A Randomized Controlled Trial Comparing Apixaban With the Vitamin K Antagonist Phenprocoumon in Patients on Chronic Hemodialysis: The AXADIA-AFNET 8 Study.

BACKGROUND: Non-vitamin K oral anticoagulants have become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation (AF). The effectiveness and safety of non-vitamin K oral anticoagulants in patients on hemodialysis is not well known. METHODS: From June 2017 through May 2022, AXADIA-AFNET 8 (Compare Apixaban and Vitamin K Antagonists in Patients With Atrial Fibrillation and End-Stage Kidney Disease), an investigator-initiated PROBE (prospective randomized open blinded end point) outcome assessment trial, randomized patients with AF on chronic hemodialysis to either apixaban (2.5 mg BID) or the vitamin K antagonist (VKA) phenprocoumon (international normalized ratio, 2.0 to 3.0). The composite primary safety outcome was defined by a first event of major bleeding, clinically relevant nonmajor bleeding, or all-cause death. The primary efficacy outcome was a composite of ischemic stroke, all-cause death, myocardial infarction, and deep vein thrombosis or pulmonary embolism. Our hypothesis was that apixaban is noninferior to VKA. RESULTS: Thirty-nine sites randomized 97 patients (30% women; mean age 75 years; mean CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex] score, 4.5; baseline characteristics balanced between groups): 48 to apixaban and 49 to VKA. The median follow-up time was 429 days (range, 37 to 1370) versus 506 days (range, 101 to 1379), respectively. Adherence to apixaban was >80% in 44 of 48 patients; the median time in therapeutic range on VKA was 50.7%. Composite primary safety outcome events occurred in 22 patients (45.8%) on apixaban and in 25 patients (51.0%) on VKA (hazard ratio, 0.93 [95% CI, 0.53-1.65]; Pnoninferiority=0.157). Composite primary efficacy outcome events occurred in 10 patients (20.8%) on apixaban and in 15 patients (30.6%) on VKA (P=0.51; log rank). There were no significant differences regarding individual outcomes (all-cause mortality, 18.8% versus 24.5%; major bleeding, 10.4% versus 12.2%; and myocardial infarction, 4.2% versus 6.1%, respectively). CONCLUSIONS: In this randomized trial comparing apixaban and VKA in patients with AF on hemodialysis with long follow-up, no differences were observed in safety or efficacy outcomes. Even on oral anticoagulation, patients with AF on hemodialysis remain at high risk of cardiovascular events. Larger randomized trials are needed to determine the optimal anticoagulation regimen for patients with AF on hemodialysis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02933697.

Effect of inferior caval valve implantation on circulating immune cells and inflammatory mediators in severe tricuspid regurgitation.

BACKGROUND: Interventional valve implantation into the inferior vena cava (CAVI) lowers venous congestion in patients with tricuspid regurgitation (TR). We evaluated the impact of a reduction of abdominal venous congestion following CAVI on circulating immune cells and inflammatory mediators. METHODS: Patients with severe TR were randomized to optimal medical therapy (OMT) + CAVI (n = 8) or OMT (n = 10). In the OMT + CAVI group, an Edwards Sapien XT valve was implanted into the inferior vena cava. Immune cells and inflammatory mediators were measured in the peripheral blood at baseline and three-month follow-up. RESULTS: Leukocytes, monocytes, basophils, eosinophils, neutrophils, lymphocytes, B, T and natural killer cells and inflammatory markers (C-reactive protein, interferon-gamma, interleukin-2, -4, -5, -10, and tumor necrosis factor-alpha) did not change substantially between baseline and three-month follow-up within the OMT + CAVI and OMT group. CONCLUSION: The present data suggest that reduction of venous congestion following OMT + CAVI may not lead to substantial changes in systemic inflammation within a short-term follow-up. CLINICAL TRIAL REGISTRATION: NCT02387697.

Associations of 2D speckle tracking echocardiography-based right heart deformation parameters and invasively assessed hemodynamic measurements in patients with pulmonary hypertension.

