Evolution of Quality of Life in Chronic Kidney Disease Stage 4-5 Patients Transitioning to Dialysis and Transplantation.

INTRODUCTION: Chronic kidney disease (CKD) has a profound effect on patients' health-related quality of life (QoL). Longitudinal studies on QoL in CKD are scarce and have explored selected patients on renal replacement therapy (RRT). We studied the evolution of QoL in patients with advanced CKD transitioning to dialysis and transplantation in a prospective follow-up study. METHODS: A total of 100 participants of the Chronic Arterial Disease, Quality of Life, and Mortality in Chronic Kidney Injury (CADKID) study were enrolled in the study. Kidney Disease Quality of Life Short Form, biochemistry, and echocardiography were obtained at baseline and after a median interval of 33 (range 12-85) months. RESULTS: At the time of the follow-up QoL assessment, 32 patients were not receiving RRT, 30 were on hemodialysis (HD), 19 on peritoneal dialysis (PD), and 19 had received a kidney transplant. Among kidney transplant recipients (KTRs), "Burden of Kidney Disease" and "General Health" domains improved compared to patients who initiated HD (p < 0.0001 and p = 0.007, respectively), PD (p = 0.0005 and p = 0.03, respectively), or remained in predialysis care (p = 0.009 and p = 0.003, respectively) while "Effects of Kidney Disease" improved compared to those who started HD (p = 0.004) or PD (p = 0.002). The change in Short Form-36 (SF-36) Physical Component Summary was not different between patients on different treatment modalities. Higher plasma albumin and cholesterol levels were associated with improved QoL in "Symptoms/Problems" (r = 0.28, p = 0.005, and r = 0.30, p = 0.004, respectively) and "Effects of Kidney Disease" (r = 0.27, p = 0.008, and r = 0.24, p = 0.03, respectively). CONCLUSION: QoL improved in KTRs in kidney disease-specific domains compared to patients initiating dialysis or those without RRT. Plasma albumin and lipids were associated with QoL over time.

Maximal Exercise Capacity in Chronic Kidney Disease Stage 4-5 Patients Transitioning to Renal Replacement Therapy or Continuing Conservative Care: A Longitudinal Follow-Up Study.

INTRODUCTION: Chronic kidney disease (CKD) is associated with impaired maximal exercise capacity (MEC). However, data are scarce on the development of MEC in CKD stage 4-5 patients transitioning to renal replacement therapy (RRT). METHODS: We explored the change in MEC measured in watts (Wlast4) with 2 consecutive maximal bicycle stress ergometry tests in 122 CKD stage 4-5 patients transitioning to dialysis and transplantation in an observational follow-up study. RESULTS: Mean age was 58.9 ± 13.9 years and 43 (35.2%) were female. Mean time between the baseline and follow-up ergometry tests was 1,012 ± 327 days and 29 (23.8%) patients had not initiated RRT, 50 (41.0%) were undergoing dialysis, and 43 (35.2%) had received a kidney transplant at the time of the follow-up ergometry test. The mean Wlast4 was 91 ± 37 W and 84 ± 37 W for the baseline and follow-up ergometry tests, respectively (p < 0.001). The mean Wlast4 declined between the baseline and follow-up ergometry tests in patients not requiring RRT (p = 0.001) and transplant recipients (p = 0.005), but not in dialysis patients (p = 0.478). There were no differences in the ratio of Wlast4 of the follow-up to the baseline ergometry tests (∆Wlast4) between patients on different treatment modalities at the time of the follow-up test (p = 0.097). Mean capillary blood bicarbonate was significantly associated with ∆Wlast4 after adjusting for age and treatment modality in the multivariate linear regression analysis (ß = 0.226, p = 0.012). CONCLUSION: MEC declined or remained poor in advanced CKD patients transitioning to RRT or continuing conservative care in this observational study. Mean capillary blood bicarbonate was independently associated with the development of MEC.

Association of maximal stress ergometry performance with troponin T and abdominal aortic calcification score in advanced chronic kidney disease.

