Effect of increasing doses of Rosuvastatin and Atorvastatin on apolipoproteins, enzymes and lipid transfer proteins involved in lipoprotein metabolism and inflammatory parameters.

UNLABELLED: This paper contains detailed results of a sub-population of the prospective randomized RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study. OBJECTIVE: Statin treatment results in substantially decreased incidence of cardiovascular events but the exact pathophysiological mechanism of their beneficial effect is yet unclear. We aimed to examine the effects of up-titrated doses of two widely used statins (atorvastatin (ATOR) and rosuvastatin (ROSU)) on parameters involved in lipoprotein metabolism, in patients with low high density lipoprotein cholesterol values (HDL-C). RESEARCH DESIGN AND METHODS: In this RADAR substudy, 80 patients, aged 40-80 years, with known cardiovascular disease and low HDL-C (<1.0 mmol/l), were randomized to receive, after an initial 6 week dietary run-in phase, either ATOR 20 mg (n = 41) or ROSU 10 mg (n = 39). The doses were up-titrated (in 6 week intervals) to 80 mg of ATOR or 40 mg of ROSU at 12 weeks. Serum lipoproteins and lipoprotein metabolism parameters were measured at baseline and at 6 and 18 weeks of follow up. RESULTS: Both statins significantly reduced total cholesterol (TChol) and non-HDL-C values with ROSU being more effective for the doses studied (p < 0.05). No statistically significant effect on HDL-C was observed for either statin. Apolipoproteins (apo) B, CI, CIII, AV and E were significantly reduced in both groups (p < 0.05), while the ratio of HDL particles containing both apoAI and apoAII (LpAI-AII) over HDL containing apoAI alone (LpAI) was changed for both statins with the decrease of LpAI being more prominent in the ATOR group (p = 0.028). Cholesterol ester transfer protein (CETP) mass and activity, phospholipid transfer protein (PLTP) activity and lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity were all significantly reduced in both treatment groups over the follow-up period (p < 0.001). ATOR displayed a more prominent decrease of PLTP activity compared to ROSU (p = 0.043), while ROSU displayed a more prominent decrease of Lp-PLA2 activity compared to ATOR (p = 0.04). Both statins effectively reduced, in a dose-dependent way, high sensitivity C-reactive protein values over time, while no effect on the levels of circulating inter cellular adhesion molecule 1 (cICAM-1) was observed. CONCLUSIONS: The effects of statin treatment extend further and beyond a mere TChol and LDL cholesterol reduction, as demonstrated by the aforementioned alterations of lipoproteins, enzymes and lipid transfer proteins involved in lipoprotein metabolism and pro-atherogenic and inflammatory molecules. ROSU and ATOR displayed a similar pattern of effect on lipid metabolism with discrete differences in the magnitude of this effect in certain variables. Despite the limitations of small population size and lack of clinical end points, reported data provide an insight for the possible pathophysiological mechanisms implicated in the effect of increasing dosages of different statin treatments.

Isolated atrial microvascular dysfunction in patients with lone recurrent atrial fibrillation.

OBJECTIVES: The purpose of this study was to assess atrial myocardial perfusion in patients with lone recurrent atrial fibrillation (LRAF). BACKGROUND: Although acute atrial ischemia has been implicated in the pathogenesis of atrial fibrillation, there are few data concerning human atrial myocardial perfusion and none for patients with LRAF. METHODS: Sixteen patients with LRAF and 15 control subjects with suitable coronary anatomy underwent time-averaged peak coronary blood flow velocity (APV) measurements (cm/s), using a Doppler guidewire in the proximal left circumflex coronary artery (LCx) and in the left atrial circumflex branch (LACB), at baseline (b) and after adenosine administration to achieve maximal hyperemia (h). Coronary flow reserve was defined as h-APV/b-APV. RESULTS: Although there were no statistically significant differences in b-APV between patients with LRAF and control subjects or between the LACB and LCx, there were significant group (p = 0.002), artery (p = 0.001), and interaction (p < 0.001) effects at maximal hyperemia. In patients with LRAF, the h-APV and coronary flow reserve of the LACB (30.4 +/- 9.5 cm/s and 2.2 +/- 0.4, respectively) were significantly lower than in the LACB of the control subjects (45.8 +/- 12.8 cm/s [p < 0.001] and 2.9 +/- 0.5 [p = 0.001], respectively) or in the patients' LCx (43.0 +/- 10.9 cm/s [p = 0.001] and 3.1 +/- 0.6 [p < 0.001], respectively). CONCLUSIONS: This study confirms for the first time isolated atrial myocardial perfusion abnormalities in patients with LRAF and coronary flow reserve impairment, indicating that microvascular dysfunction is a pathophysiological substrate associated with this arrhythmia.

