Cardiovascular disease in Switzerland - health care, mortality and geographical pattern

SUMMARY Switzerland is facing an aging population and a growing amount of patients with chronic diseases. It is crucial to display health care processes and pathways, to identify inequalities and obstacles, and to point out possibilities for improvements of the Swiss health care system (e.g. increase efficiency). The introductory part of the thesis presents a brief description of the Swiss health care system, health services research and regional variation as well as an introduction of CVD and its epidemiological key figures, aetiology and treatments. This is followed by the description of the utilized methods and data, and the objectives of this thesis. The subsequent sections present the four articles included in this thesis. The first article focuses on a small area analysis on regional variation of avoidable hospitalisations in Switzerland including density of primary care physicians and specialists, rurality and hospital supply factors as explanatory variables in the analysis. Lower rates of avoidable hospitalisations were found in areas with very high supply of primary care physicians, increased avoidable hospitalisation rates in areas with more specialists and in areas with higher proportion of rural residents. The second article aims to examine whether emergency patients with acute ST-segment elevation myocardial infarction were adequately treated, i.e. according to the treatment guidelines, in Switzerland. Results show that older and female patients were less likely to receive revascularization which suggests that the treatment guidelines may not be uniformly applied in Switzerland. Similar to the first article, also in the third article a small area analysis was performed but this time investigating regional variation in costs at the end of life. Strongest associations of cost was found with cause of death, age and language region of the decedents. The strong spatial variation of costs could only partly be explained by the included covariates. Article four aims to examine the relationship of distance to different hospital types and mortality from AMI or stroke. We found that AMI mortality in the Swiss population 30 and older and stroke mortality in those 65 and above increased with distance to central and university hospitals, while adjusting for sociodemographic and economic characteristics of the population. The presentation of the four articles is followed by a discussion, which summarizes the main findings and the strengths and limitations of the presented articles. The thesis concludes with a discussion about the challenges for policy, practice and future research.

Effect of pravastatin on cardiovascular events in people with chronic kidney disease

Background - Limited data describe the cardiovascular benefit of HMG-CoA reductase inhibitors (statins) in people with moderate chronic kidney disease (CKD). The objective of this analysis was to determine whether pravastatin reduced the incidence of cardiovascular events in people with or at high risk for coronary disease and with concomitant moderate CKD. Methods and Results - We analyzed data from the Pravastatin Pooling Project (PPP), a subject-level database combining results from 3 randomized trials of pravastatin ( 40 mg daily) versus placebo. Of 19 700 subjects, 4491 ( 22.8%) had moderate CKD, defined by an estimated glomerular filtration rate of 30 to 59.99 mL/min per 1.73 m(2) body surface area. The primary outcome was time to myocardial infarction, coronary death, or percutaneous/surgical coronary revascularization. Moderate CKD was independently associated with an increased risk of the primary outcome ( adjusted HR 1.26, 95% CI 1.07 to 1.49) compared with those with normal renal function. Among the 4491 subjects with moderate CKD, pravastatin significantly reduced the incidence of the primary outcome ( HR 0.77, 95% CI 0.68 to 0.86), similar to the effect of pravastatin on the primary outcome in subjects with normal kidney function ( HR 0.78, 95% CI 0.65 to 0.94). Pravastatin also appeared to reduce the total mortality rate in those with moderate CKD ( adjusted HR 0.86, 95% CI 0.74 to 1.00, P = 0.045). Conclusions - Pravastatin reduces cardiovascular event rates in people with or at risk for coronary disease and concomitant moderate CKD, many of whom have serum creatinine levels within the normal range. Given the high risk associated with CKD, the absolute benefit that resulted from use of pravastatin was greater than in those with normal renal function.