BACKGROUND: Cardiac biomarkers Troponin T (TnT) and N-terminal pro-B-type natriuretic peptide (proBNP) and abdominal aortic calcification score (AAC) are associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). The effects of cardiac biomarkers and AAC on maximal exercise capacity in CKD are unknown and were studied. METHODS: One hundred seventy-four CKD 4-5 patients not on maintenance dialysis underwent maximal bicycle ergometry stress testing, lateral lumbar radiograph to study AAC, echocardiography and biochemical assessments. RESULTS: The subjects with proportional maximal ergometry workload (WMAX%) less than 50% of the expected values had higher TnT, proBNP, AAC, left ventricular end-diastolic diameter, left ventricular mass index, E/e' and pulse pressure, and lower global longitudinal strain compared to the better performing patients. TnT (ß = - 0.09, p = 0.02), AAC (ß = - 1.67, p < 0.0001) and diabetes (ß = - 11.7, p < 0.0001) remained significantly associated with WMAX% in the multivariable model. Maximal ergometry workload (in Watts) was similarly associated with TnT and AAC in addition to age, male gender, hemoglobin and diastolic blood pressure in a respective multivariate model. AAC and TnT showed fair predictive power for WMAX% less than 50% of the expected value with AUCs of 0.70 and 0.75, respectively. CONCLUSIONS: TnT and AAC are independently associated with maximal ergometry stress test workload in patients with advanced CKD. TRIAL REGISTRATION: http://www.ClinicalTrials.gov NCT04223726.

Elevated Troponin T and Enlarged Left Atrium Are Associated with the Incidence of Atrial Fibrillation in Patients with CKD Stage 4-5.

INTRODUCTION: Atrial fibrillation (AF) and CKD are commonly coexisting conditions. However, data on epidemiology of AF in patients with CKD stage 4-5 is scarce. METHODS: We prospectively enrolled 210 consecutive non-dialysis patients with CKD stage 4-5 between 2013 and 2017. Follow-up data on AF incidence along with medical history, laboratory tests, and echocardiography at baseline were gathered. RESULTS: At baseline, mean age was 62 years, estimated glomerular filtration rate 12.8 mL/min, and 73/210 (34.8%) participants were female. Altogether, 41/210 (19.5%) patients had a previous diagnosis of AF. After median follow-up of 46 [IQR 27] months, new-onset AF occurred in 33/169 (19.5%) patients (69.9 events/1,000 person-years). In the Cox proportional hazard model, age >60 years (HR 4.27, CI 95% 1.57-11.64, p < 0.01), elevated troponin T (TnT) >50 ng/L (HR 3.61, CI 95% 1.55-8.37, p < 0.01), and left atrial volume index (LAVI) >30 mL/m2 (HR 4.82, CI 95% 1.11-21.00, p = 0.04) were independently associated with the incidence of new-onset AF. CONCLUSION: The prevalence and incidence of AF was markedly high in this prospective study on patients with CKD stage 4-5. Elevated TnT and increased LAVI were independently associated with the occurrence of new-onset AF in patients with severe CKD.

Quality of Life Is Associated with Cardiac Biomarkers, Echocardiographic Indices, and Mortality in CKD Stage 4-5 Patients Not on Dialysis.

INTRODUCTION: Patients with CKD have an impaired health-related quality of life (QoL). Most studies have been conducted on dialysis patients, and less is known about QoL and its determinants in predialysis patients. We studied the association between QoL and comorbidities, cardiac biomarkers, echocardiography, and mortality in patients with CKD stage 4-5 not on dialysis. METHODS: A total of 140 patients enrolled in the Chronic Arterial Disease, Quality of Life and Mortality in Chronic Kidney Injury (CADKID) study filled the Kidney Disease Quality of Life Short Form (KDQOL-SF) at the beginning of the study. Echocardiography and biochemical parameters were obtained at baseline. Patients were followed up for at least 2 years or until death. RESULTS: The median age was 66 years, and 51 (36%) patients were female. The median estimated glomerular filtration rate was 13 mL/min per 1.73 m2. Obesity, diabetes, atrial fibrillation, and congestive heart failure were associated with lower QoL scores in multiple KDQOL-SF domains. Cardiac biomarkers, troponin T (p = 0.02), N-terminal pro-B-type natriuretic peptide (p = 0.006), and the echocardiographic parameter of cardiac systolic function left ventricular global longitudinal strain (p = 0.02) were significant predictors of lower physical component summary (PCS) score in multivariable regression models after controlling for age, BMI, and diabetes. A low PCS score predicted mortality in a multivariable Cox proportional hazards model [HR 0.96 (95% CI 0.92-0.99), p = 0.03]. QoL was not associated with kidney disease progression. CONCLUSION: Impaired QoL in CKD stage 4-5 patients not on dialysis is associated with cardiac biomarker levels, echocardiographic indices, and mortality.

