Ischemia and fibrosis: the risk mechanisms of hypertensive heart disease

Mechanisms underlying risk associated with hypertensive heart disease (HHD) and left ventricular hypertrophy (LVH) are discussed in this report and provide a rationale for understanding this very common and important cause of death from hypertension and its complications. Emphasized are impaired coronary hemodynamics, endothelial dysfunction, and ventricular fibrosis from increased collagen deposition intramurally and perivascularly. Each is exacerbated by aging and, perhaps, also by increased dietary salt intake. These functional and structural changes promote further endothelial dysfunction, altered coronary hemodynamics, and diastolic as well as systolic ventricular contractile function in HHD. The clinical endpoints of HHD include angina pectoris (with or without atherosclerosis of the epicardial coronary arteries), myocardial infarction, cardiac failure, lethal dysrhythmias, and sudden death. The major concept to be derived from these alterations is that not all that is clinically recognized as LVH is true myocytic hypertrophy and structural remodeling. Other major co-morbid changes occur that serve to increase cardiovascular risk including impaired coronary hemodynamics, endothelial dysfunction, and ventricular fibrosis.

Head-to-head comparison of dipyridamole, dobutamine and pacing stress echocardiography for the detection of myocardial ischemia in an animal model of coronary artery stenosis

To compare the sensitivity of dipyridamole, dobutamine and pacing stress echocardiography for the detection of myocardial ischemia we produced a physiologically significant stenosis in the left circumflex artery of 14 open-chest dogs (range: 50 to 89% reduction in luminal diameter). In each study, dobutamine (5 to 40 µg kg-1 min-1 in 3-min stages) and pacing (20 bpm increments, each 2 min, up to 260 bpm) were performed randomly, and then followed by dipyridamole (up to 0.84 mg/kg over 10 min). The positivity of stress echocardiography tests was quantitatively determined by a significant (P<0.05) reduction of or failure to increase absolute and percent systolic wall thickening in the stenotic artery supplied wall, as compared to the opposite wall (areas related to the left anterior descending artery). Systolic and diastolic frozen images were analyzed off-line by two blinded observers in the control and stress conditions. The results showed that 1) the sensitivity of dobutamine, dipyridamole and pacing stress tests was 57, 57 and 36%, respectively; 2) in animals with positive tests, the mean percent change of wall thickening in left ventricular ischemic segments was larger in the pacing (-19 ± 11%) and dipyridamole (-18 ± 16%) tests as compared to dobutamine (-9 ± 6%) (P = 0.05), but a similar mean reduction of wall thickening was observed when this variable was normalized to a control left ventricular segment (area related to the left anterior descending artery) (pacing: -16 ± 7%; dipyridamole: -25 ± 16%; dobutamine: -26 ± 10%; not significant), and 3) a significant correlation was observed between magnitude of coronary stenosis and left ventricular segmental dysfunction induced by ischemia in dogs submitted to positive stress tests. We conclude that the dobutamine and dipyridamole stress tests showed identical sensitivities for the detection of myocardial ischemia in this one-vessel disease animal model with a wide range of left circumflex artery stenosis. The pacing stress test was less sensitive, but the difference was not statistically significant. The magnitude of segmental left ventricular dysfunction induced by ischemia was similar in all stress tests evaluated.

Relationship between microalbuminuria and cardiac structural changes in mild hypertensive patients

