Michael M.H. Cheung

Childhood Adiposity, Adult Adiposity, and Cardiovascular Risk Factors

BACKGROUND Obesity in childhood is associated with increased cardiovascular risk. It is uncertain whether this risk is attenuated in persons who are overweight or obese as children but not obese as adults. METHODS We analyzed data from four prospective cohort studies that measured childhood and adult body-mass index (BMI, the weight in kilograms divided by the square of the height in meters). The mean length of follow-up was 23 years. To define high adiposity status, international age-specific and sex-specific BMI cutoff points for overweight and obesity were used for children, and a BMI cutoff point of 30 was used for adults. RESULTS Data were available for 6328 subjects. Subjects with consistently high adiposity status from childhood to adulthood, as compared with persons who had a normal BMI as children and were nonobese as adults, had an increased risk of type 2 diabetes (relative risk, 5.4; 95% confidence interval [CI], 3.4 to 8.5), hypertension (relative risk, 2.7; 95% CI, 2.2 to 3.3), elevated low-density lipoprotein cholesterol levels (relative risk, 1.8; 95% CI, 1.4 to 2.3), reduced high-density lipoprotein cholesterol levels (relative risk, 2.1; 95% CI, 1.8 to 2.5), elevated triglyceride levels (relative risk, 3.0; 95% CI, 2.4 to 3.8), and carotid-artery atherosclerosis (increased intima-media thickness of the carotid artery) (relative risk, 1.7; 95% CI, 1.4 to 2.2) (P ≤ 0.002 for all comparisons). Persons who were overweight or obese during childhood but were nonobese as adults had risks of the outcomes that were similar to those of persons who had a normal BMI consistently from childhood to adulthood (P>0.20 for all comparisons). CONCLUSIONS Overweight or obese children who were obese as adults had increased risks of type 2 diabetes, hypertension, dyslipidemia, and carotid-artery atherosclerosis. The risks of these outcomes among overweight or obese children who became nonobese by adulthood were similar to those among persons who were never obese. (Funded by the Academy of Finland and others.).

Noninvasive Assessment of Left Ventricular Force-Frequency Relationships Using Tissue Doppler–Derived Isovolumic Acceleration Validation in an Animal Model

Background—We have demonstrated that myocardial acceleration during isovolumic contraction (IVA) is a sensitive index of right ventricular contractile function. In this study, we assessed the usefulness of IVA to measure left ventricular (LV) contractile function and force-frequency relationships in an experimental preparation. Methods and Results—In study 1, we examined 6 pigs by use of tissue Doppler imaging of LV free wall and simultaneous measurements of intraventricular pressure, volume, maximal elastance (Emax), and dP/dtmax by conductance catheterization. Animals were paced via the right atrium at a rate of 130 bpm. IVA was compared with elastance during contractility modulation by esmolol and dobutamine and assessed during preload reduction and afterload increase. In study 2, in 6 more pigs, force-frequency data were obtained during incremental atrial pacing from 120 to 180 bpm. Study 1: Esmolol led to a decrease in IVA and Emax (P <0.03 and <0.02, respectively), both of which increased during dobutamine infusion (P <0.02 and <0.03, respectively). IVA was unaffected by significant (P <0.001) acute reduction of LV volume and a significantly increased LV afterload (systolic pressure increase, P <0.001). Study 2: There was a positive correlation between IVA and dP/dtmax (r2=0.92, P <0.05). As heart rate was increased from 120 to 160 bpm, there were significant increases in both IVA and dP/dtmax (P <0.0004 and P =0.02, respectively). Over the same range of heart rates, there was no significant change in Emax (P =0.22). Conclusions—IVA is a measurement of LV contractile function that is unaffected by preload and afterload changes within a physiological range and can be used noninvasively to measure LV force-frequency relationships.