3-D magnetic resonance angiography versus conventional angiography in peripheral arterial disease: Pilot study

Angiography is usually performed as the preoperative road map for those requiring revascularization for lower extremity peripheral arterial disease (PAD). The alternative investigations are ultrasound, 3-D magnetic resonance angiography (3-D MRA) and computed tomography angiography. This pilot study aimed to assess whether 3-D MRA could replace the gold standard angiography in preoperative planning. Eight patients considered for aortoiliac or infrainguinal arterial bypass surgery were recruited. All underwent both imaging modalities within 7 days. A vascular surgeon and a radiologist each reported on the images from both the 3-D MRA and the angiography, with blinding to patient details and each others reports. Comparisons were made between the reports for the angiographic and the 3-D MRA images, and between the reports of the vascular surgeon and the radiologist. Compared to the gold standard angiogram, 3-D MRA had a sensitivity of 77% and specificity of 94% in detecting occlusion, and a sensitivity of 72% and specificity of 90% in differentiating high grade (> 50%) versus low grade (< 50%) stenoses. There was an overall concordance of 78% between the two investigations with a range of 62% in the peroneal artery to 94% in the aorta. 3-D MRA showed flow in 23% of cases where conventional angiography showed no flow. In the present pilot study, 3-D MRA had reasonable concordance with the gold standard angiography, depending on the level of the lesion. At times it showed vessel flow where occlusion was shown on conventional angiogram. 3-D MRA in peripheral vascular disease is challenging the gold standard, but is inconsistent at present.

A cost-effectiveness analysis of fluvastatin in patients with diabetes after successful percutaneous coronary intervention

Background: The Lescol Intervention Prevention Study (LIPS) was a multinational randomized controlled trial that showed a 47% reduction in the relative risk of cardiac death and a 22% reduction in major adverse cardiac events (MACEs) from the routine use of fluvastatin, compared with controls, in patients undergoing percutaneous coronary intervention (PCI, defined as angioplasty with or without stents). In this study, MACEs included cardiac death, nonfatal myocardial infarction, and subsequent PCI and coronary artery bypass graft. Diabetes was the greatest risk factor for MACEs. Objective: This study estimated the cost-effectiveness of fluvastatin when used for secondary prevention of MACEs after PCI in people with diabetes. Methods: A post hoc subgroup analysis of patients with diabetes from the LIPS was used to estimate the effectiveness of fluvastatin in reducing myocardial infarction, revascularization, and cardiac death. A probabilistic Markov model was developed using United Kingdom resource and cost data to estimate the additional costs and quality-adjusted life-years (QALYs) gained over 10 years from the perspective of the British National Health Service. The model contained 6 health states, and the transition probabilities were derived from the LIPS data. Crossover from fluvastatin to other lipid-lowering drugs, withdrawal from fluvastatin, and the use of lipid-lowering drugs in the control group were included. Results: In the subgroup of 202 patients with diabetes in the LIPS trial, 18 (15.0%) of 120 fluvastatin patients and 21 (25.6%) of 82 control participants were insulin dependent (P = NS). Compared with the control group, patients treated with fluvastatin can expect to gain an additional mean (SD) of 0.196 (0.139) QALY per patient over 10 years (P < 0.001) and will cost the health service an additional mean (SD) of 10 (E448) (P = NS) (mean [SD] US $16 [$689]). The additional cost per QALY gained was;(51 (US $78). The key determinants of cost-effectiveness included the probabilities of repeat interventions, cardiac death, the cost of fluvastatin, and the time horizon used for the evaluation. Conclusion: Fluvastatin was an economically efficient treatment to prevent MACEs in these patients with diabetes undergoing PCI.

Platelet nitric oxide responsiveness - A novel prognostic marker in acute coronary syndromes

