Borut Jug

The effects of low-dose fluvastatin and valsartan combination on arterial function: A randomized clinical trial

BACKGROUNDnAgeing progressively diminishes arterial functions, even in the absence of traditional risk factors. Our aim was to explore whether age-related arterial changes in middle-aged males could be reversed using short-term, low-dose fluvastatin/valsartan combination intervention.nnnMETHODSnForty apparently healthy, middle-aged males (43.3 ± 5.8 years) were recruited in a double-blind, randomised intervention. Individuals received either 10mg fluvastatin/20mg valsartan daily or placebo over 30 days. The brachial artery flow mediated dilation (FMD), pulse wave velocity (PWV) and common carotid artery β-stiffness were assessed at baseline and after 30 days, and again 5-10 months after therapy discontinuation.nnnRESULTSnArterial function variables significantly improved after 30 days of intervention; FMD improved by 167.7% (P<0.001), PWV by 10.9% (P<0.05) and β-stiffness by 18.8% (P<0.01), whereas no changes were obtained in the placebo group. The favourable outcomes in the intervention group were accompanied by a significant decrease of high sensitivity-C reactive protein levels (1.8-fold; P<0.05). In contrast, lipids and blood pressure remained unchanged. Surprisingly, the beneficial arterial effects were still present to a substantial degree 7 months after completing intervention (remaining % of initial improvement: FMD 82.1%, PWV 69.5% and β-stiffness 68.5%), but declined substantially after 10 months.nnnCONCLUSIONnOur results indicate that age-related arterial changes, at least in middle-aged males, can be reversed. Short-term treatment with a low-dose fluvastatin/valsartan combination resulted in a large and long lasting improvement of arterial function.

Interleukin-6 is a stronger prognostic predictor than high-sensitive C-reactive protein in patients with chronic stable heart failure.

Heart failure is characterized by activation of the immune system which is strongly associated with disease severity and outcome. We sought to compare the prognostic impact of two established inflammatory markers — interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) — in patients with chronic heart failure. In stable, optimally managed outpatients with chronic heart failure, baseline levels of hsCRP and IL-6 were determined. Clinical follow-up was obtained and the rate of events (heart failure related deaths or hospitalizations) were recorded. We included 201 patients (32.7% female, NYHA class II [66.2%] or III [33.8%], mean age 70 years). During a median follow up of 614 (367−761) days, 64 (30.9%) patients experienced an event; those with an event had higher levels of hsCRP (median 2.93 [interquartile range 2.36−8.92] vs 2.23 [1.32−5.77] mmol/l) and IL-6 (7.8 [4.7−10.3] vs 4.3 [2.6−7.9] pg/ml). However, on Cox multivariate analysis, IL-6 but not hsCRP emerged as an independent predictor of prognosis (hazard ratio HRadjusted 2.74, 95% confidence interval 1.17−6.43; P = 0.020). Our findings suggest that IL-6 is a better prognostic predictor than hsCRP in patients with chronic stable heart failure.

Prognostic impact of haemostatic derangements in chronic heart failure

Heart failure is characterised by activation of haemostasis. We sought to explore the prognostic impact of deranged haemostasis in chronic heart failure. In stable, optimally managed outpatients with chronic heart failure, baseline levels of prothrombin fragment F1+2, D-dimer, and tPA and PAI-1 antigens were determined. Clinical follow-up was obtained and the rate of events (heart failure related deaths or hospitalisations) was recorded. We included 195 patients [32.3% female, NYHA class II (66.2%) or III (33.8%), mean age 71 years]. During a median follow up of 693 (interquartile range [IQR] 574-788) days, 63 (30.9%) patients experienced an event; those with an event had higher levels of tPA antigen (median 11.8 [IQR 8.7-14.0] vs. 9.4 [7.9-12.1] microg/l; p = 0.033) and D-dimer (938 [485-1269] vs. 620 [37-1076] microg/l; p = 0.018). However, on Cox multivariate analysis, only tPA levels above optimal cut-off value of 10.2 microg/l (but not D-dimer) emerged as an independent predictor of prognosis (HR(adjusted) 2.695, 95% confidence interval 1.233-5.363; p = 0.017). Our findings suggest that elevated tPA antigen levels are an independent prognostic predictor in patients with chronic stable heart failure.