BACKGROUND: We aimed to evaluate associations of right atrial (RA) and right ventricular (RV) strain parameters assessed by 2D speckle tracking echocardiography (2D STE) with invasively measured hemodynamic parameters in patients with and without pulmonary hypertension (PH). METHODS: In this study, we analyzed 78 all-comer patients undergoing invasive hemodynamic assessment by left and right heart catheterization. Standard transthoracic echocardiographic assessment was performed under the same hemodynamic conditions. RA and RV longitudinal strain parameters were analyzed using 2D STE. PH was defined as invasively obtained mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest and was further divided into pre-capillary PH (pulmonary capillary wedge pressure [PCWP] ≤ 15 mmHg), post-capillary PH (PCWP > 15 mmHg) and combined PH (PCWP > 15 mmHg and difference between diastolic PAP and PCWP of ≥7 mmHg). Correlation analyses between variables were calculated with Pearson's or Spearman's correlation coefficient as applicable. RESULTS: Out of 78 patients, 45 presented with PH. Within the PH group, 39 had post-capillary, five had combined pre- and post-capillary PH, and one had pre-capillary PH. Patients with PH had a significantly increased RA area (PH 22.0 ± 9.2 cm2, non-PH 17.3 ± 10.7 cm2; p = 0.003) and end-systolic RV area (PH 14.7 ± 6.1, non-PH 11.9 ± 4.8 cm2; p = 0.022). RV mid strain was significantly reduced in PH (PH -17.4 ± 7.8, non-PH: - 21.6 ± 5.5; p = 0.019). Average peak systolic RA strain (RAS) and average peak systolic RV strain (RVS) showed a significant association with mPAP (r = - 0.470, p = 0.001 and r = 0.490, p = 0.001, respectively) and with PCWP (r = - 0.296, p = 0.048 and r = 0.365, p = 0.015, respectively) in patients with PH. Furthermore, RV apical, mid and basal strain as well as RV free wall strain showed moderate associations with mPAP. In patients without PH, there were no associations detectable between RA or RV strain parameters and mPAP and PCWP. CONCLUSION: In an all-comer cohort, RA and RV strain parameters showed significant associations with invasively assessed mPAP and PCWP in patients with predominantly post-capillary PH. These associations may be useful in clinical practice to assess the impact of post-capillary PH on myocardial right heart function.

Impact of inferior caval valve implantation on severity of tricuspid regurgitation and right heart function.

AIMS: Severe tricuspid regurgitation (TR) is a common finding in heart failure patients and associated with increased mortality. New interventional therapeutic options are needed as many heart failure patients are unfit for surgery. The TRICAVAL study compared valve implantation into the inferior vena cava (CAVI) with optimal medical therapy (OMT) in patients with severe TR. Here, we report details on the impact of CAVI on TR severity as well as right heart function and morphology. METHODS AND RESULTS: We randomized 28 patients with severe TR to CAVI (n = 14) with transfemoral implantation of an Edwards Sapien XT valve into the inferior vena cava or OMT (n = 14). Inclusion and exclusion criteria were based on anatomical and clinical parameters. Echocardiographic measurements were performed at baseline, at the first postoperative day and one, three, and twelve months after randomization. As proof of concept of an effective sealing of the inferior vena cava, we detected a significant decrease in systolic hepatic vein reflux volume (11.0 [6.2-21.9] mL vs 3.5 [0.6-8.5] mL, P = .016) and hepatic vein diameter (11.5 [10.0-14.8] mm vs 10.0 [9.3-11.8] mm, P = .034) at thirty-day follow-up. However, CAVI had no significant impact on TR, cardiac function, and morphology. CONCLUSIONS: Caval valve implantation significantly reduced systolic reflux into the hepatic veins but was not associated with an improvement in cardiac function, morphology, or TR severity.

Left atrial strain predicts hemodynamic parameters in cardiovascular patients.

