Diss. (sammanfattning) Umeå : Univ., 2006. / Härtill 5 uppsatser.

Podocytes play an important role in maintaining the structural integrity of glomerular capillaries. There is a limited capacity of podocytes to reproduce; therefore, they are required to support a greater capillary surface area in states of glomerular hypertrophy (i.e., reduced podocyte density). Such reductions in podocyte density can lead to podocyte dysfunction and is thought to substantially increase the susceptibility to hypertension-induced renal injury and progression of chronic kidney disease. However, the extent to which reduced podocyte density increases the susceptibility to hypertension-induced renal injury remains unknown. The goal of this study was to determine the susceptibility to hypertension-induced renal injury in a rodent model of chronic kidney disease with podocyte dysfunction. Male Sprague-Dawley rats were subjected to normotensive renal mass reduction and instrumented with a radiotelemeter for the continuous measurement of blood pressure. After a two week recovery from surgery to allow for completion of renal compensatory increases in size and function, groups of rats were administered a single dose of puromycin aminonucleoside (PAN, 75 mg/kg i.p.), which acutely injures podocytes, or saline (sham). Rats were followed for 4 weeks following PAN or saline injection. At one week post PAN injection, some groups of rats were administered antihypertensive regimens consisting of hydralazine (50-300 mg/L) + hydrochlorothiazide (HCTZ, 25-75 mg/L) or enalapril (50-300 mg/L) + HCTZ (25-75 mg/L) via the drinking water for the remainder of the study. At the end of the study, glomerulosclerosis (GS) was assessed in a blinded fashion and podocyte density was determined using immunofluorescence detection of the podocyte marker Wilms Tumor 1 (WT1) on paraffin-embedded sections from perfused-fixed kidneys. No differences were observed between antihypertensive groups, thus these data are presented as a singled group. The average systolic BP (mmHg) was higher (P<0.05) in rats administered PAN (144±3, n=12) vs. PAN + antihypertensives (127±2, n=20) and saline (130±4, n=17). The magnitude of glomerulosclerosis (GS, % glomeruli exhibiting GS in 100 evaluated) was greater (P<0.05) in rats administered PAN (64±7%) vs. PAN + antihypertensives (30±6%) vs. saline (6±2%). The slope of the relationship between BP and GS (Δ%GS vs. ΔmmHg) was significantly greater (P<0.05) in rats administered PAN (1.1) and PAN + antihypertensives (1.2) vs. saline (0.4). Podocyte density (podocytes/µm3x10-6) was assessed in non-injured glomeruli from a subset of rats from each group and was significantly greater (P<0.05) in those administered PAN + antihypertensives (63±3, n=8) and tended to be greater (P=0.09) in those administered saline (56±4, n=7) as compared to those administered PAN (47±4, n=7). The number of podocytes per glomerular tuft tended to be lower and the average glomerular tuft area tended to be higher in rats administered PAN vs. the other groups; however, these differences were not statistically significant. These data demonstrate that acute podocyte dysfunction increases the susceptibility to BP-induced GS by ~ 3-fold and that lowering BP in such states mitigates further reductions in podocyte density and progression of kidney disease.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

This thesis aims to integrate functional and nutrigenomics analyses to examine how dietary polyphenols affect human platelet function and thus may contribute to the prevention of cardiovascular diseases. Initially, 26 low molecular weight phenolic compounds were screened for their effects on platelet aggregation and P-selectin expression in vitro. Only high, non-physiological concentrations of some phenolics showed anti-platelet effects. In parallel we conducted a systematic review of the literature to assess how polyphenol-rich foodstuffs, beverages, or extracts affect platelet function in humans. Cocoa-derived flavan-3-ols were the only class of dietary polyphenols that consistently showed anti-platelet effects in both, acute and chronic settings. Consequently we conducted an acute randomised-controlled human intervention study in which healthy volunteers consumed three different types of chocolates containing different amounts of flavan-3-ols. We found that flavan-3-ol-enriched dark chocolate beneficially affected ex vivo bleeding time, platelet aggregation and P-selectin expression. These effects were gender-dependent. Bioavailability of cocoa-derived flavan-3-ols, as assessed by a targeted metabolomics approach, was also gender-dependent. Using a platelet proteomics approach, we found subtle changes in platelet protein levels 2 h after consumption of flavan-3-ol-enriched chocolate in men, which may partly explain the observed anti-platelet effects. Finally, we assessed whether flavan-3-ols are internalised in platelets after consumption of dark chocolate. No internalisation could be found up to 2.5 h after chocolate ingestion, despite these compounds appearing in plasma. In conclusion, flavan- 3-ol-enriched dark chocolate beneficially affects platelet function in a gender-dependent way, but underpinning mechanisms are still unknown. Furthermore, current insights into their bioavailability cannot fully explain the ability of flavan-3-ols to affect platelet function. Successful future progress of research into the bioavailability and mechanisms of flavan-3- ols in vitro and in vivo will depend on the availability of pure standards for the major human metabolites of flavan-3-ols.