Birth weight <1501 g and respiratory health at age 14

AIMS To determine the respiratory health in adolescence of children of birth weight <1501 g, and to compare the results with normal birthweight controls. METHODS Prospective cohort study of children born in the Royal Womens Hospital, Melbourne. Two cohorts of preterm children (86 consecutive survivors 500–999 g birth weight, and 124 consecutive survivors 1000–1500 g birth weight) and a control group of 60 randomly selected children >2499 g birth weight were studied. Children were assessed at 14 years of age. A paediatrician determined the clinical respiratory status. Lung function was measured according to standard guidelines. RESULTS Of 180 preterm children seen at age 14, 42 (23%) had bronchopulmonary dysplasia (BPD) in the newborn period. Readmission to hospital for respiratory ill health was infrequent in all groups and the rates of asthma were similar (15% in the 500–999 g birth weight group, 21% in the 1000–1500 g birth weight group, 21% in controls; 19% BPD, 18% no BPD). Overall, lung function was mostly within the normal range for all cohorts; few children had lung function abnormalities in clinically significant ranges. However, the preterm children had significantly lower values for variables reflecting flow. Lung function in children of 500–999 g birth weight was similar to children of 1000–1500 g birth weight. Preterm children with BPD had significantly lower values for variables reflecting flow than children without BPD. CONCLUSIONS The respiratory health of children of birth weight <1501 g at 14 years of age is comparable to that of term controls.

Remote ischemic preconditioning decreases adhesion and selectively modifies functional responses of human neutrophils.

OBJECTIVES Preconditioning of cells or organs by transient sublethal ischemia-reperfusion (IR), termed ischemic preconditioning (IPC), protects the cell or organ from a subsequent prolonged ischemic insult. The mechanisms of this effect remain to be fully elucidated. We have recently reported that IPC of a forearm results in alterations in gene expression profiles of circulating polymorphonuclear leukocytes. The goal of the current study was to determine if the observed changes in gene expression lead to functional changes in neutrophils. METHODS We examined the effect of repetitive transient human forearm ischemia (three cycles of 5 min ischemia, followed by 5 min of reperfusion) on the function of circulating neutrophils. Neutrophil functions were examined before, after 1 d, and after 10 d of daily transient forearm ischemia. To modulate IR-induced inflammation the neutrophils were stimulated with N-formyl-methionyl-leucyl phenylalanine (FMLP) and lipopolysaccharide (LPS). RESULTS Neutrophil adhesion was significantly decreased on day 1 and remained low on day 10 (P = 0.0149) without significant change in CD11b expression. Phagocytosis was significantly suppressed on day 10 compared with day 0 (P < 0.0001). Extracellular cytokine levels were low in the absence of an exogenous stimulus but stimulation with LPS induced significant changes on day 10. We observed a trend in reduction of apoptosis on day 1 and day 10 that did not reach statistical significance (P < 0.08). CONCLUSION This study indicates that repetitive IPC of the forearm results in substantial alterations in neutrophil function, including reduced adhesion, exocytosis, phagocytosis, and modified cytokine secretion.

Remote ischaemic preconditioning protects against cardiopulmonary bypass-induced tissue injury: a preclinical study.

Objectives: To test the hypothesis that remote ischaemic preconditioning (rIPC) reduces injury after cardiopulmonary bypass (CPB). Design: Randomised study with an experimental model of CPB (3 h CPB with 2 h of cardioplegic arrest). Twelve 15 kg pigs were randomly assigned to control or rIPC before CPB and followed up for 6 h. Intervention: rIPC was induced by four 5 min cycles of lower limb ischaemia before CPB. Main outcome measures: Troponin I, glial protein S-100B, lactate concentrations, load-independent indices (conductance catheter) of systolic and diastolic function, and pulmonary resistance and compliance were measured before and for 6 h after CPB. Results: Troponin I increased after CPB in both groups but during reperfusion the rIPC group had lower concentrations than controls (mean area under the curve −57.3 (SEM 7.3) v 89.0 (11.6) ng·h/ml, p  =  0.02). Lactate increased after CPB in both groups but during reperfusion the control group had significantly more prolonged hyperlactataemia (p  =  0.04). S-100B did not differ between groups. Indices of ventricular function did not differ. There was a tendency to improved lung compliance (p  =  0.07), and pulmonary resistance changed less in the rIPC than in the control group during reperfusion (p  =  0.02). Subsequently, peak inspiratory pressure was lower (p  =  0.001). Conclusion: rIPC significantly attenuated clinically relevant markers of myocardial and pulmonary injury after CPB. Transient limb ischaemia as an rIPC stimulus has potentially important clinical applications.