BACKGROUND: We aimed to evaluate the predictive value of left atrial (LA) reservoir, conduit, and contractile function parameters as assessed by speckle tracking echocardiography (STE) for invasively measured hemodynamic parameters in a patient cohort with myocardial and valvular diseases. METHODS: Sixty-nine patients undergoing invasive hemodynamic assessment were enrolled into the study. Invasive hemodynamic parameters were obtained by left and right heart catheterization. Transthoracic echocardiography assessment of LA reservoir, conduit, and contractile function was performed by STE. RESULTS: Forty-nine patients had sinus rhythm (SR) and 20 patients had permanent atrial fibrillation (AF). AF patients had significantly reduced LA reservoir function compared to SR patients. In patients with SR, LA reservoir, conduit, and contractile function inversely correlated with pulmonary capillary wedge pressure (PCWP), left ventricular end-diastolic pressure, and mean pulmonary artery pressure (PAP), and showed a moderate association with cardiac index. In AF patients, there were no significant correlations between LA reservoir function and invasively obtained hemodynamic parameters. In SR patients, LA contractile function with a cutoff value of 16.0% had the highest diagnostic accuracy (area under the curve, AUC: 0.895) to predict PCWP ≥18 mm Hg compared to the weaker diagnostic accuracy of average E/E' ratio with an AUC of 0.786 at a cutoff value of 14.3. In multivariate analysis, LA contractile function remained significantly associated with PCWP ≥18 mm Hg. CONCLUSION: In a cohort of patients with a broad spectrum of cardiovascular diseases LA strain shows a valuable prediction of hemodynamic parameters, specifically LV filling pressures, in the presence of SR.

High-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical studies.

High-density lipoprotein (HDL) particles transport (among other molecules) cholesterol (HDL-C). In epidemiological studies, plasma HDL-C levels have an inverse relationship to the risk of atherosclerotic cardiovascular disease. It has been assumed that this reflects the protective functions of HDL, which include their ability to promote cholesterol efflux. Yet, several recent pharmacological and genetic studies have failed to demonstrate that increased plasma levels of HDL-C resulted in decreased cardiovascular disease risk, giving rise to a controversy regarding whether plasma levels of HDL-C reflect HDL function, or that HDL is even as protective as assumed. The evidence from preclinical and (limited) clinical studies shows that HDL can promote the regression of atherosclerosis when the levels of functional particles are increased from endogenous or exogenous sources. The data show that regression results from a combination of reduced plaque lipid and macrophage contents, as well as from a reduction in its inflammatory state. Although more research will be needed regarding basic mechanisms and to establish that these changes translate clinically to reduced cardiovascular disease events, that HDL can regress plaques suggests that the recent trial failures do not eliminate HDL from consideration as an atheroprotective agent but rather emphasizes the important distinction between HDL function and plasma levels of HDL-C.

Improved Left Ventricular Structure and Function After Successful Kidney Transplantation.

BACKGROUND/AIMS: Cardiac changes observed in chronic kidney disease patients are of multifactorial origin including chronic uremia, hemodynamics or inflammation. Restoration of renal function by kidney transplantation (KTX) may reverse cardiac changes. Novel echocardiographic methods such as speckle tracking echocardiography (STE) allow early and sensitive detection of subtle changes of cardiac parameters. We evaluated changes of cardiac structure and function after KTX by advanced echocardiographic modalities. METHODS: Thirty-one KTX recipients (female n=11) were evaluated by medical examination, laboratory testing and echocardiography before and after KTX (median follow-up 19 months). Left ventricular (LV) and right ventricular (RV) diameters and function were assessed by echocardiographic standard parameters. Longitudinal 2D strain of the LV (GLPS) and left atrium (LA) was determined by 2D STE. RESULTS: After KTX, median serum creatinine level was 1.3 mg/dl (IQR, 1.2-1.5). Systolic blood pressure decreased significantly after KTX. Echocardiography showed a significant reduction in LV end-diastolic septal and posterior wall thickness and LV mass index after KTX, which was accompanied by an improvement of GLPS. There were no relevant changes in parameters of LA (reservoir, conduit or contractile) function, LV diastolic or RV function after KTX. CONCLUSION: LV hypertrophy reversed after successful KTX and was accompanied by an improvement in longitudinal LV function as assessed by STE. Diastolic function and STE-derived LA function parameters did not change significantly after KTX.

