 clearance rate constants for the RV free wall should also reflect its oxygen consumption. Therefore, RV C-11 clearance rate constants were compared with RV loading in 21 patients with aortic valve disease to assess the possible use of this technique for noninvasive evaluation of RV oxidative metabolism. RV free wall C-11 clearance rate constants correlated with the product of systolic pulmonary artery pressure and heart rate for all patients (r = 0.65, p = 0.002), but the relation was stronger if 2 patients with overt RV dysfunction were excluded (r = 0.83, p = 0.001). On the basis of mean pulmonary artery pressures, patients were stratified into subgroups with normal (group I, n = 8) and elevated (group II, n = 13) pulmonary pressures and were compared with 10 normal control subjects. RV C-11 clearance rate constants were significantly higher in group II than in group I and in normal control subjects (p less than 0.05). These data suggest that RV C-11 acetate clearance rate constants can provide noninvasive evaluation of RV oxidative metabolism. This technique may allow serial assessment of RV performance in various cardiac and pulmonary diseases, and particularly of changes associated with therapeutic interventions.

[Pre- and postoperative nutritional assessment of cardiac cachexia].

Pre- and postoperative nutritional states were studied in fifty patients undergoing cardiac surgery. Seven of them were cardiac cachectic patients. There was no hospital death except one patient with cardiac cachexia. Preoperative measurements showed decreased %standard body weight (80.7%), %standard AMC (86.1%), and %standard TSF (61.5%) in cachectic patients. Resting energy expenditure (REE) and circulating blood volume were significantly higher in cachectic patients throughout the pre- and postoperative periods, and a significant correlations were admitted between them (p less than 0.05). REE increased to 33.6 kcal/kg/day 1 week after operation. Serum proteins, including rapid turnover proteins (RTP), when expressed in g/dl or mg/dl, did not show any difference between two groups. However by correction with circulating plasma volume and body weight (mg/kg), cardiac cachectic patients had significantly higher protein contents preoperatively and seventh post-operative day (p less than 0.05). There was no difference in urinary excretion of 3-methylhistidine between two groups throughout the study period, but urinary excretion of urea was higher in 1st and 3rd postoperative days in non cachectic patients. Serum cortisol and urinary excretion of vanillymandelic acid were higher, and serum insulin level tended to be lower in cachectic patients postoperatively. These results indicate that, in cardiac cachexia, increased blood volume and hypermetabolic state cause higher energy expenditure, resulting in weight loss and chronic heart failure.

[Assessment of the relation between bone mineral metabolism and mitral annular calcification or aortic valve sclerosis--the relation between mitral annular calcification and postmenopausal osteoporosis in elderly patients].

We assessed the effect of bone mineral metabolism on mitral annular calcification (MAC) and aortic valve sclerosis or calcification (AVS) in elderly patients. Both MAC and AVS were derived by 2-D echocardiography, and bone mineral content (BMC) of vertebral bodies was obtained by quantitative computed tomography using a calibrated phantom system. The calcium (Ca), phosphate (P), parathyroid hormone (PTH-c), calcitonin (CLT), vitamin-D (25-(OH)D) and osteocalcin (OC) in serum were examined within a period of one month. The 265 patients were classified into three groups according to the echocardiographic findings. The control (CNT) group consisted of 122 patients (44 males, 78 females) without MAC or AVS, the MAC group consisted of 64 patients (16 males, 48 females) with MAC, and the AVS group consisted of 79 patients (31 males, 48 females) with AVS. 1) The incidences of MAC and AVS in both males and females were found to increase in proportion to aging. 2) The incidence of MAC in females (28%) was higher than that of males (18%). 3) AVS in males (34%) was more frequent than in females (27%). 4) In females of the eighth and ninth decade of age, BMC in the MAC group was significantly less than in the CNT group (eighth p less than 0.05, ninth p less than 0.01), but no difference was seen in males. 5) In both males and females, BMC in the AVS group was not significantly different from that in the CNT group. 6) In all subjects of the eighth and ninth decades, the serum levels of Ca and P were within normal ranges. PTH-c, CLT and 25-(OH)D showed subnormal or lower normal values, while OC showed supernormal or upper normal values. However, the was no difference among the three groups. These results suggest that MAC may be attributed to ectopic calcium deposit, probably related to decalcification from bone in postmenopausal osteoporosis. However, in the present study, there was no relation between the incidence of MAC and humoral factors of calcium metabolism. On the other hand, AVS may be caused by other factors, mainly prolonged and sustained pressure or stress loading.