Hypertensive left ventricular hypertrophy (LVH) increases the risk for the development of heart failure with systolic chamber dysfunction. However, the exact mechanisms and hence best therapeutic approach to prevent this transition process is uncertain. One potential mechanism is through excessive β-adrenergic receptor (-AR) activation, but the risks of β-AR blocker therapy may outweigh the benefits. Since activation of -AR augments function of the renin-angiotensin-aldosterone system, I therefore explored whether mineralocorticoid receptor (MR) blockade prevents the transition from hypertensive LVH to systolic chamber decompensation produced by excessive β-AR activation, and the mechanisms thereof. The role of hypertensive LVH as a predisposing factor to systolic chamber decompensation post-myocardial infarction (MI) is controversial. In the present thesis I therefore also evaluated this question. The effect of spironolactone (SPIRO, 80 mg.kg-1.day-1), an MR blocker, on LV chamber remodelling and function was evaluated in spontaneously hypertensive rats (SHR) in whom decompensation was induced by administering a low dose of the -AR agonist, isoproterenol (ISO) for 4.5 months. ISO administration resulted in an increased urinary aldosterone excretion and LV cavity dimensions, a right shift in LV diastolic pressure-volume relations, and a decreased LV relative wall thickness without further enhancing an increased myocardial norepinephrine (NE) release in SHR. ISO reduced LV systolic chamber function (decreased LV endocardial fractional shortening and the slope of the LV systolic pressure- volume relationship) without modifying intrinsic myocardial systolic function (as assessed from LV midwall fractional shortening and the slope of systolic stress-strain relationship). SPIRO abolished ISO-induced chamber dilatation, wall thinning and systolic dysfunction, but failed to modify blood pressure, volume preloads, intrinsic myocardial systolic function, or myocardial NE release. These results suggest that MR activation, through load-independent effects, may be critical in mediating the transition from compensated hypertensive LVH to dilatation and LV systolic chamber dysfunction. In SHR, ISO increased myocardial matrix metalloproteinase (MMP)-2 activity (zymography) after only 4-5 days of administration, a change that was associated with MMP-2, but not TIMP expression. The increased MMP-2 activity persisted until 4.5 months of the study and these changes were prevented by SPIRO. At 4.5 months, ISO resulted in increased non-cross-linked, but not cross-linked myocardial collagen concentrations in SHR, an effect that was abolished by SPIRO. Although at 4.5 months ISO administration was not associated with an increased cardiomyocyte apoptosis (TUNEL), an early (4-5 days) ISO-induced apoptotic effect was noted, which was prevented by SPIRO. Neither ISO nor SPIRO influenced cardiomyocyte length (image analysis and flow cytometry) in SHR. Thus MR blockade may prevent the adverse effects of β-AR activation in hypertensive LVH through alterations in the cardiac interstitium and cardiomyocyte apoptosis. Six-to-seven months after ligation of the left anterior descending coronary artery, LV myocardial systolic function as assessed from % shortening of the non-infarcted lateral wall segmental length determined over a range of filling pressures (ultrasonic transducers placed in the lateral wall in anaesthetized, open-chest, ventilated rats) and % thickening of the posterior wall (echocardiography) was reduced in infarcted SHR (SHR-MI) (p<0.05), but not in normotensive Wistar Kyoto (WKY-MI) animals as compared to corresponding controls (SHR-Sham, WKY-Sham). This change in regional myocardial function in SHR-MI, but not in WKY- MI, occurred despite a similar degree of LV dilatation in SHR-MI and WKY-MI rats and a lack of difference in LV relative wall thinning, LV wall stress, apoptosis (TUNEL) or necrosis (pathological score) between SHR-MI and WKY-MI rats. Although the change in regional myocardial function in the SHR-MI group was not associated with a greater reduction in resting global LV chamber systolic function (endocardial fractional shortening-FSend and end-systolic elastance [LV Ees] determined in the absence of an adrenergic stimulus), in the presence of an ISO challenge a reduction in LV Ees in SHR-MI compared to WKY-MI and SHR and WKY-Sham rats was noted (p<0.04). These data suggest that with chronic MI, the hypertensive heart is susceptible to development of viable tissue myocardial dysfunction, a change which cannot be attributed to excessive chamber dilatation, apoptosis or necrosis, but which in-turn, contributes toward a reduced cardiac adrenergic-inotropic reserve. The present thesis therefore suggests that MR blockade may prevent the transition from hypertensive LVH to systolic chamber decompensation, and that pre-existing hypertensive LVH increases the susceptibility to a depressed LV regional myocardial systolic function in the non-infarcted LV myocardium subsequent to MI, an effect that translates into a reduced inotropic reserve.