Extended-release niacin/laropiprant improves endothelial function in patients after myocardial infarction

Raising high-density lipoprotein cholesterol (HDL-C) is an important strategy for reducing residual cardiovascular risk. In the present study, we sought to assess the effect of extended-release niacin/laropiprant on endothelial function in patients after a myocardial infarction with target low-density lipoprotein cholesterol (LDL-C). In this double-blind, placebo-controlled trial, 63 men (35–60xa0years of age) after a myocardial infarction were randomized to either niacin/laropiprant (1000/20xa0mg daily for 4xa0weeks and 2000/40xa0mg daily thereafter) or placebo. Flow-mediated dilation (FMD) and nitroglycerin-induced (GTN) dilation of the brachial artery, total cholesterol (TC), LDL-C, HDL-C, triglycerides (TG), lipoprotein(a) [Lp(a)], and apolipoprotein (Apo) A1/B were measured at baseline and after 12xa0weeks of intervention. FMD significantly increased (from 3.9xa0±xa05.1 to 9.8xa0±xa04.4xa0%, pxa0<xa00.001) in the niacin/laropiprant group, but not in the placebo group (4.6xa0±xa04.4 to 6.1xa0±xa04.4xa0%, pxa0=xa00.16) (pxa0=xa00.02 for comparison of interventions). GTN dilation also increased in the niacin/laropiprant group (from 12.5xa0±xa06.1 to 16.7xa0±xa04.8xa0%, pxa0=xa00.02), but not in the placebo group (13.4xa0±xa05.0 to 15.1xa0±xa05.2xa0%, pxa0=xa00.18), (pxa0=xa00.60 for comparison of interventions). Niacin/laropiprant reduced TC and LDL-C (pxa0=xa00.05 for both) and increased HDL-C (pxa0<xa00.001) without influencing TG, with no changes in the placebo group. Lp(a) (pxa0=xa00.026) and ApoB (pxa0=xa00.014) were significantly lower in the niacin/laropiprant group, with no difference in the placebo group. ApoA1 did not change in either of the groups (pxa0=xa00.13; pxa0=xa00.26). FMD and GTN dilation improvements did not correlate with changes in the lipid profile. Niacin/laropiprant improves endothelium-dependent and endothelium-independent dilation of the brachial artery. This improvement does not correlate with changes in lipid parameters.

Atrial fibrillation is an independent determinant of increased NT-proBNP levels in outpatients with signs and symptoms of heart failure

