Juha Salenius

Carbonic anhydrases II and XII are up-regulated in osteoclast-like cells in advanced human atherosclerotic plaques—Tampere Vascular Study

Abstract Background and aims. Carbonic anhydrases (CA) play a central role in osteoclast function and bone remodeling by catalyzing the formation of bicarbonate and proton from carbon dioxide. According to previous histochemical studies, advanced atherosclerotic plaques share similarities with bone. However, whether CAs are expressed in plaques is not known. Methods and results. Whole genome expression array of arterial samples (n = 24) confirmed that several genes indicating osteoblastogenesis and osteoclastogenesis were up-regulated in plaques when compared to control vessel samples from internal thoracic arteries (n = 6), including CA2 and CA12, expression of which was also verified with quantitative reverse transcription polymerase chain reaction (RT-PCR). In atherosclerotic plaques there was 11.6-fold (P < 0.0001) and 11.4-fold (P < 0.0001) up-regulation of CA2 and CA12, compared to controls, respectively. According to quantitative PCR, CA2 expression was elevated in carotid (12.3-fold, P < 0.0001), femoral (13.2-fold, P < 0.01), and aortic plaques (7.5-fold, P < 0.0001). CA12 expression was elevated in carotid (11.6-fold, P < 0.0001), femoral (11.5-fold, P < 0.01), and aortic plaques (9.7-fold, P < 0.0001). CAII, CAXII, and CD68 and tartrate-resistant acid phosphatase (TRAP), a marker of osteoclast-like cells, were found to be co-localized in multinucleated giant cells in the atherosclerotic plaques using immunohistochemistry and double-staining immunofluorescence analysis. Conclusions. The present findings provide evidence for the involvement of CAs in advanced atherosclerosis in osteoclast-like cells of monocyte-macrophage lineage.

Biochemical composition of human peripheral arteries examined with nearinfrared Raman spectroscopy

PURPOSE Near-infrared Raman spectroscopy provides an important new means of analyzing the chemical composition of the arterial wall. The objective of this study was to show that Raman spectroscopy can be used to evaluate the lipid and calcium salt contents of human peripheral arteries. The results extend a recently developed Raman-based method for analyzing the chemical composition of coronary arteries. METHODS AND RESULTS We studied 167 segments of carotid and femoral artery wall in various pathologic states. The Raman spectra from these samples was accurately modeled. The resulting chemical concentrations were compared with the amounts of cholesterol and calcium mineral determined at histologic evaluation by an experienced cardiovascular pathologist. Strong correlations between spectroscopic measurements and morphologic findings were demonstrated and validated the applicability of the method to peripheral arteries. CONCLUSIONS Raman spectroscopy can provide reliable histochemical information about peripheral and coronary arteries. Such information may help identify rupture-prone plaques before the onset of symptoms and allow aggressive and directed intervention. Accurate knowledge of the chemical composition of a lesion may be useful in selecting the most appropriate treatment.