Interatrial block, P terminal force or fragmented QRS do not predict new-onset atrial fibrillation in patients with severe chronic kidney disease.

BACKGROUND: The prevalence of left atrial enlargement (LAE) and fragmented QRS (fQRS) diagnosed using ECG criteria in patients with severe chronic kidney disease (CKD) is unknown. Furthermore, there is limited data on predicting new-onset atrial fibrillation (AF) with LAE or fQRS in this patient group. METHODS: We enrolled 165 consecutive non-dialysis patients with CKD stage 4-5 without prior AF diagnosis between 2013 and 2017 in a prospective follow-up cohort study. LAE was defined as total P-wave duration ≥120 ms in lead II ± > 1 biphasic P-waves in leads II, III or aVF; or duration of terminal negative portion of P-wave > 40 ms or depth of terminal negative portion of P-wave > 1 mm in lead V1 from a baseline ECG, respectively. fQRS was defined as the presence of a notched R or S wave or the presence of ≥1 additional R waves (R') or; in the presence of a wide QRS complex (> 120 ms), > 2 notches in R or S waves in two contiguous leads corresponding to a myocardial region, respectively. RESULTS: Mean age of the patients was 59 (SD 14) years, 56/165 (33.9%) were female and the mean estimated glomerular filtration rate was 12.8 ml/min/1.73m2. Altogether 29/165 (17.6%) patients were observed with new-onset AF within median follow-up of 3 [IQR 3, range 2-6] years. At baseline, 137/165 (83.0%) and 144/165 (87.3%) patients were observed with LAE and fQRS, respectively. Furthermore, LAE and fQRS co-existed in 121/165 (73.3%) patients. Neither findings were associated with the risk of new-onset AF within follow-up. CONCLUSION: The prevalence of LAE and fQRS at baseline in this study on CKD stage 4-5 patients not on dialysis was very high. However, LAE or fQRS failed to predict occurrence of new-onset AF in these patients.

Cardiovascular Determinants of Mortality in Advanced Chronic Kidney Disease.

BACKGROUND: Patients with advanced chronic kidney disease (CKD stage 4-5) have an increased risk of death. To study the determinants of all-cause mortality, we recruited 210 consecutive CKD stage 4-5 patients not on dialysis to the prospective Chronic Arterial Disease, quality of life and mortality in chronic KIDney injury (CADKID) study. METHODS: One hundred seventy-four patients underwent maximal bicycle ergometry stress testing and lateral lumbar radiography to study abdominal aortic calcification score and echocardiography. Carotid and femoral artery intima-media thickness and elasticity and brachial artery flow-mediated dilatation were measured in 156 patients. RESULTS: The duration of follow-up was 42 ± 17 months (range 134-2,217 days). The mean age was 61 ± 14 years, and the estimated glomerular filtration rate was 12 (11-15) mL/min/1.73 m2. Thirty-six (21%) patients died during follow-up (time to death 835 ± 372 days). Seventy-five and 21 patients had diabetes and coronary artery disease, respectively, and all but one had hypertension. In the respective multivariate proportional hazards models adjusted for age, sex, and coronary artery disease, the significant determinants of mortality were troponin T, N-terminal pro-B-type natriuretic peptide, maximal ergometry performance, abdominal aortic calcification score, E/e' ratio, and albumin. CONCLUSION: Stress ergometry performance, abdominal aortic calcification score, E/e' of echocardiography, and plasma cardiac biomarkers and albumin predict mortality in advanced CKD.

Reversibility of myocardial metabolism and remodelling in morbidly obese patients 6 months after bariatric surgery.

AIMS: To study myocardial substrate uptake, structure and function, before and after bariatric surgery, to clarify the interaction between myocardial metabolism and cardiac remodelling in morbid obesity. METHODS: We studied 46 obese patients (age 44 ± 10 years, body mass index [BMI] 42 ± 4 kg/m2 ), including 18 with type 2 diabetes (T2D) before and 6 months after bariatric surgery and 25 healthy age-matched control group subjects. Myocardial fasting free fatty acid uptake (MFAU) and insulin-stimulated myocardial glucose uptake (MGU) were measured using positron-emission tomography. Myocardial structure and function, and myocardial triglyceride content (MTGC) and intrathoracic fat were measured using magnetic resonance imaging and magnetic resonance spectroscopy. RESULTS: The morbidly obese study participants, with or without T2D, had cardiac hypertrophy, impaired myocardial function and substrate metabolism compared with the control group. Surgery led to marked weight reduction and remission of T2D in most of the participants. Postoperatively, myocardial function and structure improved and myocardial substrate metabolism normalized. Intrathoracic fat, but not MTGC, was reduced. Before surgery, BMI and MFAU correlated with left ventricular hypertrophy, and BMI, age and intrathoracic fat mass were the main variables associated with cardiac function. The improvement in whole-body insulin sensitivity correlated positively with the increase in MGU and the decrease in MFAU. CONCLUSIONS: In the present study, obesity and age, rather than myocardial substrate uptake, were the causes of cardiac remodelling in morbidly obese patients with or without T2D. Cardiac remodelling and impaired myocardial substrate metabolism are reversible after surgically induced weight loss and amelioration of T2D.