ZusammenfassungHINTERGRUND UND FRAGESTELLUNG: Das N-terminale pro-B-Typ natriuretische Peptid (NT-proBNP) wird zunehmend sowohl in der Diagnostik als auch bei der prognostischen Einschätzung von Herzinsuffizienz verwendet. Allerdings ist der Einfluss des Vorhofflimmerns auf die NT-proBNP-Werte noch unklar. Deshalb haben wir den Einfluss von Vorhofflimmern auf die NT-proBNP Werte bei Patienten mit Herzinsuffizienzsymptomatik analysiert. PATIENTEN UND METHODIK: Zufällig ausgewählte Patienten (n = 306), die in die Ambulanz für Herzinsuffizienz der Universitätsklinik Ljubljana aufgrund von Symptome und klinischen Zeichen einer Herzinsuffizienz eingewiesen wurden, wurden klinisch und elektrokardiographisch untersucht. Außerdem wurde bei jedem Patienten das NT-proBNP bestimmt (durch Einsatz einer Sandwich chemiluminescent immunoassay Methode mit zwei Antikörpern auf dem Elecsys Analysator). ERGEBNISSE: Vorhofflimmern war sowohl bei den Patienten mit (mediane Konzentration 1944 vs. 1390 pg/mL) als auch ohne strukturelle Herzkrankheit (1093 vs. 172 pg/ml) (p < 0,001) mit höheren Werten von NT-proBNP assoziiert. Vorhofflimmern blieb sogar unter Berücksichtigung möglicher Störfaktoren wie linksventrikuläre Pumpfunktion, end-diastolischer Durchmesser, Durchmesser des linken Vorhofes, Vorliegen einer Mitralinsuffizienz, Alter, Geschlecht, NYHA-Stadium bzw. Herzfrequenz eine unabhängige Determinante der NT-proBNP Werte (Propensity Score der linearen Regressionsanalyse: p = 0.023). SCHLUSSFOLGERUNG: Das Vorhofflimmern ist eine unabhängige Determinante von erhöhten NT-proBNP Werten. Diese Assoziation sollte immer in Betracht gezogen werden, wenn NT-proBNP Werte in der Diagnostik von Herzinsuffizienz bei Patienten mit Vorhofflimmern herangezogen werden.SummaryBACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is increasingly used in the diagnosis and prognostic assessment of heart failure; however, the possible influence of atrial fibrillation on BNP is still a matter of controversy. We assessed the influence of atrial fibrillation on NT-proBNP levels in outpatients with signs and symptoms of heart failure. METHODS: Consecutive outpatients (n = 306) referred to a university hospital heart-failure clinic for evaluation of signs and symptoms of heart failure underwent clinical and echocardiographic assessment and had their NT-proBNP levels determined in a sandwich chemiluminescent immunoassay with two antibodies on an Elecsys analyzer. The influence of atrial fibrillation on NT-proBNP levels was assessed using a non-parsimonious linear regression model with propensity score adjustments to balance for possible confounders. RESULTS: Atrial fibrillation was associated with increased NT-proBNP levels in patients with (median concentration 1944 vs. 1390 pg/ml) and without (1093 vs. 172 pg/ml) underlying structural disease (P < 0.001). In a linear regression model with a propensity score, atrial fibrillation emerged as an independent determinant of NT-proBNP levels (P = 0.023), even after allowing for possible confounders (left ventricular ejection fraction and end-diastolic diameter, left atrial diameter, mitral insufficiency, age, sex, NYHA class or heart rate). CONCLUSIONS: Atrial fibrillation is an independent determinant of increased NT-proBNP levels. This association should be taken into account when NT-proBNP levels are used in the diagnosis of heart failure in patients with atrial fibrillation.

Orosomucoid is an independent predictor of prognosis in chronic heart failure

SummaryBackgroundHeart failure is associated with low-grade inflammation. In the present study we sought to assess the prognostic impact of orosomucoid, axa0marker of inflammation, in outpatients with heart failure.MethodsIn outpatients with chronic heart failure (no change in clinical status and/or therapy >3xa0months prior to inclusion), baseline levels of orosomucoid were determined. Clinical follow-up was obtained and the rate of heart failure-related deaths and hospitalisations recorded.ResultsAxa0total of 134 patients (median age 71, 33.3u2009% female, mean left ventricular ejection fraction [LVEF] 36u2009%) weren included. During axa0median follow-up of 695 (456–811) days, 54xa0patients (40.1u2009%) experienced an event. On Coxn multivariate analysis, orosomucoid levels above the median (>497xa0mg/l) emerged as an independent predictor ofn prognosis (hazard ratioxa0= 2.86, 95u2009% confidence interval 1.48–5.52 after adjusting for age, gender, ischaemic vs. non-ischaemic aetiology, LVEF, NT-proBNP and NYHA class).ConclusionOrosomucoid levels are an independent predictor of heart failure-related mortality and hospitalisations in patients with chronic heart failure.

Exercise training in adults with repaired tetralogy of Fallot: A randomized controlled pilot study of continuous versus interval training