The aim of this study was to determine the relationship between urinary albumin excretion (UAE), cardiac structural changes upon echocardiography and 24-h ambulatory blood pressure (ABPM) levels. Twenty mild hypertensive patients (mean age 56.8 ± 9.6 years) were evaluated. After 2 weeks of a washout period of all antihypertensive drugs, all patients underwent an echocardiographic evaluation, a 24-h ABPM and an overnight urine collection. Systolic and diastolic blood pressure during 24-h ABPM was 145 ± 14/91 ± 10 mmHg (daytime) and 130 ± 14/76 ± 8 mmHg (nighttime), respectively. Seven (35%) patients presented UAE > or = 15 µg/min, and for the whole group, the geometric mean value for UAE was 10.2 x/÷ 3.86 µg/min. Cardiac measurements showed mean values of interventricular septum thickness (IVS) of 11 ± 2.3 mm, left ventricular posterior wall thickness (PWT) of 10 ± 2.0 mm, left ventricular mass (LVM) of 165 ± 52 g, and left ventricular mass index (LVMI) of 99 ± 31 g/m². A forward stepwise regression model indicated that blood pressure levels did not influence UAE. Significant correlations were observed between UAE and cardiac structural parameters such as IVS (r = 0.71, P<0.001), PWT (r = 0.64, P<0.005), LVM (r = 0.65, P<0.005) and LVMI (r = 0.57, P<0.01). Compared with normoalbuminuric patients, those who had microalbuminuria presented higher values of all cardiac parameters measured. The predictive positive and negative values of UAE > or = 15 µg/min for the presence of geometric cardiac abnormalities were 75 and 91.6%. These data indicate that microalbuminuria in essential hypertension represents an early marker of cardiac structural damage.

Effect of lung resection and sham surgery on the frequency of infection in alloxan-diabetic rats

The present study was carried out in order to determine the effect of lung resection on the frequency of infections in alloxan-diabetic rats. Adult female Wistar rats were injected with alloxan (40 mg/kg, iv) to induce diabetes mellitus (group D; N = 45) or with vehicle (1.0 ml/kg, iv) to be used as controls (group C; N = 45). Thirty-six days after receiving alloxan both groups were randomly divided into three subgroups: no operation (NO; N = 15), sham operation (SO; N = 15), and left pneumonectomy (PE; N = 15). The rats were sacrificed 36 days after surgery and their lungs were examined microscopically and macroscopically. The occurrence of thoracic wall infection, thoracic wall abscess, lung abscess and pleural empyema was similar in groups D and C. In contrast, the overall infection rate was higher (P<0.05) in the diabetic rats (SO-D and PE-D subgroups, but not in the NO-D subgroup). Considering that the overall infection rate was similar in the SO-D and PE-D subgroups, we suggest that surgery but not pneumonectomy was related to the higher prevalence of infection in diabetic rats.

Long-chain n-3 fatty acids and inflammation: potential application in surgical and trauma patients

Lipids used in nutritional support of surgical or critically ill patients have been based on soybean oil, which is rich in the n-6 fatty acid linoleic acid (18:2n-6). Linoleic acid is the precursor of arachidonic acid (20:4n-6). In turn, arachidonic acid in cell membrane phospholipids is the substrate for the synthesis of a range of biologically active compounds (eicosanoids) including prostaglandins, thromboxanes, and leukotrienes. These compounds can act as mediators in their own right and can also act as regulators of other processes, such as platelet aggregation, blood clotting, smooth muscle contraction, leukocyte chemotaxis, inflammatory cytokine production, and immune function. There is a view that an excess of n-6 fatty acids should be avoided since this could contribute to a state where physiological processes become dysregulated. One alternative is the use of fish oil. The rationale of this latter approach is that fish oil contains long chain n-3 fatty acids, such as eicosapentaenoic acid. When fish oil is provided, eicosapentaenoic acid is incorporated into cell membrane phospholipids, partly at the expense of arachidonic acid. Thus, there is less arachidonic acid available for eicosanoid synthesis. Hence, fish oil decreases production of prostaglandins like PGE2 and of leukotrienes like LTB4. Thus, n-3 fatty acids can potentially reduce platelet aggregation, blood clotting, smooth muscle contraction, and leukocyte chemotaxis, and can modulate inflammatory cytokine production and immune function. These effects have been demonstrated in cell culture, animal feeding and healthy volunteer studies. Fish oil decreases the host metabolic response and improves survival to endotoxin in laboratory animals. Recently clinical studies performed in various patient groups have indicated benefit from this approach.