Effects of native and myeloperoxidase-modified apolipoprotein a-I on reverse cholesterol transport and atherosclerosis in mice.

OBJECTIVE: Preclinical and clinical studies have shown beneficial effects of infusions of apolipoprotein A-I (ApoA-I) on atherosclerosis. ApoA-I is also a target for myeloperoxidase-mediated oxidation, leading in vitro to a loss of its ability to promote ATP-binding cassette transporter A1-dependent macrophage cholesterol efflux. Therefore, we hypothesized that myeloperoxidase-mediated ApoA-I oxidation would impair its promotion of reverse cholesterol transport in vivo and the beneficial effects on atherosclerotic plaques. APPROACH AND RESULTS: ApoA-I(-/-) or apolipoprotein E-deficient mice were subcutaneously injected with native human ApoA-I, oxidized human ApoA-I (myeloperoxidase/hydrogen peroxide/chloride treated), or carrier. Although early postinjection (8 hours) levels of total ApoA-I in plasma were similar for native versus oxidized human ApoA-I, native ApoA-I primarily resided within the high-density lipoprotein fraction, whereas the majority of oxidized human ApoA-I was highly cross-linked and not high-density lipoprotein particle associated, consistent with impaired ATP-binding cassette transporter A1 interaction. In ApoA-I(-/-) mice, ApoA-I oxidation significantly impaired reverse cholesterol transport in vivo. In advanced aortic root atherosclerotic plaques of apolipoprotein E-deficient mice, native ApoA-I injections led to significant decreases in lipid content, macrophage number, and an increase in collagen content; in contrast, oxidized human ApoA-I failed to mediate these changes. The decrease in plaque macrophages with native ApoA-I was accompanied by significant induction of their chemokine receptor CCR7. Furthermore, only native ApoA-I injections led to a significant reduction of inflammatory M1 and increase in anti-inflammatory M2 macrophage markers in the plaques. CONCLUSIONS: Myeloperoxidase-mediated oxidation renders ApoA-I dysfunctional and unable to (1) promote reverse cholesterol transport, (2) mediate beneficial changes in the composition of atherosclerotic plaques, and (3) pacify the inflammatory status of plaque macrophages.

Midterm echocardiographic follow-up of cardiac function after living kidney donation.

BACKGROUND: Living kidney donation (LKD) has become increasingly important as more patients reach end-stage renal disease. While safety of the donor is of utmost importance, recent data have suggested an increased risk for cardiovascular mortality after LKD. Therefore, we assessed the changes of cardiac structure and function after LKD by advanced echocardiographic methods. METHODS: 30 living kidney donors were evaluated by medical examination, laboratory testing, and echocardiography before and after LKD (median follow-up 19.5 months). Left ventricular (LV) and right ventricular (RV) function was assessed by echocardiographic standard indices. Longitudinal 2D strain of the LV and left atrium (LA) was determined by 2D speckle tracking. RESULTS: Serum creatinine increased significantly from 0.80 ± 0.12 mg/dL to 1.18 ± 0.21 mg/ dL (p < 0.001) after LKD. There was a trend to higher blood pressure after LKD, accompanied with significantly higher intake of antihypertensive drugs. Echocardiographic parameters of LV, LA, and RV function did not change significantly after LKD. N-terminal pro-brain natriuretic peptide (NT-proBNP) levels remained within normal ranges after LKD. CONCLUSION: The rise in serum creatinine and blood pressure indicates that patients have a potentially higher cardiac risk after LKD. However, our pilot study found no evidence for detrimental effects of LKD on cardiac structure and function within a relatively short-term follow-up.

Cardiac and renal function in a large cohort of amateur marathon runners.