Background: Type 2 diabetes mellitus (T2DM) is defined by an increase in serum glucose, however, this leads to the belief that only the serum glucose levels need be monitored and treated. Hence many other risk factors such as obesity, lipids and blood pressure which increase the risk of coronary heart disease, myocardial infarction, stroke and peripheral vascular disease are neglected. Consequently, T2DM patients that are at greater risk of developing cardiovascular disease (CVD), are often not receiving optimal comprehensive care. Aims: To identify the treatment gaps of cardiovascular risk factors in patients with T2DM using both national and international current treatment guidelines. Methods: Using a public sector database, data was obtained on the treatment of 666 T2DM patients. Records of patients were selected on the basis of established T2DM diagnoses, receiving oral hypoglycaemic and/or insulin therapy. The following patient data was recorded: demographics (age, gender, ethnicity), systolic blood pressure (SBP), diastolic blood pressure (DBP), glycated haemoglobin (HbA1c), total cholesterol (TC), triglycerides (TG), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C) , family history, cardiovascular history and all chronic medications. The following parameters were applied to the cohort: SBP <130 mmHg, DBP <80 mmHg. In the event of proteinuria: SBP ≤120 mmHg, DBP ≤70 mmHg. HbA1c <7.0%, TC <4.5 mmol/L, LDL-C <2.5 mmol/L, HDL-C >1.0 mmol/L (males), HDL-C >1.2 mmol/L (females) and TG <1.7 mmol/L. In patients with established CVD, LDL-C target: ≤1.8 mmol/L. Results: The study cohort consisted of 666 T2DM-patients. 55% females. Mean age was 63 years (SD: 11.8), mean HbA1c was 8.7% (SD: 2.4). The mean SBP and DBP readings for the cohort were 133.66 (SD: 19.9) and 78.07 mmHg (SD: 11.6), respectively. Mean LDL-cholesterol was 2.6 mmol/L (SD: 0.9). 26.2% reached HbA1c of ≤7%, 45.8% reached ≤130/80 mm Hg blood pressure targets, 53.8% reached LDL-C of ≤2.5mmol/L and all 3 were reached by 7.5% of the cohort. TC ≤4.5 mmol/L was reached by 53.8%, 60.2% reached TG ≤1.7mmol/L, 58.6% males and 52.8% females reached HDL-C targets of ≥1.0 mmol/L and ≥1.2 mmol/L, respectively. There were 17.9% of patients with CVD reaching targets of LDL-C ≤1.8 mmol/L whilst 16.4% of patients with nephropathy reaching targets of ≤120/70 mm Hg. Almost half (48.2%) were not receiving lipid-lowering therapy, yet would be deemed eligible for therapy. Blood pressure targets may have been better reached with appropriate dosage reductions in addition to the introduction of further antihypertensive combination therapy. CVD was present in 15.5%. Conclusions: T2DM patients are at high-risk for CVD. Many trials have demonstrated the benefits of targeting CVD risk factors (HbA1c, blood pressure, serum lipids) in T2DM. Less than 10% of CVD risk factor targets were reached by the study cohort despite treatment guideline recommendations. The data from the study suggests poor control of modifiable cardiovascular risk factors and significant under treatment of T2DM in clinical practice. Whether improvement lies in the form of therapeutic titration adjustment or an increase in patient education, there needs to be a more aggressive multi-factorial therapeutic approach to treating this high risk group of patients in order to reduce overall morbidity, mortality and improve patient outcomes.

INTRODUCTION Cardiovascular diseases (CVD) are more common in kidney transplant recipients (KTRs) than in the general population. The high incidence of CVD in the KTRs can be attributed to traditional risk factors, additional risk factors associated with graft dysfunction and those specifically related to transplantation. Carotid intima-media thickness (cIMT) is a proven surrogate of atherosclerosis; it correlates with vessel pathology and is precisely imaged using ultrasound technology. This study was aimed at determining the prevalence and predictors of cardiovascular risk among KTRs at the Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) and to examine the relationship between cardiovascular risk factors and carotid intima media thickness. METHODS Patients aged 18 years and above who received a kidney transplant at the CMJAH between January 2005 and December 2009 were recruited. A questionnaire that captured cardiovascular risk factors was administered. Patients records were assessed for information on their post transplant follow up. All patients had echocardiography and carotid doppler done for measurement of intima-media thickness. The Framingham Risk Score was used to categorize patients into low, moderate, high risk and very high risk groups. Results were analyzed using statistical package for social sciences (SPSS) version 17, p value of 0.05 was considered significant. RESULTS One hundred (KTRs) 63 male (63%) and 37 female (37%) were recruited ranging in age from 19 to 70 years, with a mean age of 42.2 ± 12.42. Thirty six patients (36%) were found to have high cardiovascular risk. Multiple regression showed proteinuria (p = 0.022), higher cumulative steroid dosage (p = 0.028), elevated serum triglycerides (p = 0.04) and the presence of plaques in the carotid artery (p = 0.012) as predictors of higher cardiovascular risk.Carotid intima-media thickness correlates with higher CVD risk. Fourteen patients (14%) had a carotid artery plaque. Twenty five patients (25%) had cIMT of >0.7 mm. CONCLUSION Kidney transplant recipients in CMJAH were found to have high cardiovascular risk (36%) and carotid intima-media thickness correlates with this high CVD risk. Routine follow up of KTRs should include measurement of cIMT as it provides a simple non-invasive assessment of subclinical atherosclerosis.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 109-126).

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2007. / Härtill 5 uppsatser.