Long-term outcome of surgical revascularization of supraaortic vessels

The aim of this study was to evaluate long-term results of different surgical reconstructions of supraaortic vessels, particularly the subclavian and innominate arteries. It is a retrospective review of 33 years experience in a teaching hospital; 80 surgical revascularizations were performed in 76 patients who suffered occlusive disease of subclavian or innominate artery from 1965 to 1998. These included 38 bypass (BP) Operations (28 carotid-subclavian, 4 aorto-subclavian, 3 aorto-innominate, and 3 subclavian transpositions) and 42 endarterectomies (EA). All available patients (34) were reassessed clinically, and by triplex scanning. The mean clinical follow-up was 9 months (range 1 to 116 months) for all patients and for control-examined patients 158 months (range 6 to 346 months). Four patients were lost to follow-up. The perioperative mortality was 2.5% (BP, 0%; EA, 5%). The overall patency rate for both the BP and the EA procedures was 95% at 1 and 5 years; 91% at 10 years (BP, 89%; EA, 93%) and 89% (BP, 87%; EA, 90%) at 15 years. Most of the patients (84%) were satisfied with the clinical result in the long term. We conclude that surgical revascularization of supraaortic vessels is an infrequent procedure, and all surgical techniques give good and durable long-term outcome.RésuméLe but de cette étude a été d’évaluer les résultats à long terme de reconstruction chirurgicale des vaisseaux supra-aortiques, et en particulier des artères sous-ciavière (SC) et innommée (AI). Selon une revue rétrospective sur 33 ans dans un hôpital universitaire, on a réalisé 80 revascularisations chirurgicales chez 76 patients porteurs de maladie occlusive des artères sous-clavière ou innominée entre 1965 et 1998. Celles-ci comprenaient 38 pontages (P) (28 carotido-sous-claviers, quatre aorto-sous-claviers, trois aorto-innominés et trois transpositions sous-clavières) et 42 endartérectomies (EA). Tous les patients disponibles (n=34) ont été ré-évalués cliniquement, et par Duplex scanning. Le suivi clinique moyen a été de 9 mois (extrêmes 1–116 mois) pour tous les patients et 158 mois (extrêmes 6–346 mois) pour les patients au moment de l’examen de contrôle (1998). Quatre patients ont été perdus de vue. La mortalité périopératoire a été de 2.5% (P 0%, EA 5%). Le taux de perméabilité globale a été similaire pour les P et pour les EA: 95% à 1 an et à 5 ans pour les deux, 91% à 10 ans (P 89%, EA 93%) et de 89% (P 87%, EA 90%) à 15 ans. Après un suivi à long terme, on a constaté que la plupart des patients (84%) étaient satisfaits des résultats cliniques. Nous concluons que la revascularisation des vaisseaux supra-aortiques est un procédé peu fréquent, mais que toutes les techniques chirurgicales donnent de bons résultats durables à long terme.ResumenEvaluar los resultados tardíos de diferentes técnicas de reconstructión de a los vasos supraaórticos especialmente de las arterias subclavia (SCA) y tronco innominado (INA). Se efectúa, en un hospital universitario, un estudio retrospectivo de 33 años. Entre 1965 y 1998 se realizaron 80 operaciones revascularizadoras en 76 pacientes con enfermedad oclusiva de la SCA o del INA. 38 (BP) bypass derivativos (28 carotida-subclavia, 4 aorto-subclavia, 3 aorto-tronco innominado y 3 transposiciones subclavias) y 42 endoarteriectomías (EA). 34 pacientes pudieron ser reexaminados mediante escanografía helicoidal y estudio clínico. El seguimiento medio para todos los pacientes fue de 9 meses (rango 1–116 meses) y para los pacientes controlados y reexplorados de 158 meses (rango 6–346 meses). Durante el seguimiento se perdieron 4 pacientes. La mortalidad perioperatoria fue de 2.5% (BP 0%, EA 5%). La permeabilidad global tanto para los procedimientos de BP como de EA fue del 95% a los 1–5 años, del 91% a los 10 años (BP 89%, EA 93%) y del 89% a los 15 años (BP 87%, EA 90%). La mayoría de los pacientes se mostraron satisfechos con los resultados clínicos tardíos. Las intervenciones revascularizadoras de los troncos supraaórticos son raras, pero todos los procedimientos quirúrgicos proporcionan buenos y perdurables resultados.

Peripheral arterial disease, diabetes and postural balance among elderly Finns: a population-based study

Background and aims: Little is known about the role of peripheral arterial disease (PAD)in the development of balance impairment. The aim of this study was to assess postural balance among people having PAD or PAD combined with diabetes. Methods: As part of the comprehensive health examination of the Health 2000 survey (two-stage stratified cluster sampling), 1323 people aged 65 years or older took part in balance assessments using a force platform system. The presence of PAD was confirmed with data from the National Hospital Discharge Registry. Individuals with hospitalization due to PAD were regarded as having severe disease, whereas those with solely self-reported diagnosis were considered possible cases. Diabetes was ascertained on the basis of self-reported physicians’ diagnoses subsequently confirmed in a clinical examination. Results: Forty-five (3.4%) individuals had previously been hospitalized due to PAD, and 32 (2.4%) reported that they had been diagnosed with the disease. 413 (31%) participants had diabetes. Compared with people without PAD, those with confirmed diagnoses exhibited significantly increased movement of the center of pressure while standing, indicating deteriorated balance. Those with possible PAD formed an intermediate group. Diabetes exacerbated the deterioration in balance, but the interaction term between PAD and diabetes did not reach statistical significance. The risk of failing tandem stance tests was over three-fold (OR 3.20, 95% CI 1.09–9.37) among those with confirmed PAD and almost one and a half-fold (OR 1.44, 95% CI 1.07–1.93) among those with diabetes, in comparison to those without these diseases. Conclusions: Individuals over 65 years of age with severe PAD showed increased balance impairment, a known risk factor for falls and disability in aged people. Diabetes affected balance somewhat less than PAD, but there was no formal evidence of the synergetic effect of the two diseases. Additional studies are indicated to reveal the possible effect of proper treatment of PAD and diabetes, combined with suitabletraining interventions on slowing down the progression of balance impairment.