BACKGROUND: Participation of amateur runners in endurance races continues to increase. Previous studies of marathon runners have raised concerns about exercise-induced myocardial and renal dysfunction and damage. In our pooled analysis, we aimed to characterize changes of cardiac and renal function after marathon running in a large cohort of mostly elderly amateur marathon runners. METHODS: A total of 167 participants of the Berlin-Marathon (female n = 89, male n = 78; age = 50.3 ± 11.4 years) were included and cardiac and renal function was analyzed prior to, immediately after and 2 weeks following the race by echocardiography and blood tests (including cardiac troponin T, NT-proBNP and cystatin C). RESULTS: Among the runners, 58% exhibited a significant increase in cardiac biomarkers after completion of the marathon. Overall, the changes in echocardiographic parameters for systolic or diastolic left and right ventricular function did not indicate relevant myocardial dysfunction. Notably, 30% of all participants showed >25% decrease in cystatin C-estimated glomerular filtration rate (GFR) from baseline directly after the marathon; in 8%, we observed a decline of more than 50%. All cardiac and renal parameters returned to baseline ranges within 2 weeks after the marathon. CONCLUSIONS: The increase in cardiac biomarkers after completing a marathon was not accompanied by relevant cardiac dysfunction as assessed by echocardiography. After the race, a high proportion of runners experienced a decrease in cystatin C-estimated GFR, which is suggestive of transient, exercise-related alteration of renal function. However, we did not observe persistent detrimental effects on renal function.

LDL, HDL, VLDL, and CVD Prevention: Lessons from Genetics?

Over the past years, genetic studies on lipid traits have substantially extended our understanding of the relationship between lipid metabolism and coronary artery disease (CAD). Thereby, novel pathways and interactions in lipid metabolism unraveled by genetic studies have led to promising novel treatment strategies that are currently evaluated for prevention and treatment of CAD, such as low-density lipoprotein cholesterol (LDL-C) lowering by inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9). This review article discusses findings from recent genetic studies and their implications for the understanding of the relation between lipid metabolism and CAD as well as the development of novel therapeutic strategies supported by these studies.

Hypoxia induces netrin-1 and Unc5b in atherosclerotic plaques: mechanism for macrophage retention and survival.

OBJECTIVE: Hypoxia is intimately linked to atherosclerosis and has become recognized as a primary impetus of inflammation. We recently demonstrated that the neuroimmune guidance cue netrin-1 (Ntn1) inhibits macrophage emigration from atherosclerotic plaques, thereby fostering chronic inflammation. However, the mechanisms governing netrin-1 expression in atherosclerosis are not well understood. In this study, we investigate the role of hypoxia in regulating expression of netrin-1 and its receptor uncoordinated-5-B receptor (Unc5b) in plaque macrophages and its functional consequences on these immune cells. APPROACH AND RESULTS: We show by immunostaining that netrin-1 and Unc5b are expressed in macrophages in hypoxia-rich regions of human and mouse plaques. In vitro, Ntn1 and Unc5b mRNA are upregulated in macrophages treated with oxidized low-density lipoprotein or inducers of oxidative stress (CoCl2, dimethyloxalylglycine, 1% O2). These responses are abrogated by inhibiting hypoxia-inducible transcription factor (HIF)-1α, indicating a causal role for this transcription factor in regulating Ntn1 and Unc5b expression in macrophages. Indeed, using promoter-luciferase reporter genes, we show that Ntn1- and Unc5b-promoter activities are induced by oxidized low-density lipoprotein and require HIF-1α. Correspondingly, J774 macrophages overexpressing active HIF-1α show increased netrin-1 and Unc5b expression and reduced migratory capacity compared with control cells, which was restored by blocking the effects of netrin-1. Finally, we show that netrin-1 protects macrophages from apoptosis under hypoxic conditions in a HIF-1α-dependent manner. CONCLUSIONS: These findings provide a molecular mechanism by which netrin-1 and its receptor Unc5b are expressed in atherosclerotic plaques and implicate hypoxia and HIF-1α-induced netrin-1/Unc5b in sustaining inflammation by inhibiting the emigration and promoting the survival of lesional macrophages.