Expression of inducible nitric oxide synthase is increased in patients with heart failure due to ischemic disease

The objective of the present study was to determine the relationship between nitric oxide synthases (NOS) and heart failure in cardiac tissue from patients with and without cardiac decompensation. Right atrial tissue was excised from patients with coronary artery disease (CAD) and left ventricular ejection fraction (LVEF) <35% (N = 10), and from patients with CAD and LVEF >60% (N = 10) during cardiac surgery. NOS activity was measured by the conversion of L-[H³]-arginine to L-[H³]-citrulline. Gene expression was quantified by the competitive reverse transcription-polymerase chain reaction. Both endothelial NOS (eNOS) activity and expression were significantly reduced in failing hearts compared to non-failing hearts: 0.36 ± 0.18 vs 1.51 ± 0.31 pmol mg-1 min-1 (P < 0.0001) and 0.37 ± 0.08 vs 0.78 ± 0.09 relative cDNA absorbance at 320 nm (P < 0.0001), respectively. In contrast, inducible NOS (iNOS) activity and expression were significantly higher in failing hearts than in non-failing hearts: 4.00 ± 0.90 vs 1.54 ± 0.65 pmol mg-1 min-1 (P < 0.0001) and 2.19 ± 0.27 vs 1.43 ± 0.13 cDNA absorbance at 320 nm (P < 0.0001), respectively. We conclude that heart failure down-regulates both eNOS activity and expression in cardiac tissue from patients with LVEF <35%. In contrast, iNOS activity and expression are increased in failing hearts and may represent an alternative mechanism for nitric oxide production in heart failure due to ischemic disease.

The role of secondary hyperparathyroidism in left ventricular hypertrophy of patients under chronic hemodialysis

End-stage renal disease (ESRD) patients frequently develop structural cardiac abnormalities, particularly left ventricular hypertrophy (LVH). The mechanisms involved in these processes are not completely understood. In the present study, we evaluated a possible association between parathyroid hormone (PTH) levels and left ventricular mass (LVM) in patients with ESRD. Stable uremic patients on intermittent hemodialysis treatment were evaluated by standard two-dimensional echocardiography and their sera were analyzed for intact PTH. Forty-one patients (mean age 45 years, range 18 to 61 years), 61% males, who had been on hemodialysis for 3 to 186 months, were evaluated. Patients were stratified into 3 groups according to serum PTH: low levels (<100 pg/ml; group I = 10 patients), intermediate levels (100 to 280 pg/ml; group II = 10 patients) and high levels (>280 pg/ml; group III = 21 patients). A positive statistically significant association between LVM index and PTH was identified (r = 0.34; P = 0.03, Pearson's correlation coefficient) in the sample as a whole. In subgroup analyses, we did not observe significant associations in the low and intermediate PTH groups; nevertheless, PTH and LVM index were correlated in patients with high PTH levels (r = 0.62; P = 0.003). LVM index was also inversely associated with hemoglobin (r = -0.34; P = 0.03). In multivariate analysis, after adjustment for age, hemoglobin, body mass index, and blood pressure, the only independent predictor of LVM index was PTH level. Therefore, PTH is an independent predictor of LVH in patients undergoing chronic hemodialysis. Secondary hyperparathyroidism may contribute to the elevated cardiovascular morbidity associated with LVH in ESRD.

Mechanical cardiac remodeling and new-onset atrial fibrillation in long-term follow-up of subjects with chronic Chagas' disease