Objectives - Nitric oxide (NO) is critically important in the regulation of vascular tone and the inhibition of platelet aggregation. We have shown previously that patients with acute coronary syndromes (ACS) or stable angina pectoris have impaired platelet responses to NO donors when compared with normal subjects. We tested the hypotheses that platelet hyporesponsiveness to NO is a predictor of (1) cardiovascular readmission and/or death and (2) all-cause mortality in patients with ACS (unstable angina pectoris or non-Q-wave myocardial infarction). Methods and Results - Patients (n = 51) with ACS had evaluation of platelet aggregation within 24 hours of coronary care unit admission using impedance aggregometry. Patients were categorized as having normal (>= 32% inhibition of ADP-induced aggregation with the NO donor sodium nitroprusside; 10 mu mol/L; n = 18) or impaired (>= 32% inhibition of ADP-induced aggregation; n = 33) NO responses. We then compared the incidence of cardiovascular readmission and death during a median of 7 years of follow-up in these 2 groups. Using a Cox proportional hazards model adjusting for age, sex, index event, postdischarge medical treatment, revascularization status, left ventricular systolic dysfunction, concurrent disease states, and cardiac risk factors, impaired NO responsiveness was associated with an increased risk of the combination of cardiovascular readmission and/or death (relative risk, 2.7; 95% CI, 1.03 to 7.10; P = 0.041) and all-cause mortality (relative risk, 6.3; 95% CI, 1.09 to 36.7; P = 0.033). Conclusions - Impaired platelet NO responsiveness is a novel, independent predictor of increased mortality and cardiovascular morbidity in patients with high-risk ACS.

EphA4 regulates central nervous system vascular formation

Molecules involved in axon guidance have recently also been shown to play a role in blood vessel guidance. To examine whether axon guidance molecules, such as the EphA4 receptor tyrosine kinase, might also play a role in development of the central nervous system (CNS) vasculature and repair following CNS injury, we examined wild-type and EphA4 null mutant (-/-) mice. EphA4-/- mice exhibited an abnormal CNS vascular structure in both the cerebral cortex and the spinal cord, with disorganized branching and a 30% smaller diameter. During development, EphA4 was expressed on endothelial cells. This pattern of expression was not maintained in the adult. After spinal cord injury in wild-type mice, expression of EphA4 was markedly up-regulated on activated astrocytes, many of which were tightly associated with blood vessels. In EphA4-/- spinal cord following injury, astrocytes were not as tightly associated with blood vessels as the wild-type astrocytes. In uninjured EphA4-/- mice, the blood-brain barrier (BBB) appeared normal, but it showed prolonged leakage following spinal cord injury. These results support a role for EphA4 in CNS vascular formation and guidance during development and an additional role in BBB repair.

Incremental cost-effectiveness of exercise echocardiography vs. SPECT imaging for the evaluation of stable chest pain

Aims Technological advances in cardiac imaging have led to dramatic increases in test utilization and consumption of a growing proportion of cardiovascular healthcare costs. The opportunity costs of strategies favouring exercise echocardiography or SPECT imaging have been incompletely evaluated. Methods and results We examined prognosis and cost-effectiveness of exercise echocardiography (n=4884) vs. SPECT (n=4637) imaging in stable, intermediate risk, chest pain patients. Ischaemia extent was defined as the number of vascular territories with echocardiographic wall motion or SPECT perfusion abnormalities. Cox proportional hazard models were employed to assess time to cardiac death or myocardial infarction (MI). Total cardiovascular costs were summed (discounted and inflation-corrected) throughout follow-up. A cost-effectiveness ratio = 2% annual event risk), SPECT ischaemia was associated with earlier and greater utilization of coronary revascularization (P < 0.0001) resulting in an incremental cost-effectiveness ratio of $32 381/LYS. Conclusion Health care policies aimed at allocating limited resources can be effectively guided by applying clinical and economic outcomes evidence. A strategy aimed at cost-effective testing would support using echocardiography in low-risk patients with suspected coronary disease, whereas those higher risk patients benefit from referral to SPECT imaging.

Local geometric changes in left ventricular remodeling post-infarction can lead to apparent reduction in scar thickness