Risk factors for ischaemic heart disease in a Cretan rural population: a twelve year follow-up study.

BACKGROUND: Crete has been of great epidemiological interest ever since the publication of the Seven Countries Study. In 1988 a well-defined area of rural Crete was studied, with only scarce signs of coronary heart disease (CHD) despite the unfavorable risk profile. The same population was re-examined twelve years later aiming to describe the trends of CHD risk factors over time and discuss some key points on the natural course of coronary heart disease in a rural population of Crete. METHODS AND RESULTS: We re-examined 200 subjects (80.7% of those still living in the area, 62.4 +/- 17.0 years old). The prevalence of risk factors for CHD was high with 65.9% of men and 65.1% of women being hypertensive, 14.3% of men and 16.5% of women being diabetic, 44% of men being active smokers and more than 40% of both sexes having hyperlipidaemia. Accordingly, 77.5% of the population had a calculated Framingham Risk Score (FRS) > or = 15%, significantly higher compared to baseline (p < 0.001). The overall occurrence rate for CHD events was calculated at 7.1 per 1000 person-years (95% confidence interval: 6.8-7.3). CONCLUSION: The study confirms the unfavorable risk factor profile of a well defined rural population in Crete. Its actual effect on the observed incidence of coronary events in Cretans remains yet to be defined.

Altered expression of early cardiac marker genes in circulating cells of patients with hypertrophic cardiomyopathy.

BACKGROUND: Early cardiac marker genes, such as cardiac-specific homeobox (Csx/Nkx2.5), myocardin, homeodomain only protein, GATA4, and myocyte enhancer factor 2C, are thought to participate in cardiomyocyte differentiation and to contribute to heart hypertrophy in animal models. In this study, we investigated whether the expression of early cardiac genes is altered in the peripheral blood of patients with hypertrophic cardiomyopathy. METHODS: Peripheral blood mononuclear cells were isolated from 30 consecutive hypertrophic cardiomyopathy patients and 20 healthy controls, and gene expression was determined by quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: Csx/Nkx2.5, myocardin, and GATA4 expressions were significantly higher in hypertrophic cardiomyopathy patients by 5.14+/-0.89 (P<.001), 1.65+/-0.21 (P<.05), and 2.04+/-0.41 (P<.04) times, respectively, while homeodomain only protein showed a fourfold decrease in expression (P<.02) compared to controls. In addition, expression of the differentiation-specific marker genes beta-myosin heavy chain and smooth muscle myosin heavy chain was significantly higher in hypertrophic cardiomyopathy patients by 3.72+/-0.82 (P<.02) and 2.57+/-0.72 (P<.05) times, respectively, compared to controls. Myocyte enhancer factor 2C expression was not different between patients and controls. Furthermore, increased expression of GATA4, myocardin, and beta-myosin heavy chain positively correlated with increased left ventricular mass. CONCLUSIONS: In conclusion, we found altered expressions of early cardiac marker genes and differentiation-specific marker genes in peripheral blood mononuclear cells of hypertrophic cardiomyopathy patients compared to control individuals, possibly reflecting changes in response to disease.

Angiotensin II type 1 receptor inhibition is associated with reduced tachyarrhythmia-induced ventricular interstitial fibrosis in a goat atrial fibrillation model.

BACKGROUND: Using a goat animal model, we tested the hypothesis that angiotensin-II inhibition reduces fibrotic degeneration of both the atrial and ventricular myocardium as well as AF induction susceptibility. METHODS: We studied three groups of five goats over a 6-month period. The study animals in the first two groups were implanted with a pacemaker capable of maintaining AF with burst pacing. Additionally, in one group, goats were administered candesartan (AF+candesartan group). The third group (SR group) of animals served as control. Animals were tested for AF induction on day 0, 1, 30, 90 and 180. A "Vulnerability Index" (VI) for AF induction was calculated, defined as the ratio of total time in AF per number of bursts needed to induce sustained AF, in each session. At the end of the study, all four heart chambers were examined and fibrosis quantified. RESULTS: Both AF goat groups developed cardiomegaly due to tachy-cardiomyopathy. Although, the VI was significantly increased in AF group over time (28.8+/-43 to 284.7+/-291, p=0.045), this was not the case for AF+candesartan group (30.3+/-40 to 170.8+/-243, p=0.23). Histology revealed a significant increase of fibrous tissue in goats with induced AF, noticeable in all four heart chambers, compared to controls. However, the degree of fibrosis was significantly lower in AF animals on candesartan. CONCLUSIONS: Our study demonstrated a beneficial effect of angiotensin II inhibition on tachyarrhythmia-induced ventricular fibrosis. It is also consistent with previous studies indicating a reduction in burst-induced AF susceptibility in goats and confirms the favorable effects in atrial structural remodeling.