Atrial fibrillation (AF) affects subjects with Chagas' disease and is an indicator of poor prognosis. We investigated clinical, echocardiographic and electrocardiographic variables of Chagas' disease in a long-term longitudinal study as predictors of a new-onset AF episode lasting >24 h, nonfatal embolic stroke and cardiac death. Fifty adult outpatients (34 to 74 years old, 62% females) staged according to the Los Andes classification were enrolled. During a follow-up of (mean ± SD) 84.2 ± 39.0 months, 9 subjects developed AF (incidence: 3.3 ± 1.0%/year), 5 had nonfatal stroke (incidence: 1.3 ± 1.0%/year), and nine died (mortality rate: 2.3 ± 0.8%/year). The progression rate of left ventricular mass and left ventricular ejection fraction was significantly greater in subjects who experienced AF (16.4 ± 20.0 g/year and -8.6 ± 7.6%/year, respectively) than in those who did not (8.2 ± 8.4 g/year; P = 0.03, and -3.0 ± 2.5%/year; P = 0.04, respectively). In univariate analysis, left atrial diameter ≥3.2 cm (P = 0.002), pulmonary arterial hypertension (P = 0.035), frequent premature supraventricular and ventricular contraction counts/24 h (P = 0.005 and P = 0.007, respectively), ventricular couplets/24 h (P = 0.002), and ventricular tachycardia (P = 0.004) were long-term predictors of AF. P-wave signal-averaged ECG revealed a limited long-term predictive value for AF. In chronic Chagas' disease, large left atrial diameter, pulmonary arterial hypertension, frequent supraventricular and ventricular premature beats, and ventricular tachycardia are long-term predictors of AF. The rate of left ventricular mass enlargement and systolic function deterioration impact AF incidence in this population.

Association of angiotensin-converting enzyme activity and polymorphism with echocardiographic measures in familial and nonfamilial hypertrophic cardiomyopathy

Angiotensin-converting enzyme (ACE) activity and polymorphism contribute significantly to the prognosis of patients with cardiomyopathy. The aim of this study was to determine the activity and type of ACE polymorphism in patients with familial and nonfamilial hypertrophic cardiomyopathy (HCM) and to correlate these with echocardiographic measurements (echo-Doppler). We studied 136 patients (76 males) with HCM (69 familial and 67 nonfamilial cases). Mean age was 41 ± 17 years. DNA was extracted from blood samples for the polymerase chain reaction and the determination of plasma ACE levels. Left ventricular mass, interventricular septum, and wall thickness were measured. Mean left ventricular mass index, interventricular septum and wall thickness in familial and nonfamilial forms were 154 ± 63 and 174 ± 57 g/m² (P = 0.008), 19 ± 5 and 21 ± 5 mm (P = 0.02), and 10 ± 2 and 12 ± 3 mm (P = 0.0001), respectively. ACE genotype frequencies were DD = 35%, ID = 52%, and II = 13%. A positive association was observed between serum ACE activity and left ventricular mass index (P = 0.04). Logistic regression showed that ACE activity was twice as high in patients with familial HCM and left ventricular mass index ≥190 g/m² compared with the nonfamilial form (P = 0.02). No other correlation was observed between ACE polymorphisms and the degree of myocardial hypertrophy. In conclusion, ACE activity, but not ACE polymorphisms, was associated with the degree of myocardial hypertrophy in the patients with HCM.

Hind limb ischemic preconditioning induces an anti-inflammatory response by remote organs in rats

Ischemic preconditioning (IPC), a strategy used to attenuate ischemia-reperfusion injury, consists of brief ischemic periods, each followed by reperfusion, prior to a sustained ischemic insult. The purpose of the present study was to evaluate the local and systemic anti-inflammatory effects of hind limb IPC in male Wistar rat (200-250 g) models of acute inflammation. IPC was induced with right hind limb ischemia for 10 min by placing an elastic rubber band tourniquet on the proximal part of the limb followed by 30 min of reperfusion. Groups (N = 6-8) were submitted to right or left paw edema (PE) with carrageenan (100 µg) or Dextran (200 µg), hemorrhagic cystitis with ifosfamide (200 mg/kg, ip) or gastric injury (GI) with indomethacin (20 mg/kg, vo). Controls received similar treatments, without IPC (Sham-IPC). PE is reported as variation of paw volume (mL), vesical edema (VE) as vesical wet weight (mg), vascular permeability (VP) with Evans blue extravasation (µg), GI with the gastric lesion index (GLI; total length of all erosions, mm), and neutrophil migration (NM) from myeloperoxidase activity. The statistical significance (P < 0.05) was determined by ANOVA, followed by the Tukey test. Carrageenan or Dextran-induced PE and VP in either paw were reduced by IPC (42-58.7%). IPC inhibited VE (38.8%) and VP (54%) in ifosfamide-induced hemorrhagic cystitis. GI and NM induced by indomethacin were inhibited by IPC (GLI: 90.3%; NM: 64%). This study shows for the first time that IPC produces local and systemic anti-inflammatory effects in models of acute inflammation other than ischemia-reperfusion injury.