Assessment of right ventricular function using tissue Doppler imaging in infants with pulmonary hypertension.

Background: In infants with pulmonary hypertension (PHT), right ventricular (RV) function may be altered and contribute to disease severity. Tissue Doppler imaging (TDI) is a new echocardiographic modality which directly measures myocardial velocities and may allow quantitative assessment of systolic and diastolic ventricular function in infants. Objective: To measure and compare RV myocardial velocities in infants with PHT and in normal control infants, using TDI. Methods: This was a prospective case-control study. Twenty-eight control infants and 15 infants with PHT, of whom 11 had congenital diaphragmatic hernia (CDH), were recruited. TDI was used to obtain systolic and diastolic myocardial velocities in the RV and interventricular septum in all infants. Results: There were significant reductions in systolic isovolumic contraction velocity (IVV; 5.3 vs. 6.6 cm/s) and systolic ejection velocity (S; 6.6 vs. 9.2 cm/s) in the PHT group compared to the control group. Early diastolic myocardial velocity, E’, was also significantly reduced in the RV in the PHT infants compared to controls (–4.3 vs. 8.6 cm/s). The same significant reductions in systolic and early diastolic TDI velocities were observed in the subgroup of CDH infants alone. Conclusions: TDI permits non-invasive assessment of RV myocardial velocities in infants. Reduced systolic and diastolic velocities in PHT may represent impaired systolic contraction and early diastolic relaxation. Therapies which target inotropic and lusitropic function may be appropriate in infants with PHT and RV dysfunction. The load-dependency of TDI measures in infants and the effects of specific therapies on RV function in PHT require further investigation.

Surgical treatment of congenital mitral valve disease: Midterm results of a repair-oriented policy

OBJECTIVE Management of congenital mitral valve disease is challenging because of a wide morphologic spectrum, frequent associated lesions, and small patient size. We evaluated the results of a repair-oriented policy. METHODS All consecutive patients with congenital mitral valve disease who underwent surgery between 1996 and 2006 were studied retrospectively. Patients with atrioventricular canal, atrioventricular discordance, or ischemic regurgitation were excluded. RESULTS During this period, 71 children (median age 2.9 years, range 3 days-20.8 years) underwent surgery. All but 1 underwent primary mitral valve repair. Twenty-two (30%) were younger than 12 months. Associated cardiac lesions were present in 45 children (63%) and were addressed concurrently in 35; previous cardiac procedures had been performed in 17 patients (24%). Mitral incompetence was predominant in 60 (85%) and stenosis in 11 (15%). During a median follow-up of 47.8 months (range 2-120 months), 14 patients underwent 17 mitral reinterventions: 14 repairs and 3 replacements. After 60 months, overall survival was 94% +/- 2.8%; freedoms from reoperation and prosthesis implantation were 76% +/- 5.6% and 94% +/- 3.6%, respectively. There were 4 deaths, and all survivors remain in New York Heart Association class I or II with moderate (6 patients) or less mitral dysfunction. CONCLUSION Surgical repair of the congenital mitral valve can be successfully performed with low mortality, satisfactory valvular function at midterm follow-up, and acceptable reoperation rate while obviating risks associated with valvular prostheses. Suboptimal primary repair was significant predictor for reoperation but re-repair was often successful.

Non-invasive assessment of ventricular force–frequency relations in the univentricular circulation by tissue Doppler echocardiography: a novel method of assessing myocardial performance in congenital heart disease