Neuroimmune guidance cue Semaphorin 3E is expressed in atherosclerotic plaques and regulates macrophage retention.

OBJECTIVE: The persistence of myeloid-derived cells in the artery wall is a characteristic of advanced atherosclerotic plaques. However, the mechanisms by which these cells are retained are poorly understood. Semaphorins, a class of neuronal guidance molecules, play a critical role in vascular patterning and development, and recent studies suggest that they may also have immunomodulatory functions. The present study evaluates the expression of Semaphorin 3E (Sema3E) in settings relevant to atherosclerosis and its contribution to macrophage accumulation in plaques. APPROACH AND RESULTS: Immunofluorescence staining of Sema3E, and its receptor PlexinD1, demonstrated their expression in macrophages of advanced atherosclerotic lesions of Apoe(-/-) mice. Notably, in 2 different mouse models of atherosclerosis regression, Sema3E mRNA was highly downregulated in plaque macrophages, coincident with a reduction in plaque macrophage content and an enrichment in markers of reparative M2 macrophages. In vitro, Sema3E mRNA was highly expressed in inflammatory M1 macrophages and in macrophages treated with physiological drivers of plaque progression and inflammation, such as oxidized low-density lipoprotein and hypoxia. To explore mechanistically how Sema3E affects macrophage behavior, we treated macrophages with recombinant protein in the presence/absence of chemokines, including CCL19, a chemokine implicated in the egress of macrophages from atherosclerotic plaques. Sema3E blocked actin polymerization and macrophage migration stimulated by the chemokines, suggesting that it may immobilize these cells in the plaque. CONCLUSIONS: Sema3E is upregulated in macrophages of advanced plaques, is dynamically regulated by multiple atherosclerosis-relevant factors, and acts as a negative regulator of macrophage migration, which may promote macrophage retention and chronic inflammation in vivo.

Echocardiographic follow-up of patients with systemic sclerosis by 2D speckle tracking echocardiography of the left ventricle.

BACKGROUND: Subclinical myocardial involvement is common in systemic sclerosis (SSc) and associated with poor prognosis. Early detection, particularly during follow-up, is important. Two-dimensional speckle tracking echocardiography (STE) has already been shown to detect early left ventricular systolic impairment in SSc patients with advanced disease. The aim of this study was to assess the ability of STE to diagnose changes in left ventricular function in patients with SSc with preserved LV ejection fraction (LVEF) and normal pulmonary pressure over time. METHODS: This single-center pilot study included nineteen SSc patients without pulmonary hypertension and preserved LVEF (55.2 ± 10.8 years, 13 women, mean modified Rodnan Skin Score of 8.2 ± 6.5, median disease duration 6 ± 4.5 years). We performed STE at baseline and after two years (mean 756.6 ± 8.8 days). Pulmonary hypertension was ruled out in all patients by right heart catheterization (average mean PAP 17.7 ± 3.5 mmHg). RESULTS: The LVEF remained unchanged (63.3 ± 4.2% vs. 63.2 ± 5.0%, P = ns), but the global longitudinal peak systolic strain of the left ventricle was significantly lower: baseline -22.0 ± 2.3% vs. follow-up -20.8 ± 2.1% (P = 0.04). The regional analysis showed a heterogeneous distribution of segmental systolic dysfunction that did not match any particular coronary artery distribution. In contrast, the LV diastolic function remained stable during follow-up. CONCLUSION: STE might be a sensititive and valuable method to detect early LV systolic impairment in patients with SSc and preserved LVEF during two years. Prospective evaluations are needed for prognostic implications of these changes.

Increased Expression of Inactive Rhomboid Protein 2 in Circulating Monocytes after Acute Myocardial Infarction.