INTRODUCTIONnAdults with repaired tetralogy of Fallot (ToF) have impaired exercise capacity, vascular and cardiac autonomic function, and quality of life (QoL). Specific effects of high-intensity interval or moderate continuous exercise training on these parameters in adults with repaired ToF remain unknown.nnnMETHODS AND RESULTSnThirty adults with repaired ToF were randomized to either high-intensity interval, moderate intensity continuous training (36 sessions, 2-3 times a week) or usual care (no supervised exercise). Exercise capacity, flow-mediated vasodilation, pulse wave velocity, NT-proBNP and fibrinogen levels, heart rate variability and recovery, and QoL (SF-36 questionnaire) were determined at baseline and after the intervention period. Twenty-seven patients (mean age 39±9years, 63% females, 9 from each group) completed this pilot study. Both training groups improved in at least some parameters of cardiovascular health compared to no exercise. Interval-but not continuous-training improved VO2peak (21.2 to 22.9ml/kg/min, p=0.004), flow-mediated vasodilation (8.4 to 12.9%, p=0.019), pulse wave velocity (5.4 to 4.8m/s, p=0.028), NT-proBNP (202 to 190ng/L, p=0.032) and fibrinogen levels (2.67 to 2.46g/L, p=0.018). Conversely, continuous-but not interval-training improved heart rate variability (low-frequency domain, 0.32 to 0.22, p=0.039), heart rate recovery after 2min post-exercise (40 to 47 beats, p=0.023) and mental domain of SF-36 (87 to 95, p=0.028).nnnCONCLUSIONnBoth interval and continuous exercise training modalities were safe. Interval training seems more efficacious in improving exercise capacity, vascular function, NT-proBNP and fibrinogen levels, while continuous training seems more efficacious in improving cardiac autonomic function and QoL. (Clinicaltrials.gov, NCT02643810).

Cardiovascular autonomic dysfunction and carotid stiffness in adults with repaired tetralogy of Fallot

PurposeAdults after surgical repair of tetralogy of Fallot (ToF) may have impaired vascular and cardiac autonomic function. Thus, we wanted to assess interrelations between heart rate variability (HRV) and heart rate recovery (HRR), as parameters of cardiac autonomic function, and arterial stiffness, as a parameter of vascular function, in adults with repaired ToF as compared to healthy controls.MethodsIn a case-control study of adults with repaired ToF and healthy age-matched controls we measured: 5-min HRV variability (with time and frequency domain data collected), carotid artery stiffness (through pulse-wave analysis using echo-tracking ultrasound) and post-exercise HRR (cycle ergometer exercise testing).ResultsTwenty-five patients with repaired ToF (mean age 38xa0±xa010xa0years) and 10 healthy controls (mean age 39xa0±xa08xa0years) were included. Selected HRR and HRV (time-domain) parameters, but not arterial stiffness were significantly reduced in adults after ToF repair. Moreover, a strong association between late/slow HRR (after 2, 3 and 4xa0min) and carotid artery stiffness was detected in ToF patients (rxa0=xa0−0.404, pxa0=xa00.045; rxa0=xa0−0.545, pxa0=xa00.005 and rxa0=xa0−0.545, pxa0=xa00.005, respectively), with statistical significance retained even after adjusting for age, gender, resting heart rate and β-blockers use (rxa0=xa0−0.393, pxa0=xa00.024 for HRR after 3xa0min).ConclusionAutonomic cardiac function is impaired in patients with repaired ToF, and independently associated with vascular function in adults after ToF repair, but not in age-matched healthy controls. These results might help in introducing new predictors of cardiovascular morbidity in a growing population of adults after surgical repair of ToF.

Early atherosclerosis in HIV-infected patients below the age of 55 years: Slovenian national study.