Objective: To describe the first clinical application of a novel tissue Doppler derived index of contractility, isovolumic acceleration (IVA), in the assessment of the ventricular myocardial force–frequency relation (FFR) in the univentricular heart (UVH). Design: Prospective study. Setting: Tertiary referral centre. Interventions: Non-invasive assessment of the myocardial FFR by tissue Doppler echocardiography during atrial pacing. Results: IVA was used to measure the FFR of the systemic ventricle in patients with structurally normal hearts and in patients with UVHs. Basal IVA of the normal hearts (mean (SD) 1.9 (0.3) m/s2) was significantly greater than that of UVHs in patients with a dominant right ventricle (RV) (1.0 (0.3) m/s2) or left ventricle (LV) (0.8 (0.7) m/s2; p < 0.05 for both). Neither the absolute nor percentage change from basal to peak values of IVA with pacing differed between the three groups. Peak force developed by the normal LV was significantly greater than that of the UVH, dominant LV group but not different from that of the UVH, dominant RV group. Conclusion: Contractility at basal heart rate is depressed in patients with UVH compared with the normal LV. Analysis of ventricular FFRs exposes further differences in myocardial contractility. There is no evidence that contractile function of the dominant RV is inferior to that of the dominant LV over a physiological range of heart rates.

Long-term results of a strategy of aortic valve repair in the pediatric population

OBJECTIVES To determine rate of reoperation subsequent to primary valve repair in a pediatric population. METHODS Between 1996 and 2009, 142 consecutive patients underwent aortic valve repair in our institution. Median age at surgery was 9 years, with 30 being younger than age 1 year. Indication for surgery was stenosis (n = 76), regurgitation (n = 55), and both (n = 11). Forty-six patients underwent repair with no addition of patch, whereas 96 patients required addition of patches of glutaraldehyde preserved autologous pericardium for cusp extension (n = 51) and other repair (n = 45). RESULTS In the early postoperative period after cusp extension repair, 2 patients had a sudden unexplained death and 1 had cardiac arrest requiring mechanical support and heart transplantation. Two additional patients with cusp extension displayed signs of coronary ischemia. After a mean follow-up of 3.4 ± 3.5 years, only 1 patient died of a noncardiac cause. Seven-year freedom from reoperation was 80% (95% confidence interval [CI], 66-89). By multivariate analysis, the only predictors of reintervention were cusp extension (hazard ratio [HR], 5.4; 95% CI, 1.7-16.8; P = .004) and infants (HR, 5.6; 95% CI, 1.7-18.4; P = .005). At final echocardiography follow-up, 23 of 119 survivors without reoperation had moderate (19%), 1 had moderate-severe (1%), and 1 had severe regurgitation (1%), whereas 12 (10%) had a moderate degree of stenosis. CONCLUSIONS Aortic valve repair in pediatric populations is effective in postponing reintervention. The longevity of the repair is shorter after cusp extension and when performed in infants. Caution should be used when performing tricsupidization and cusp extension of bicuspid valves because it can be responsible for mortality related to occlusion of the coronary ostia by patches.

Twenty-four-hour ambulatory blood pressure monitoring detects a high prevalence of hypertension late after coarctation repair in patients with hypoplastic arches.

OBJECTIVES To determine by 24-hour blood pressure monitoring the risk of hypertension late after coarctation repair in patients with arch hypoplasia. METHODS Sixty-two of 116 consecutive patients (age, ≥10 years) who had coarctation repair and were quoted subjectively by the surgeon or the cardiologist to have arch hypoplasia at the time of the repair underwent a transthoracic echocardiogram and 24-hour blood pressure monitoring. Median age at repair was 11 days (range, 6-48 days). Mean preoperative z score of the proximal transverse arch was -2.43 ± 0.46. Eight patients had a repair via sternotomy (6 end-to-side anastomoses, 2 patch repairs) and 54 had a conventional repair via thoracotomy. RESULTS After a follow-up of 18 ± 5 years, 27% of the patients (17/62) had resting hypertension and 60% (37/62) had abnormal ambulatory blood pressure. Sensitivity of high resting blood pressure in detecting an abnormal 24-hour ambulatory blood pressure was 41%. Twenty patients had arch obstruction at last follow-up. Eighteen of them (90%) had abnormal ambulatory blood pressure. None of the patients operated on with end-to-side repair via sternotomy had reobstruction compared with 33% (18/54) of those repaired via thoracotomy. CONCLUSIONS Patients with a hypoplastic arch operated via thoracotomy have an alarming prevalence of hypertension. Regular follow-up with 24-hour ambulatory blood pressure monitoring is warranted, especially in patients who have had a smaller aortic arch at the time of the initial operation.