Increased TNF-α levels following acute myocardial infarction (AMI) contribute to impaired recovery of myocardial function. Interaction of inactive rhomboid protein 2 (iRhom2) with TNF-α converting enzyme (TACE) is required for TNF-α shedding from immune cells. We hypothesized that iRhom2 expression increases in circulating monocytes following AMI. Transcript levels of iRhom2, TACE and TNF-α were evaluated by quantitative real-time PCR in isolated monocytes of 50 AMI patients at admission (d1) and 3 days (d3) after. We observed a significant increase in levels of iRhom2 mRNA expression in monocytes between d1-3, while TNF-α and TACE mRNA expression remained unchanged. At d3, iRhom2 mRNA expression positively correlated with levels of intermediate monocytes or serum TNF-α, and negatively with LV systolic function. iRhom2 may contribute to regulation of post-infarction inflammation and is associated with LV dysfunction following AMI. iRhom2 modulation should be evaluated as a potential therapeutic strategy to attenuate cardiac remodeling following AMI.

High-density lipoprotein function, dysfunction, and reverse cholesterol transport.

Although high high-density lipoprotein (HDL)-cholesterol levels are associated with decreased cardiovascular risk in epidemiological studies, recent genetic and pharmacological findings have raised doubts about the beneficial effects of HDL. Raising HDL levels in animal models by infusion or overexpression of apolipoprotein A-I has shown clear vascular improvements, such as delayed atherosclerotic lesion progression and accelerated lesion regression, along with increased reverse cholesterol transport. Inflammation and other factors, such as myeloperoxidase-mediated oxidation, can impair HDL production and HDL function, with regard to its reverse cholesterol transport, antioxidant, and anti-inflammatory activities. Thus, tests of HDL function, which have not yet been developed as routine diagnostic assays, may prove useful and be a better predictor of cardiovascular risk than HDL-cholesterol levels.

Attenuation of early atherogenesis in low-density lipoprotein receptor-deficient mice by proteasome inhibition.

OBJECTIVE: Low and nontoxic proteasome inhibition has anti-inflammatory, antiproliferative, and antioxidative effects on vascular cells in vitro and in vivo. We hypothesized that low-dose inhibition of the proteasome could provide antiatherogenic protection. The present study investigated the effect of low-dose proteasome inhibition on early lesion formation in low-density lipoprotein receptor-deficient mice fed a Western-type diet. METHODS AND RESULTS: Male low-density lipoprotein receptor-deficient mice, 10 weeks old, were fed a Western-type diet for 6 weeks with intraperitoneal injections of bortezomib or solvent. Bortezomib was injected at a dose of 50 µg/kg body weight. Cholesterol plasma levels were not affected by bortezomib treatment. En face Oil Red O staining of aortae and aortic root cryosections demonstrated significant reduction of atherosclerotic lesion coverage in bortezomib-treated animals. Bortezomib significantly reduced vascular cellular adhesion molecule-1 expression and macrophage infiltration as shown by histological analysis. Bortezomib treatment resulted in a significant reduction of superoxide content, lipid peroxidation and protein oxidation products, serum levels of monocyte chemoattractant protein-1, and interleukin-6. Gene expression microarray analysis showed that expressional changes induced by Western-type diet were attenuated by treatment with low-dose bortezomib. CONCLUSIONS: Low-dose proteasome inhibition exerts antioxidative and anti-inflammatory effects and attenuates development of atherosclerotic lesions in low-density lipoprotein receptor-deficient mice.

Rationale for cholesteryl ester transfer protein inhibition.