Serial reduction in scar thickness has been shown in animal models. We sought whether this reduction in scar thickness may be a result of dilatation of the left ventricle (LV) with stretching and thinning of the wall. Contrast enhanced magnetic resonance imaging (CMRI) was performed to delineate radial scar thickness in 25 patients (age 63±10, 21 men) after myocardial infarction. The LV was divided into 16 segts and the absolute radial scar thickness (ST) and percentage scar to total wall thickness (%ST) were measured. Regional end diastolic (EDV) and end systolic volumes (ESV) of corresponding segments were measured on CMRI. All patients underwent revascularization and serial changes in ST, %ST, and regional volumes were assessed with a mean follow up of 15±5 months. CMRI identified a total of 93 scar segments. An increase in EDV or ESV was associated with a serial reduction inST(versusEDV, r =−0.3, p = 0.01; versusESV, r =−0.3, p = 0.005) and%ST(versusEDV, r =−0.2, p = 0.04; versus ESV, r =−0.3, p = 0.001). For segts associated with a positive increase in EDV (group I) or ESV (group II) there was a significant decrease in ST and %ST, but in those segts with stable EDV (group III) or ESV (group IV) there were no significant changes in ST and %ST (Table).

Rotational co-culture of clonal β-cells with endothelial cells:effect of PPAR-γ agonism in vitro on insulin and VEGF secretion

Aim: Delayed graft revascularization impedes the success of human islet transplantation. This study utilized rotational co-culture of insulin secreting ß-cells with human umbilical vein endothelial cells (HUVECs) and a peroxisome proliferator-activated receptor gamma (PPAR-?) agonist to promote insulin and vascular endothelial growth factor (VEGF) secretory function. Methods: Clonal BRIN-BD11 (D11) cells were maintained in static culture (SC) and rotational culture (RC) ± HUVEC and ± the TZD (thiazolidinedione) rosiglitazone (10 mmol/l) as a specific PPAR-? agonist. HUVECs were cultured in SC and RC ± D11 and ± TZD. D11 insulin secretion was induced by static incubation with low glucose (1.67 mmol/l), high glucose (16.7 mmol/l) and high glucose with 10 mmol/l theophylline (G+T) and assessed by enzyme-linked immunosorbent assay (ELISA). HUVEC proliferation was determined by ATP luminescence, whereas VEGF secretion was quantified by ELISA. Co-cultured cells were characterized by immunostaining for insulin and CD31. Results: D11 SC and RC showed enhanced insulin secretion in response to 16.7 mmol/l and G+T (p <0.01); without significant alteration by the TZD. Co-culture with HUVEC in SC and RC also increased D11 insulin secretion when challenged with 16.7 mmol/l and G+T (p <0.01), and this was slightly enhanced by the TZD. The presence of HUVEC increased D11 SC and RC insulin secretion in response to high glucose and G+T, respectively (p <0.01). Addition of the TZD increased SC and RC HUVEC ATP content (p <0.01) and VEGF production (p <0.01) in the presence and absence of D11 cells. Conclusions: Rotational co-culture of insulin secreting cells with endothelial cells, and exposure to a PPAR-? agonist may improve the prospects for graft revascularization and function after implantation. © 2011 Blackwell Publishing Ltd.

Monocyte subpopulation counts and associations with left ventricular ejection fraction post ST elevation myocardial infarction

Background: Monocytes are implicated in the initiation and progression of the atherosclerotic plaque contributing to plaque instability and rupture. Little is known about the role of the three phenotypically and functionally different monocyte subpopulations in determining ventricular remodelling following ST elevation myocardial infarction (STEMI). Mon1 are the ‘classical’ monocytes with inflammatory action, whilst Mon3 are considered reparative with fibroblast deposition ability. The function of the newly described Mon2 subset is yet to be fully described. Method: STEMI patients (n=196, mean age 62±13 years; 72% male) treated with percutaneous revascularization were recruited within the first 24 h post-infarction. Peripheral blood monocyte subpopulations were enumerated and characterised using flow cytometry after staining for CD14, CD16 and CCR2. Phenotypically, monocyte subpopulations are defined as: CD14++CD16-CCR2+ (Mon1), CD14++CD16+CCR2+ (Mon2) and CD14+CD16++CCR2- (Mon3) cells. Transthoracic 2D echocardiography was performed within 7 days and at 6 months post infarct to assess ventricular volumes, mass, systolic, and diastolic functions as well as strain and strain rate. Results: Using linear regression analysis higher counts for Mon1, and lower counts for Mon2 and Mon3 were significantly associated with the baseline left ventricular ejection fraction (LVEF) within 7 days post infarct (table 1). At 6 months post STEMI lower counts of Mon2 remained positively associated with a decrease in LVEF at completion of remodelling (p=0.002). Conclusion: Peripheral monocytes of all three subsets correlate with LVEF after a myocardial infarction. High counts of the inflammatory Mon1 are associated with the reduced baseline ejection fraction post infarction. After remodelling, the convalescent ejection fraction was independently predicted by monocyte subpopulation 2. As lower counts depicted negative ventricular remodelling, this suggests a possible myofibroblast deposition and angiogenesis role for the newly described intermediate monocyte subpopulation Mon2 as opposed to the previously anticipated inflammatory role.