Left ventricular vascular and metabolic adaptations to high-intensity interval and moderate intensity continuous training: a randomized trial in healthy middle-aged men.

KEY POINTS: High-intensity interval training (HIIT) has become popular, time-sparing alternative to moderate intensity continuous training (MICT), although the cardiac vascular and metabolic effects of HIIT are incompletely known. We compared the effects of 2-week interventions with HIIT and MICT on myocardial perfusion and free fatty acid and glucose uptake. Insulin-stimulated myocardial glucose uptake was decreased by training without any significantly different response between the groups, whereas free fatty acid uptake remained unchanged. Adenosine-stimulated myocardial perfusion responded differently to the training modes (change in mean HIIT: -19%; MICT: +9%; P = 0.03 for interaction) and was correlated with myocardial glucose uptake for the entire dataset and especially after HIIT training. HIIT and MICT induce similar metabolic and functional changes in the heart, although myocardial vascular hyperaemic reactivity is impaired after HIIT, and this should be considered when prescribing very intense HIIT for previously untrained subjects. ABSTRACT: High-intensity interval training (HIIT) is a time-efficient way of obtaining the health benefits of exercise, although the cardiac effects of this training mode are incompletely known. We compared the effects of short-term HIIT and moderate intensity continuous training (MICT) interventions on myocardial perfusion and metabolism and cardiac function in healthy, sedentary, middle-aged men. Twenty-eight healthy, middle-aged men were randomized to either HIIT or MICT groups (n = 14 in both) and underwent six cycle ergometer training sessions within 2 weeks (HIIT session: 4-6 × 30 s all-out cycling/4 min recovery, MICT session 40-60 min at 60% V̇O2 peak ). Cardiac magnetic resonance imaging (CMRI) was performed to measure cardiac structure and function and positron emission tomography was used to measure myocardial perfusion at baseline and during adenosine stimulation, insulin-stimulated glucose uptake (MGU) and fasting free fatty acid uptake (MFFAU). End-diastolic and end-systolic volumes increased and ejection fraction slightly decreased with both training modes, although no other changes in CMRI were observed. MFFAU and basal myocardial perfusion remained unchanged. MGU was decreased by training (HIIT from 46.5 to 35.9; MICT from 47.4 to 44.4 mmol 100 g-1  min-1 , P = 0.007 for time, P = 0.11 for group × time). Adenosine-stimulated myocardial perfusion responded differently to the training modes (change in mean HIIT: -19%; MICT: +9%; P = 0.03 for group × time interaction). HIIT and MICT induce similar metabolic and functional changes in the heart, although myocardial vascular hyperaemic reactivity is impaired after HIIT. This should be taken into account when prescribing very intense HIIT for previously untrained subjects.

Linear relation between spirometric volume and the motion of cardiac structures: MRI and clinical PET study.

BACKGROUND: In cardiac PET, CT, and MRI respiration is major reason for impaired image quality of small targets such as coronary arteries. Strong correlations between heart motion and respiratory signals have been detected but quantitative relation between signals and motion of cardiac structures in MRI or PET is not reported . METHODS: Relation between spirometric lung volume or pressure belt signal and motion of coronary vessels in MRI was studied on nine healthy volunteers. Spirometry was further applied to (18)F-FDG cardiac PET study to determine quantitative relation between volume change and motion of center of myocardium activity (CMA) on nine CAD patients. RESULTS: Correlation coefficients (CC) between vessel motions and volume or pressure changes were 0.90-0.92 or 0.86-0.84, respectively. The linear equations based on volume or pressure changes derived 2.0-2.6 or 2.9-3.3 mm mean estimation error for vessel motions. In PET CC value of 0.93 was determined between volume changes and CMA motions. The linear equation based on volume change derived maximum estimation error of 2.5 mm for CMA motion. CONCLUSION: The spirometric volume change linearly estimates motion of myocardium in PET with good accuracy and have potential to guide selection of optimal number of respiratory gates in cardiac PET.