Upstream Transcription Factor 1 (USF1) allelic variants regulate lipoprotein metabolism in women and USF1 expression in atherosclerotic plaque

Upstream transcription factor 1 (USF1) allelic variants significantly influence future risk of cardiovascular disease and overall mortality in females. We investigated sex-specific effects of USF1 gene allelic variants on serum indices of lipoprotein metabolism, early markers of asymptomatic atherosclerosis and their changes during six years of follow-up. In addition, we investigated the cis-regulatory role of these USF1 variants in artery wall tissues in Caucasians. In the Cardiovascular Risk in Young Finns Study, 1,608 participants (56% women, aged 31.9 ± 4.9) with lipids and cIMT data were included. For functional study, whole genome mRNA expression profiling was performed in 91 histologically classified atherosclerotic samples. In females, serum total, LDL cholesterol and apoB levels increased gradually according to USF1 rs2516839 genotypes TT < CT < CC and rs1556259 AA < AG < GG as well as according to USF1 H3 (GCCCGG) copy number 0 < 1 < 2. Furthermore, the carriers of minor alleles of rs2516839 (C) and rs1556259 (G) of USF1 gene had decreased USF1 expression in atherosclerotic plaques (P = 0.028 and 0.08, respectively) as compared to non-carriers. The genetic variation in USF1 influence USF1 transcript expression in advanced atherosclerosis and regulates levels and metabolism of circulating apoB and apoB-containing lipoprotein particles in sex-dependent manner, but is not a major determinant of early markers of atherosclerosis.

Vascular comorbidities and demographics of patients with ruptured abdominal aortic aneurysms

BACKGROUND The results of previous studies reporting the epidemiology of ruptured abdominal aortic aneurysm (RAAA) are highly heterogeneous. Furthermore, although RAAA and the preceding abnormal dilation of the abdominal aorta (AAA) are associated with other cardiovascular comorbidities, the demographic profile of all patients with RAAA has not been thoroughly investigated. OBJECTIVE To document accurately the epidemiology, survival, and demographic data (including vascular comorbidities and previous use of health care services) in RAAA-patients. MATERIAL AND METHODS We conducted a comprehensive retrospective register study of all RAAA patients (operatively treated RAAA patients as well as in- and out-of-hospital nonsurvivors) in a well-defined geographic area during an 11-year period. RESULTS We found 488 RAAA cases in a catchment area of 689,000. The annual incidence of RAAA was 6.5/100,000. Of these patients 43.2% were underwent surgery. Overall mortality was 79.5%, and 27.5% of the population died out-of-hospital. Age was the only independent risk factor affecting survival (P < .0001). The mean age at the time of RAAA was 73.6 years for men and 82.3 years for women. Off all unexpected RAAA patients, 40% had a previous history of cardiovascular disease (most often coronary artery disease: 32%), and 38% had visited a physician within the previous year. CONCLUSION RAAA remains a highly lethal condition with age as the only significant risk factor for mortality. The proportion of women increases strongly with age. A large proportion of patients with unexpected RAAA have history of cardiovascular disease.

Peripheral arterial disease and its clinical significance in nonagenarians

Background and aims: The purpose of this study was to characterize the prevalence and clinical features of peripheral arterial disease (PAD) among 90-year-old individuals and to assess its relationship to lower extremity functional status and survival over one year. Methods: A prospective, population-based study of all 90-year-old residents of Jyväskylä, Finland. Fifty-eight out of the 79 registered residents were examined for ankle-brachial index (ABI). Lower extremity functional status was assessed as self-reported difficulty in performing specific physical activities of daily living (PADL). In a subgroup of 36 individuals, lower extremity functioning was further assessed by measuring walking endurance and walking velocity. Death dates were collected for one year after the examination from the hospital register. Results: Thirteen persons (22%) had an ABI<0.9. PAD was asymptomatic in 11 of them and the diagnosis of PAD new to 12 of them. Thirty (52%) subjects had a normal ABI (0.9–1.4) and in 15 (26%) cases the ABI was pathologically high (>1.4). A significant accumulation of cardiovascular risk factors was observed among those with an ABI<0.9 compared with those with normal or high ABI (2.0±0.8 vs 1.3±0.8 vs 1.5±0.5, p=0.03). Those with low or high ABI reported more difficulties in the PADL tasks than those with normal ABI, but the results did not reach statistical significance. No difference in maximal walking velocity was observed according to ABI in the subgroup with data available. After one year, nine people had died, of whom only two (7%) with normal ABI and seven with low or high ABI (25%) (p=0.05). Conclusions: PAD was found to be mainly asymptomatic among 90-year-old people. An abnormal ABI was also associated with increased mortality risk over a one-year follow-up. Although our study was small-scale, it does provide novel information about the prevalence of PAD and clinical significance of ABI in very old people.