PURPOSE OF REVIEW: Raising HDL cholesterol (HDL-C) has become an attractive therapeutic target to lower cardiovascular risk in addition to statins. Inhibition of the cholesteryl ester transfer protein (CETP), which mediates the transfer of cholesteryl esters from HDL to apolipoprotein B-containing particles, leads to a substantial increase in HDL-C levels. Various CETP inhibitors are currently being evaluated in phase II and phase III clinical trials. However, the beneficial effect of CETP inhibition on cardiovascular outcome remains to be established. RECENT FINDINGS: Torcetrapib, the first CETP inhibitor tested in a phase III clinical trial (ILLUMINATE), failed in 2006 because of an increase in all-cause mortality and cardiovascular events that subsequently were attributed to nonclass-related off-target effects (particularly increased blood pressure and low serum potassium) related to the stimulation of aldosterone production. Anacetrapib, another potent CETP inhibitor, raises HDL-C levels by approximately 138% and decreases LDL cholesterol (LDL-C) levels by approximately 40%, without the adverse off-targets effects of torcetrapib (DEFINE study). The CETP modulator dalcetrapib raises HDL-C levels by approximately 30% (with only minimal effect on LDL-C levels) and proved safety in the dal-VESSEL and dal-PLAQUE trials involving a total of nearly 600 patients. Evacetrapib, a relatively new CETP inhibitor, exhibited favorable changes in the lipid profile in a phase II study. SUMMARY: The two ongoing outcome trials, dal-OUTCOMES (dalcetrapib) and REVEAL (anacetrapib), will provide more conclusive answers for the concept of reducing cardiovascular risk by raising HDL-C with CETP inhibition.

Deficiency of inactive rhomboid protein 2 (iRhom2) attenuates diet-induced hyperlipidaemia and early atherogenesis.

AIMS: Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall and anti-inflammatory treatment strategies are currently pursued to lower cardiovascular disease burden. Modulation of recently discovered inactive rhomboid protein 2 (iRhom2) attenuates shedding of tumour necrosis factor-alpha (TNF-α) selectively from immune cells. The present study aims at investigating the impact of iRhom2 deficiency on the development of atherosclerosis. METHODS AND RESULTS: Low-density lipoprotein receptor (LDLR)-deficient mice with additional deficiency of iRhom2 (LDLR-/-iRhom2-/-) and control (LDLR-/-) mice were fed a Western-type diet (WD) for 8 or 20 weeks to induce early or advanced atherosclerosis. Deficiency of iRhom2 resulted in a significant decrease in the size of early atherosclerotic plaques as determined in aortic root cross-sections. LDLR-/-iRhom2-/- mice exhibited significantly lower serum levels of TNF-α and lower circulating and hepatic levels of cholesterol and triglycerides compared to LDLR-/- mice at 8 weeks of WD. Analyses of hepatic bile acid concentration and gene expression at 8 weeks of WD revealed that iRhom2 deficiency prevented WD-induced repression of hepatic bile acid synthesis in LDLR-/- mice. In contrast, at 20 weeks of WD, plaque size, plaque composition, and serum levels of TNF-α or cholesterol were not different between genotypes. CONCLUSION: Modulation of inflammation by iRhom2 deficiency attenuated diet-induced hyperlipidaemia and early atherogenesis in LDLR-/- mice. iRhom2 deficiency did not affect diet-induced plaque burden and composition in advanced atherosclerosis in LDLR-/- mice.

Renal and hepatic function of patients with severe tricuspid regurgitation undergoing inferior caval valve implantation.

Due to progressive abdominal-venous congestion severe tricuspid regurgitation (TR) is a common cause of cardiorenal and cardiohepatic syndrome. We initiated the TRICAVAL study to compare interventional valve implantation into the inferior vena cava (CAVI) versus optimal medical therapy (OMT) in severe TR. In the present subanalysis, we aimed to evaluate the effects of CAVI on clinical signs of congestion, renal and hepatic function. TRICAVAL was an investigator-initiated, randomized trial. Twenty-eight patients with severe TR were randomized to OMT or CAVI using an Edwards Sapien XT valve. Probands who completed the 3-month follow-up (CAVI [n = 8], OMT [n = 10]) were evaluated by medical history, clinical examination, and laboratory testing at baseline, 3 and 12 months. After 3 months, the CAVI group exhibited a significant reduction of body weight (from 80.7 [69.0-87.7] kg to 75.5 [63.8-84.6] kg, p < 0.05) and abdominal circumference (from 101.5 ± 13.8 cm to 96.3 ± 15.4 cm, p ≤ 0.01) and a trend to lower doses of diuretics compared to OMT. Renal and hepatic function parameters did not change significantly. Within a short-term follow-up, CAVI led to an improvement of clinical signs of venous congestion and a non-significant reduction of diuretic doses compared to OMT.