Myocardial glucose uptake in patients with the m.3243A > G mutation in mitochondrial DNA.

Mitochondrial mutations impair glucose oxidation and increase glucose uptake in cell cultures and lead to cardiomyopathy in patients. Here we characterize cardiac glucose uptake in 14 patients with the m.3243A > G mutation in mitochondrial DNA. The 14 patients with m.3243A > G and 13 controls were similar in age, physical activity and body mass index. Ten patients had diabetes. Left ventricular glucose uptake per tissue mass (LVGU) was measured with 2-[(18) F]fluoro-2-deoxyglucose positron emission tomography during euglycemic hyperinsulinemia. Cardiac morphology and function were assessed with magnetic resonance imaging. We found that the LVGU was 25% lower in the patients than that in the controls (P = 0.029). LVGU was inversely correlated with mutation heteroplasmy, glycated haemoglobin and fasting lactate in patients. The seven patients with mutation heteroplasmy ≥ 49% had 44% lower LVGU than the seven patients with heteroplasmy < 49%. This difference remained significant after adjustment for concurrent free fatty acid concentration or glycated haemoglobin or glucose uptake in skeletal muscle or all (p < 0.048 [All]). Patients with m.3243A > G had a lower stroke volume and a higher heart rate than the controls, whereas cardiac output and work were similar. Myocardial glucose uptake is not increased but decreased with a threshold effect pattern in patients with the m.3243A > G mutation. The glucose hypometabolism adds to the impaired cardiac energetics and likely contributes to the progression of the mitochondrial cardiomyopathy.

Different Predictors of Right and Left Ventricular Metabolism in Healthy Middle-Aged Men.

Dysfunction of the right ventricle (RV) plays a crucial role in the outcome of various cardiovascular diseases. Previous studies on RV metabolism are sparse although evidence implies it may differ from left ventricular (LV) metabolism. Therefore, the aims of this study were (1) to determine predictors of RV glucose uptake (GU) and free fatty acid uptake (FFAU) and (2) to compare them to predictors of LV metabolism in healthy middle-aged men. Altogether 28 healthy, sedentary, middle-aged (40-55 years) men were studied. Insulin-stimulated GU and fasting FFAU were measured by positron emission tomography and RV and LV structural and functional parameters by cardiac magnetic resonance. Several parameters related to whole-body health were also measured. Predictors of RV and LV metabolism were determined by pairwise correlation analysis, lasso regression models, and variable clustering using heatmap. RVGU was most strongly predicted by age and moderately by RV ejection fraction (EF). The strongest determinants of RVFFAU were exercise capacity (peak oxygen uptake), resting heart rate, LVEF, and whole-body insulin-stimulated glucose uptake rate. When considering LV metabolism, age and RVEF were associated also with LVGU. In addition, LVGU was strongly, and negatively, influenced by whole-body insulin-stimulated glucose uptake rate. LVFFAU was predicted only by LVEF. This study shows that while RV and LV metabolism have shared characteristics, they also have unique properties. Age of the subject should be taken into account when measuring myocardial glucose utilization. Ejection fraction is related to myocardial metabolism, and even so that RVEF may be more closely related to GU of both ventricles and LVEF to FFAU of both ventricles, a finding supporting the ventricular interdependence. However, only RV fatty acid utilization associates with exercise capacity so that better physical fitness in a relatively sedentary population is related with decreased RV fat metabolism. To conclude, this study highlights the need for further study designed specifically on less-known RV, as the results on LV metabolism and physiology may not be directly applicable to the RV.

Therapeutic potential of thymosin ß4 in myocardial infarct and heart failure.

Thymosin ß4 (Tß4) is a peptide known for its abilities to protect and facilitate regeneration in a number of tissues following injury. Its cardioprotective effects have been evaluated in different animal models and, currently, a clinical trial is being planned in patients suffering from acute myocardial infarction. This paper focuses on the effects of Tß4 on cardiac function in animal studies utilizing different imaging modalities for outcome measurements.

Effects of acute and one-week fatty acid lowering on cardiac function and insulin sensitivity in relation with myocardial and muscle fat and adiponectin levels.