Monocyte subpopulation counts and TNF alpha associations with clinical outcome post ST elevation myocardial infarction

Background Monocytes are implicated in the initiation and progression of the atherosclerotic plaque contributing to its instability and rupture. Although peripheral monocytosis has been related to poor clinical outcome post ST elevation myocardial infarction (STEMI), only scarce information is available of mechanisms of this association. Tumour necrosis factor alpha (TNFα) is a key cytokine in the acute phase inflammatory response, and it is predominantly produced by inflammatory macrophages. Little is known about TNFα association with circulating monocyte subpopulations post STEMI. Method A total of 142 STEMI patients (mean age 62±13 years; 72% male) treated with percutaneous revascularization were recruited with blood samples obtained within first 24 hours from the onset and on day 10-14. Peripheral blood monocyte subpopulations were enumerated and characterized using flow cytometry after staining for CD14, CD16 and CCR2 and were defined as: CD14++CD16-CCR2+ (Mon1), CD14++CD16+CCR+ (Mon2) and CD14+CD16++CCR2- (Mon3) cells. Plasma levels of TNFα were measured by enzyme-linked immunosorbent assay (ELISA, Peprotec system, UK). Major adverse cardiac events (MACE), defined as recurrent STEMI, new diagnosis of heart failure and death were recorded at follow up, mean of 164±134 days. Results TNFα levels were significantly higher 24 hours post STEMI, compared to day 14 (paired t-test, p <0.001) with day 1 levels weakly correlated with total monocyte count as well as Mon1 (Spearman’s correlation, r=0.19, p=0.02 and r=0.22, p=0.01, respectively). There was no correlation between TNFα and Mon2 or Mon3 subpopulations. TNFα levels were significantly higher in patients with a recorded MACE (n=28, Mann-Whitney test, p<0.001) (figure 1).⇓

Monocyte subset counts associations with left ventricular systolic function post ST elevation myocardial infarction

Background: Monocytes are implicated in the initiation and progression of theatherosclerotic plaque contributing to plaque instability and rupture. Little is knownof the role played by the 3 phenotypically and functionally different monocytesubpopulations in determining ventricular remodeling following ST elevation my-ocardial infarction (STEMI). Mon1 are "classical" inflammatory monocytes, whilstMon3 are considered reparative with fibroblast deposition ability. The function ofthe newly described Mon2 is yet to be elucidated. Method: STEMI patients (n=196, mean age 62±13 years; 72% male) treatedwith percutaneous revascularization were recruited within the first 24 hours. Pe-ripheral blood monocyte subpopulations were enumerated and characterizedusing flow cytometry after staining for CD14, CD16 and CCR2. Phenotypi-cally, monocyte subpopulations are defined as: CD14+CD16-CCR2+ (Mon1),CD14+CD16+CCR+ (Mon2) and CD14lowCD16+CCR2- (Mon3) cells. Transtho-racic 2D echocardiography was performed within 7 days and 6 months post infarctto assess ventricular volumes, mass, systolic, and diastolic functions. Results: Using linear regression analysis higher counts for Mon1, and lowercounts for Mon2 and Mon3 were significantly associated with the baseline leftventricular ejection fraction (LVEF) within seven days post infarction. At 6 monthspost STEMI lower counts of Mon2 remained positively associated with decreasedLVEF (p value= 0.002).Monocyte subsets correlation with LVEFMonocytes mean florescence Baseline left ventricular Left ventricular ejectionintensity (cells/μl) ejection fraction (%) fraction (%) at 6 months post infarctβ-value P-valueβ-value P-valueTotal Mon0.31 P<0.001 0.360.009Mon 10.019 0.020.070.62Mon 2−0.28 0.001 −0.420.002Mon 3−0.27 0.001 −0.180.21 Conclusion: Peripheral monocytes of all three subsets correlate with LVEF af-ter a myocardial infarction. High counts of the inflammatory Mon1 are associatedwith reduction in the baseline LVEF. Post remodelling, the convalescent EF wasindependently predicted by monocyte subpopulation 2. As lower counts depictednegative ventricular remodeling, this suggests a reparative role for the newly de-scribed Mon2, possibly via myofibroblast deposition and angiogenesis, in contrastto an anticipated inflammatory role.