A safety and feasibility study of cell therapy in dilated cardiomyopathy

The aim of this study was to determine if bone marrow mononuclear cell (BMMC) transplantation is safe for moderate to severe idiopathic dilated cardiomyopathy (IDC). Clinical trials have shown that this procedure is safe and effective for ischemic patients, but little information is available regarding non-ischemic patients. Twenty-four patients with IDC, optimized therapy, age 46 ± 11.6 years, 17 males, NYHA classes II-IV, and left ventricular ejection fraction <35% were enrolled in the study. Clinical evaluation at baseline and 6 months after stem cell therapy to assess heart function included echocardiogram, magnetic resonance imaging, cardiopulmonary test, Minnesota Quality of Life Questionnaire, and NYHA classification. After cell transplantation 1 patient showed a transient increase in enzyme levels and 2 patients presented arrhythmias that were reversed within 72 h. Four patients died during follow-up, between 6 and 12 weeks after therapy. Clinical evaluation showed improvement in most patients as reflected by statistically significant decreases in Minnesota Quality of Life Questionnaire (63 ± 17.9 baseline vs 28.8 ± 16.75 at 6 months) and in class III-IV NYHA patients (18/24 baseline vs 2/20 at 6 months). Cardiopulmonary exercise tests demonstrated increased peak oxygen consumption (12.2 ± 2.4 at baseline vs 15.8 ± 7.1 mL·kg-1·min-1 at 6 months) and walked distance (377.2 ± 85.4 vs 444.1 ± 77.9 m at 6 months) in the 6-min walk test, which was not accompanied by increased left ventricular ejection fraction. Our findings indicate that BMMC therapy in IDC patients with severe ventricular dysfunction is feasible and that larger, randomized and placebo-controlled trials are warranted.

Longitudinal brain volumetric changes during one year in non-elderly healthy adults: a voxel-based morphometry study

Previous cross-sectional magnetic resonance imaging (MRI) studies of healthy aging in young adults have indicated the presence of significant inverse correlations between age and gray matter volumes, although not homogeneously across all brain regions. However, such cross-sectional studies have important limitations and there is a scarcity of detailed longitudinal MRI studies with repeated measures obtained in the same individuals in order to investigate regional gray matter changes during short periods of time in non-elderly healthy adults. In the present study, 52 healthy young adults aged 18 to 50 years (27 males and 25 females) were followed with repeated MRI acquisitions over approximately 15 months. Gray matter volumes were compared between the two times using voxel-based morphometry, with the prediction that volume changes would be detectable in the frontal lobe, temporal neocortex and hippocampus. Voxel-wise analyses showed significant (P < 0.05, family-wise error corrected) relative volume reductions of gray matter in two small foci located in the right orbitofrontal cortex and left hippocampus. Separate comparisons for males and females showed bilateral gray matter relative reductions in the orbitofrontal cortex over time only in males. We conclude that, in non-elderly healthy adults, subtle gray matter volume alterations are detectable after short periods of time. This underscores the dynamic nature of gray matter changes in the brain during adult life, with regional volume reductions being detectable in brain regions that are relevant to cognitive and emotional processes.