BACKGROUND/AIM: We tested the hypothesis that a persistent reduction in free fatty acid (FFA) levels improves cardiac function and systemic insulin sensitivity via a reduction in the myocardial and skeletal muscle adiposities and a modulation in adipokine release. METHODS: Study subjects (body mass index 22-30 kg/m(2), 57 ± 3 yr old) underwent magnetic resonance imaging and spectroscopy to measure the cardiac function and the amounts of fat inside and around the myocardium and skeletal muscle, before (n = 10) and after acute (n = 8) and 1 wk (n = 7, one excluded from analysis) lowering of circulating FFA by acipimox. Circulating adipokines (leptin, adiponectin, resistin, TNFα, IL-6, IL-8, plasminogen activator inhibitor-I, macrophage chemoattractant protein-1) were measured. RESULTS: The ejection fraction (62 ± 2 vs. 56 ± 1%, P = 0.0035), cardiac output (6.6 ± 0.3 vs. 5.5 ± 0.2 liters/min, P = 0.0018), and forward work (708 ± 49 vs. 539 ± 44 mm Hg × liters/min, P = 0.018) were significantly lower after 1 wk of FFA lowering. In the six subjects undergoing all sessions, the stroke and end-diastolic volumes were also reduced, insulin sensitivity was increased by 33%, and adiponectinemia was decreased (-26%, P = 0.03). No change in intracellular cardiac and skeletal muscle triglyceride levels was observed. Metabolic changes correlated with the lowering of FFA. The reduction in cardiac function was related with changes in glycemia and insulin sensitivity, whereas the deflection in left ventricular work was correlated with the decline in FFA, lipid, and blood pressure levels. CONCLUSIONS: A 1-wk FFA depletion suppressed cardiac function and improved insulin sensitivity. Intracellular triglyceride deposits in the heart and skeletal muscle played no role in the observed changes. Our data show that FFA participate in the physiological regulation of adipokine levels.

Cardiac Function, Perfusion, Metabolism, and Innervation following Autologous Stem Cell Therapy for Acute ST-Elevation Myocardial Infarction. A FINCELL-INSIGHT Sub-Study with PET and MRI.

PURPOSE: Beneficial mechanisms of bone marrow cell (BMC) therapy for acute ST-segment elevation myocardial infarct (STEMI) are largely unknown in humans. Therefore, we evaluated the feasibility of serial positron emission tomography (PET) and MRI studies to provide insight into the effects of BMCs on the healing process of ischemic myocardial damage. METHODS: Nineteen patients with successful primary reteplase thrombolysis (mean 2.4 h after symptoms) for STEMI were randomized for BMC therapy (2.9 × 10(6) CD34+ cells) or placebo after bone marrow aspiration in a double-blind, multi-center study. Three days post-MI, coronary angioplasty, and paclitaxel eluting stent implantation preceded either BMC or placebo therapy. Cardiac PET and MRI studies were performed 7-12 days after therapies and repeated after 6 months, and images were analyzed at a central core laboratory. RESULTS: In BMC-treated patients, there was a decrease in [(11)C]-HED defect size (-4.9 ± 4.0 vs. -1.6 ± 2.2%, p = 0.08) and an increase in [(18)F]-FDG uptake in the infarct area at risk (0.06 ± 0.09 vs. -0.05 ± 0.16, p = 0.07) compared to controls, as well as less left ventricular dilatation (-4.4 ± 13.3 vs. 8.0 ± 16.7 mL/m(2), p = 0.12) at 6 months follow-up. However, BMC treatment was inferior to placebo in terms of changes in rest perfusion in the area at risk (-0.09 ± 0.17 vs. 0.10 ± 0.17, p = 0.03) and infarct size (0.4 ± 4.2 vs. -5.1 ± 5.9 g, p = 0.047), and no effect was observed on ejection fraction (p = 0.37). CONCLUSION: After the acute phase of STEMI, BMC therapy showed only minor trends of long-term benefit in patients with rapid successful thrombolysis. There was a trend of more decrease in innervation defect size and enhanced glucose metabolism in the infarct-related myocardium and also a trend of less ventricular dilatation in the BMC-treated group compared to placebo. However, no consistently better outcome was observed in the BMC-treated group compared to placebo.

Intracoronary Levosimendan during Ischemia Prevents Myocardial Apoptosis.