Endothelial cell redox regulation of ischemic angiogenesis

The endothelium produces and responds to reactive oxygen and nitrogen species (RONS), providing important redox regulation to the cardiovascular system in physiology and disease. In no other situation are RONS more critical than in the response to tissue ischemia. Here, tissue healing requires growth factor-mediated angiogenesis that is in part dependent on low levels of RONS, which paradoxically must overcome the damaging effects of high levels of RONS generated as a result of ischemia. While generation of endothelial cell RONS in hypoxia/reoxygenation is acknowledged, the mechanism for their role in angiogenesis is still poorly understood. During ischemia, the major low molecular weight thiol glutathione (GSH) reacts with RONS and protein cysteines, producing GSH-protein adducts. Recent data indicate that GSH adducts on certain proteins are essential to growth factor responses in endothelial cells. Genetic deletion of the enzyme glutaredoxin-1, which selectively removes GSH protein adducts, improves, while its overexpression impairs, revascularization of the ischemic hindlimb of mice. Ischemia-induced GSH adducts on specific cysteine residues of several proteins, including p65 NFkB and the sarcoplasmic reticulum calcium ATPase-2 (SERCA2), appear to promote ischemic angiogenesis. Identifying the specific proteins in the redox response to ischemia has provided therapeutic opportunities to improve clinical outcomes of ischemia.

Endothelial cell-derived Pentraxin 3 limits the vasoreparative therapeutic potential of Circulating Angiogenic Cells

AIMS: Circulating Angiogenic Cells (CACs) promote revascularization of ischemic tissues although their underlying mechanism of action and the consequences of delivering varying numbers of these cells for therapy remain unknown. This study investigates molecular mechanisms underpinning CAC modulation of blood vessel formation.

METHODS & RESULTS: CACs at low (2x10(5)cells/ml) and mid (2x10(6)cells/ml) cellular densities significantly enhanced endothelial cell (EC) tube formation in vitro, while high density CACs (2x10(7)cells/ml) significantly inhibited this angiogenic process. In vivo, Matrigel-based angiogenesis assays confirmed mid-density CACs as pro-angiogenic and high density CACs as anti-angiogenic. Secretome characterization of CAC-EC conditioned media identified pentraxin 3 (PTX3) as only present in the high density CAC-EC co-culture. Recombinant PTX3 inhibited endothelial tube formation in vitro and in vivo Importantly, our data revealed that the anti-angiogenic effect observed in high density CAC-EC co-cultures was significantly abrogated when PTX3 bioactivity was blocked using neutralizing antibodies or PTX3 siRNA in endothelial cells. We show evidence for an endothelial source of PTX3, triggered by exposure to high density CACs. In addition, we confirmed that PTX3 inhibits FGF2-mediated angiogenesis, and that the PTX3 N-terminus, containing the FGF-binding site, is responsible for such anti-angiogenic effects.

CONCLUSIONS: Endothelium, when exposed to high density CACs, releases PTX3 which markedly impairs the vascular regenerative response in an autocrine manner. Therefore, CAC density and accompanying release of angiocrine PTX3 are critical considerations when using these cells as a cell therapy for ischemic disease.