SummaryBackgroundIncreased life expectancy of human immunodeficiency virus (HIV)-infected patients appears to be coupled with increased incidence of cardiovascular disease (CVD).AimThe aim of our study was to determine the presence of early atherosclerosis among Slovenian HIV-infected patients below the age of 55 years.MethodsA total of 86 HIV-infected male patients below the age of 55 years participated in our study. Ankle-brachial index (ABI) was measured using a handheld Doppler ultrasonic probe and a blood pressure cuff. Carotid intima-media thickness (CIMT) was assessed by the B-mode high-resolution ultrasound technique. Low ABI, CIMT >u20090.8xa0mm or presence of carotid plaques were considered markers of early atherosclerosis.ResultsAverage CIMT was lowest among treatment-naïve patients (0.65xa0mm); 10 (38.4u2009%) had CIMT >u20090.8xa0mm, and carotid plaques were detected in 1 (3.8u2009%). Average CIMT among treated patients was 0.71xa0mm; 30 (50.0u2009%) had CIMT >u20090.8xa0mm, and plaques were detected in 11 (18.3u2009%). Low ABI (≤u20090.90) was found in five patients (5.8u2009%) without symptoms of peripheral artery disease; two were treatment-naïve, and three received antiretroviral therapy. Early atherosclerosis was found in 43 (50.0u2009%) patients; 10 (38.4u2009%) were in treatment-naïve and 33 (55.0u2009%) in the treated group.ConclusionsIncreased prevalence of early atherosclerosis among Slovenian HIV-infected patients below the age of 55 years has been demonstrated. Screening for early atherosclerosis should be implemented in the evaluation of young HIV-infected patients because a more aggressive treatment approach, aimed to delay the progression of atherosclerosis, may be warranted especially when carotid plaques are detected. We have shown that although ABI contributes to CVD risk assessment, CIMT assessment remains the more sensitive method.ZusammenfassungGrundlagenEine höhere Lebenserwartung der HIV-Patienten scheint mit einer erhöhten Inzidenz kardiovaskulärer Erkrankungen gekoppelt zu sein.ZielIn der Studie wurden slowenische HIV-Patienten unter 55 Jahren auf Vorliegen einer Atherosklerose im Frühstadium untersucht.MethodikAn der Studie nahmen 86 HIV-Patienten unter 55 Jahren teil. Der Knöchel-Arm-Index (ankle-brachial index, ABI) wurde mit der manuellen Doppler-Ultraschallsonde gemessen. Die Intima-Media-Dicke der Karotis (carotid intima media thickness, CIMT) wurde mit Hilfe der B-Bild-Ultraschallmethode bestimmt. ABI-Werte ≤u20090,90, CIMT-Werte >u20090,8xa0mm oder Karotis-Plaques wurden als Marker des Atherosklerose-Frühstadiums gewertet.ErgebnisseBei nicht-behandelten Patienten war der durchschnittliche CIMT-Wert am niedrigsten (0,65xa0mm). Bei 10 Patienten (38,4u2009%) betrug der CIMT-Wert >u20090,8xa0mm; Karotis-Plaque wurde bei 1 Patienten (3,8u2009%) festgestellt. Bei behandelten Patienten betrug der durchschnittliche CIMT-Wert 0,71xa0mm, 30 Patienten (55,5u2009%) wiesen einen CIMT-Wert >u20090,8xa0mm auf, bei 11 Patienten (18,3u2009%) wurden Karotis-Plaques nachgewiesen. Bei 5 von 86 Patienten (5,8u2009%) wurde ein niedriger ABI-Wert (≤u20090,90) festgestellt, ohne Symptomatik einer peripheren arteriellen Erkrankung. Zwei Patienten wurden nicht therapiert, die anderen Patienten erhielten antiretrovirale Therapie.SchlussfolgerungenUnsere Studie zeigt eine erhöhte Prävalenz der Atherosklerose im Frühstadium bei slowenischen HIV-Patienten unter 55 Jahren. Die ABI-Messung trägt zwar zur Bewertung des Entwicklungsrisikos der kardiovaskulären Erkrankungen bei, die CIMT-Messung bleibt jedoch die effektivere Methode für die Einordnung langfristiger Risiken bei HIV-Patienten unter 55 Jahren.

Clinical impact of exercise in patients with peripheral arterial disease

Increasing prevalence, high morbidity and mortality, and decreased health-related quality of life are hallmarks of peripheral arterial disease. About one-third of peripheral arterial disease patients have intermittent claudication with deleterious effects on everyday activities, such as walking. Exercise training improves peripheral arterial disease symptoms and is recommended as first line therapy for peripheral arterial disease. This review examines the effects of exercise training beyond improvements in walking distance, namely on vascular function, parameters of inflammation, activated hemostasis and oxidative stress, and quality of life. Exercise training not only increases walking distance and physiologic parameters in patients with peripheral arterial disease, but also improves the cardiovascular risk profile by helping patients achieve better control of hypertension, hyperglycemia, obesity and dyslipidemia, thus further reducing cardiovascular risk and the prevalence of coexistent atherosclerotic diseases. American guidelines suggest supervised exercise training, performed for a minimum of 30–45u2009min, at least three times per week, for at least 12 weeks. Walking is the most studied exercise modality and its efficacy in improving cardiovascular parameters in patients with peripheral arterial disease has been extensively proven. As studies have shown that supervised exercise training improves walking performance, cardiovascular parameters and quality of life in patients with peripheral arterial disease, it should be encouraged and more often prescribed.