BACKGROUND: Levosimendan is a calcium sensitizer that has been shown to prevent myocardial contractile depression in patients post cardiac surgery. This drug exhibits an anti-apoptotic property; however, the underlying mechanism remains elusive. In this report, we characterized the myocardial protective of levosimendan in preventing cardiomyocyte apoptosis and post-operative stunning in an experimental ischemia-reperfusion model. METHODS: Three groups of pigs (n = 8 per group) were subjected to 40 min of global, cardioplegic ischemia followed by 240 min of reperfusion. Levosimendan (65 µg/kg body weight) was given to pigs by intravenous infusion (L-IV) before ischemia or intracoronary administration during ischemia (L-IC). The Control group did not receive any levosimendan. Echocardiography was used to monitor cardiac function in all groups. Apoptosis levels were assessed from the left ventricle using the terminal transferase mediated dUTP nick end labeling (TUNEL) assay and immunocytochemical detection of Caspase-3. RESULTS: Pigs after ischemia-reperfusion had a much higher TUNEL%, suggesting that our treatment protocol was effective. Levels of apoptosis were significantly increased in Control pigs that did not receive any levosimendan (0.062 ± 0.044%) relative to those received levosimendan either before (0.02 ± 0.017%, p = 0.03) or during (0.02 ± 0.017%, p = 0.03) the ischemia phase. Longitudinal left ventricular contraction in pigs that received levosimendan before ischemia (0.75 ± 0.12 mm) was significantly higher than those received levosimendan during ischemia (0.53 ± 0.11 mm, p = 0.003) or Control pigs (0.54 ± 0.11 mm, p = 0.01). CONCLUSION: Our results suggested that pigs received levosimendan displayed a markedly improved cell survival post I-R. The effect on cardiac contractility was only significant in our perfusion heart model when levosimendan was delivered intravenously before ischemia.

Trimetazidine reduces endogenous free fatty acid oxidation and improves myocardial efficiency in obese humans.

INTRODUCTION: The metabolic modulator trimetazidine (TMZ) has been suggested to induce a metabolic shift from myocardial fatty acid oxidation (FAO) to glucose utilization, but this mechanism remains unproven in humans. The oxidation of plasma derived FA is commonly measured in humans, whereas the contribution of FA from triglycerides stored in the myocardium has been poorly characterized. AIMS: To verify the hypothesis that TMZ induces a metabolic shift, we combined positron emission tomography (PET) and magnetic resonance spectroscopy ((1)H-MRS) to measure myocardial FAO from plasma and intracellular lipids, and myocardial glucose metabolism. Nine obese subjects were studied before and after 1 month of TMZ treatment. Myocardial glucose and FA metabolism were assessed by PET with (18)F-fluorodeoxyglucose and (11)C-palmitate. (1)H-MRS was used to measure myocardial lipids, the latter being integrated into the PET data analysis to quantify myocardial triglyceride turnover. RESULTS: Myocardial FAO derived from intracellular lipids was at least equal to that of plasma FAs (P = NS). BMI and cardiac work were positively associated with the oxidation of plasma derived FA (P ≤ 0.01). TMZ halved total and triglyceride-derived myocardial FAO (32.7 ± 8.0 to 19.6 ± 4.0 µmol/min and 23.7 ± 7.5 to 10.3 ± 2.7 µmol/min, respectively; P ≤ 0.05). These changes were accompanied by increased cardiac efficiency since unchanged LV work (1.6 ± 0.2 to 1.6 ± 0.1 Watt/g × 10(2), NS) was associated with decreased work energy from the intramyocardial triglyceride oxidation (1.6 ± 0.5 to 0.4 ± 0.1 Watt/g × 10(2), P = 0.036). CONCLUSIONS: In obese subjects, we demonstrate that myocardial intracellular triglyceride oxidation significantly provides FA-derived energy for mechanical work. TMZ reduced the oxidation of triglyceride-derived myocardial FAs improving myocardial efficiency.

Cardiomyocyte apoptosis after antegrade and retrograde cardioplegia during aortic valve surgery.