Effect of scanner acoustic background noise on strict resting-state fMRI

Functional MRI (fMRI) resting-state experiments are aimed at identifying brain networks that support basal brain function. Although most investigators consider a ‘resting-state’ fMRI experiment with no specific external stimulation, subjects are unavoidably under heavy acoustic noise produced by the equipment. In the present study, we evaluated the influence of auditory input on the resting-state networks (RSNs). Twenty-two healthy subjects were scanned using two similar echo-planar imaging sequences in the same 3T MRI scanner: a default pulse sequence and a reduced “silent” pulse sequence. Experimental sessions consisted of two consecutive 7-min runs with noise conditions (default or silent) counterbalanced across subjects. A self-organizing group independent component analysis was applied to fMRI data in order to recognize the RSNs. The insula, left middle frontal gyrus and right precentral and left inferior parietal lobules showed significant differences in the voxel-wise comparison between RSNs depending on noise condition. In the presence of low-level noise, these areas Granger-cause oscillations in RSNs with cognitive implications (dorsal attention and entorhinal), while during high noise acquisition, these connectivities are reduced or inverted. Applying low noise MR acquisitions in research may allow the detection of subtle differences of the RSNs, with implications in experimental planning for resting-state studies, data analysis, and ergonomic factors.

Cleavages in contemporary Finland : a study on party-voter ties

Cleavages have been central in understanding the relationship between political parties and voters but the credibility of cleavage approach has been increasingly debated. This is because of decreasing party loyalty, fewer ideological differences between the parties and general social structural change amongst other factors. By definition, cleavages arise when social structural groups recognize their clashing interests, which are reflected in common values and attitudes, and vote for parties that are dedicated to defend the interests of the groups concerned. This study assesses relevance of cleavage approach in the Finnish context. The research problem in this study is “what kind of a cleavage structure exists in Finland at the beginning of the 21st century? Finland represents a case that has traditionally been characterized by a strong and diverse cleavage structure, notable ideological fragmentation in the electorate and an ideologically diverse party system. Nevertheless, the picture of the party-voter ties in Finland still remains incomplete with regard to a thorough analysis of cleavages. In addition, despite the vast amount of literature on cleavages in political science, studies that thoroughly analyze national cleavage structures by assessing the relationship between social structural position, values and attitudes and party choice have been rare. The research questions are approached by deploying statistical analyses, and using Finnish National Election Studies from 2003, 2007 and 2011as data. In this study, seven different social structural cleavage bases are analyzed: native language, type of residential area, occupational class, education, denomination, gender and age cohorts. Four different value/attitudinal dimensions were identified in this study: economic right and authority, regional and socioeconomic equality, sociocultural and European Union dimensions. This study shows that despite the weak overall effect of social structural positions on values and attitudes, a few rather strong connections between them were identified. The overall impact of social structural position and values and attitudes on party choice varies significantly between parties. Cleavages still exist in Finland and the cleavage structure partly reflects the old basis in the Finnish party system. The cleavage that is based on the type of residential area and reflected in regional and socioeconomic equality dimensions concerns primarily the voters of the Centre Party and the Coalition Party. The linguistic cleavage concerns mostly the voters of the Swedish People’s Party. The classic class cleavage reflected in the regional and socioeconomic equality dimension concerns in turn first and foremost the blue-collar voters of the Left Alliance and the Social Democratic Party, the agricultural entrepreneur voters of the Centre Party and higher professional and manager voters of the Coalition Party. The conflict with the most potential as a cleavage is the one based on social status (occupational class and education) and it is reflected in sociocultural and EU dimensions. It sets the voters of the True Finns against the voters of the Green League and the Coalition Party. The study underlines the challenges the old parties have met after the volatile election in 2011, which shook the cleavage structure. It also describes the complexity involved in the Finnish conflict structure and the multidimensionality in the electoral competition between the parties.

1968 BUSA Council

Pictured here from right to left and back to front are Geoff Eden, Bob Campbell, Pat Beard, Doug Chapman, Mike Wheeler, Peter Dixon, ?, John Auld, ?, Richard Harlow, Nigel Hussey, Ian Beddis, and Tom Goldspink.