Long-Term Experience of Endovascular Repair for Thoracic Aortic Aneurysms and Dissections

Purpose: To report the long-term results of thoracic endovascular aortic repair (TEVAR) in both elective and emergency cases of thoracic aortic aneurysm (TAA) and type B dissection. Material and Methods: A prospective single-center study of 78 TEVAR patients treated between February 1998 and February 2013. Stent-graft implantation was performed in 51 (65%) patients for TAA (43 elective and 8 emergency cases) and in 27 (35%) patients for type B dissection (11 elective and 16 emergency cases). Short- and long-term results were evaluated, and a subgroup of patients with left subclavian artery (LSA) coverage was also analyzed. Results: The patients were followed for a mean of 55 months (1-160 months). The technical success rate was 81% and 30-day mortality 6.4% (n = 5). The stroke rate was 7.7% (n = 6) and permanent paraparesis 2.6% (n = 2). In follow-up, there were 28 (36%) primary (15 type I and 13 type II) and 10 secondary endoleaks (8 type I and 2 type II). Multivariate analysis showed no significant predictive factors for developing a type I endoleak. Secondary interventions were required in 24% of the patients. There was 1 late thoracic aortic rupture and 1 late conversion (1.3%). Patients with LSA coverage had a higher incidence of stroke (12.5% vs 4.3%, P = .18) and paraparesis (3.1% vs 2.2%, P = .79) compared to those without LSA coverage, although this difference was not statistically significant. Stroke rates were significantly higher in patients treated in an emergency setting (P = .048). Conclusion: Thoracic endovascular aortic repair is a relatively safe and effective therapy for different aortic pathologies with good long-term success. The risk of stroke and paraparesis is notable whether the LSA is covered, and strokes clearly accumulate in the emergency setting. A type I endoleak is the most common complication, but there are no predictive factors for its development.

Differentially expressed genes and canonical pathway expression in human atherosclerotic plaques – Tampere Vascular Study

Cardiovascular diseases due to atherosclerosis are the leading cause of death globally. We aimed to investigate the potentially altered gene and pathway expression in advanced peripheral atherosclerotic plaques in comparison to healthy control arteries. Gene expression analysis was performed (Illumina HumanHT-12 version 3 Expression BeadChip) for 68 advanced atherosclerotic plaques (15 aortic, 29 carotid and 24 femoral plaques) and 28 controls (left internal thoracic artery (LITA)) from Tampere Vascular Study. Dysregulation of individual genes was compared to healthy controls and between plaques from different arterial beds and Ingenuity pathway analysis was conducted on genes with a fold change (FC) > ±1.5 and false discovery rate (FDR) < 0.05. 787 genes were significantly differentially expressed in atherosclerotic plaques. The most up-regulated genes were osteopontin and multiple MMPs, and the most down-regulated were cell death-inducing DFFA-like effector C and A (CIDEC, CIDEA) and apolipoprotein D (FC > 20). 156 pathways were differentially expressed in atherosclerotic plaques, mostly inflammation-related, especially related with leukocyte trafficking and signaling. In artery specific plaque analysis 50.4% of canonical pathways and 41.2% GO terms differentially expressed were in common for all three arterial beds. Our results confirm the inflammatory nature of advanced atherosclerosis and show novel pathway differences between different arterial beds.

Hybrid Repair of Thoracoabdominal Aortic Aneurysms Is a Durable Option for High-Risk Patients in the Endovascular Era:

Objective: To report our long-term experience in using the hybrid technique in complex thoracoabdominal aortic aneurysms (TAAAs). Methods: Between March 2005 and September 2013, 10 patients with TAAA underwent hybrid procedures with open renovisceral revascularization and thoracoabdominal aortic endografting. Patients were analyzed retrospectively. Results: Six men and 4 women with a mean age of 66 years (range 54-81 years) were treated electively during the study period. All 4 visceral vessels were revascularized in 8 patients, whereas 1 patient underwent 3-vessel revascularization and another 2-vessel revascularization. The primary technical success rate was 100%. Eight of the procedures were single staged, and the 2 most recent cases were performed in 2 stages. Perioperative and 30-day mortality was 0%. The mean follow-up was 55 months (4-133 months). None of the patients died due to aortic complications. Major complications included paraplegia (10%, n = 1) and bowel ischemia (n = 1). Postoperative cerebrospinal fluid (CSF) pressure and mean arterial pressure measurements were systematically monitored and corrected. The CSF drainage solved another 4 cases of paraparesis. Three patients required postoperative dialysis, but none of them required permanently. Postoperative spinal cord ischemia and renal complications accumulated in extensive TAAA cases. One renal graft was occluded 45 days after the initial procedure but was successfully treated with thrombolysis. One type I and 1 type III endoleak were noted and successfully treated with an additional stent graft. Two cases of type II endoleak were detected—one with a growing aneurysm sac was treated successfully and another showed no growth and further procedures were abandoned after 2 embolization attempts. In long-term follow-up, 90% of the aneurysms showed shrinkage by a mean of 23 mm (range 7-45 mm). Conclusion: The results of hybrid repair on high-risk patients with complex TAAAs are encouraging, and this approach is a valuable alternative when branched and fenestrated endovascular techniques are not considered an option.