BACKGROUND: Retrograde delivery is associated with inadequate perfusion of cardioplegia to all regions of the heart, but the effects on cardiomyocyte death and functional outcome remain unknown. We compared antegrade and retrograde cardioplegia in a randomized clinical trial to see whether it has effect on cardiomyocyte apoptosis and left ventricular function. METHODS: Patients underwent elective aortic valve replacement surgery due to aortic valve stenosis. They were randomly allocated to receive antegrade (n = 10) or retrograde (n = 10) cardioplegia. Apoptotic cardiomyocytes (terminal transferase-mediated dUTP nick end labeling, caspase activation) and RNA levels of apoptosis-regulating proteins were studied in transmyocardial biopsies obtained before and after the operation. Magnetic resonance imaging and transesophageal echocardiography were performed, and cardiac enzymes were measured. RESULTS: Clinical outcome and cardiac enzyme release were comparable between the groups. Cardiomyocyte apoptosis was significantly increased (terminal transferase-mediated dUTP nick end labeling) in the left ventricle after the operation in the retrograde, but not in the antegrade group (respectively, 0.00% [0.039%] versus 0.092% [0.205%], p = 0.01; and 0.00% [0.00%] versus 0.023% [0.054%], p = 0.14). Expression of apoptosis-regulating proteins BAX, BAD, and BCL-2 were comparable between groups. By transesophageal echocardiography, the systolic mitral annulus movement was decreased immediately after the operation in the retrograde group. By magnetic resonance imaging, the left ventricle mass index was reduced preoperatively to 9 months postoperatively in the antegrade group. CONCLUSIONS: In contrast to antegrade cardioplegia, retrograde cardioplegia is associated with increased cardiomyocyte apoptosis, impaired immediate postoperative systolic function, and lack of long-term favorable left ventricle remodeling after aortic valve replacement, suggesting inadequate myocardial protection.

Diagnostic performance of cardiac magnetic resonance imaging in coronary artery disease.

BACKGROUND: Cardiac magnetic resonance imaging (CMR) is a promising method for detecting coronary artery disease (CAD). The first reports of new diagnostic techniques indicated generally unrealistic diagnostic performance relying on retrospectively observed cut-off values of quantitative parameters. Although visual analysis of CMR is the most applicable method for clinical work, its diagnostic performance is not fully elucidated for study components such as wall motion, perfusion and late enhancement in patients with different severity of CAD. METHODS: A total of 30 subjects including 20 patients with CAD and 10 healthy volunteers were selected for the study. Of the patients, ten had stable CAD, five confirmed myocardial infarction (MI) without Q-waves in electrocardiogram (ECG) and five confirmed MI with Q-waves in ECG. All patients underwent coronary angiography and CMR for evaluating resting wall motion, rest and stress perfusion and late enhancement. RESULTS: Combining the data from the three CMR techniques, 12 out of 20 patients were correctly identified as having CAD, and all controls were found to be healthy. Sensitivity, specificity, accuracy, positive and negative predictive values were 60.0%, 100.0%, 73.0%, 100.0% and 55.6%, respectively. Of the CMR components, resting wall motion and late enhancement gave the most diagnostic yield. CONCLUSIONS: We conclude that evaluation of CAD is feasible in patients with different severity of CAD using visually analysed CMR, especially when available CMR methodologies are combined together.

Contribution of glucose tolerance and gender to cardiac adiposity.

CONTEXT AND OBJECTIVE: To examine whether pericardial and myocardial fat depots may contribute to the association between diabetes and cardiovascular risk, including sex-related differences, and the role of adiponectin, we evaluated data in patients with obesity and without diabetes [nondiabetic (ND)] or with impaired glucose tolerance or type 2 diabetes and in lean ND controls. METHODS: Magnetic resonance imaging and spectroscopy were used to measure left ventricular (LV) function and abdominal sc and visceral fat areas to estimate respective masses, pericardial fat depots, and myocardial triglyceride content in 53 subjects (10 lean ND, 25 obese ND, six impaired-glucose-tolerance, and 12 type 2 diabetic patients with macrovascular disease); gender effects and adiponectin levels were evaluated in the available subset of subjects. RESULTS: Myocardial and pericardial fat increased progressively across study groups. They were lower in obese women than men (P = 0.002), but cardiac steatosis caught up in hyperglycemic women (+81% vs. ND, P = 0.01). Adiponectin was inversely related with both fat depots (P < 0.01) and LV mass (P = 0.003) and positively with LV function (P = 0.03). In multiple regression analysis, myocardial and pericardial fat were independently related with plasma glucose levels, only pericardial fat mass was associated with visceral adiposity and myocardial fat with cardiac output and work. CONCLUSIONS: We conclude that glycemia, gender, adiponectin, and cardiac workload are associated with, and hyperglycemia and male gender are independent positive predictors of, heart adiposity. Once glucose tolerance becomes impaired, the evolution of cardiac steatosis is more pronounced in women.