Atrial fibrillation is associated with increased neurohumoral activation and reduced exercise tolerance in patients with non-ischemic dilated cardiomyopathy.

OBJECTIVES: To assess atrial fibrillation (AF) associated differences in proinflammatory cytokines, natriuretic peptide levels and exercise capacity in patients with heart failure (HF) secondary to non-ischemic dilated cardiomyopathy (NIDC). METHODS: We studied 147 NIDC patients, mean age 58.3+/-12.5 years, left ventricular (LV) ejection fraction 27.8+/-10.9% and NYHA class II-III. Neurohumoral activation was assessed by measurement of interleukin IL-1, IL-6, tumor necrosis factor-a (TNF-a), its soluble receptors sTNFR I and II, N-terminal atrial (NT-ANP) and -brain (NT-BNP) natriuretic peptide levels, and functional class was assessed by cardiopulmonary exercise test. RESULTS: Forty patients (27.5%) had chronic AF and they did not differ in age, LV ejection fraction or HF duration compared to patients in sinus rhythm (SR). AF was associated with increased levels of IL-6 (p=0.001), TNF-a (p=0.002), sTNFRI (p=0.023), NT-ANP (p<0.001) and NT-BNP (p=0.003), decreased exercise duration (p<0.001) and slightly reduced maximal oxygen consumption at peak exercise (p=0.07) compared to SR patients. No significant differences in cytokine and natriuretic peptide levels or exercise tolerance were noted when patients in AF were compared to the subgroup of SR with restrictive LV filling pattern. Multivariate analysis showed that NT-ANP (p=0.003) and IL-6 (p=0.006) plasma levels were independently associated with the presence of AF in our patient population. CONCLUSION: AF is associated with increased inflammatory state, natriuretic peptide levels and reduced exercise capacity in patients with HF secondary to NIDC. These findings suggest that the presence of AF in HF represents a more advanced stage of the syndrome.

Continuous positive airway pressure therapy lowers vagal tone in patients with obstructive sleep apnoea-hypopnoea syndrome.

INTRODUCTION: Sleep apnoea, which constitutes a major social problem because of its high prevalence and its emerging association with cardiovascular morbidity and mortality, is known to affect autonomic nervous system activity. We assessed the hypothesis that treatment of sleep apnoea patients with continuous positive airway pressure (CPAP) alters the indices of heart rate variability (HRV) that reflect sympathetic and parasympathetic autonomic nervous system activity. METHODS: We studied 26 patients (18 men, aged 49.2 +/- 7.6 years) with obstructive sleep apnoea-hypopnoea syndrome. In all patients, a 24-hour Holter recording was obtained one week before initiation of CPAP treatment and another one two months later. From these recordings we assessed the time domain indices of HRV (pNN50, rMSSD, SDNN, SDANN, SD) during the day (08:00-23:00) and during the night hours (23:00-08:00) as well as their post-treatment changes. The same HRV indices were also assessed in a group of 19 age and sex matched controls, without sleep apnoea. RESULTS: No significant differences in the HRV indices were observed during the daytime hours, while during the night both pNN50 and rMSSD were significantly higher in patients compared to controls (19.5 +/- 12.5 vs. 13.8 +/- 9.7, p=0.001, for pNN50 and 54.7 +/- 23.1 vs. 44.0 +/- 15.9, p=0.001, for rMSSD, for patients and controls respectively). No such differences were observed in any of the monitored indices following CPAP treatment. CONCLUSIONS: The indices that reflect parasympathetic activity are increased during the night in patients with obstructive sleep apnoea syndrome. CPAP treatment reduces the night time vagal indices of HRV to resemble those of normal controls. The reduction of parasympathetic activity may be one of the mechanisms responsible for the alleviation of bradyarrhythmic episodes following the initiation of CPAP therapy.