Mechanisms underlying the vasorelaxant effect of hydrogen sulfide on human saphenous vein.

Hydrogen sulfide (H2 S) represents the third and the youngest member of the gaseous transmitters family. The dominant effect of H2 S on isolated vessels is vasodilation. As the mechanism of H2 S-induced relaxation in human vessels remains unclear, the present study aimed to investigate the effects of H2 S donor, sodium hydrosulfide (NaHS), on isolated human saphenous vein (HSV) and to determine the mechanism of action. Our results showed that NaHS (1 µM-3 mM) induced a concentration-dependent relaxation of endothelium-intact HSV rings pre-contracted by phenylephrine. Pre-treatment with L-NAME, ODQ and KT5823 significantly inhibited NaHS-induced relaxation, while indomethacin induced partial inhibition. Among K+ channel blockers, the combination of apamin and TRAM-34 significantly affected the relaxation produced by NaHS, while iberiotoxin and glibenclamide only reduced maximal relaxation of HSV. NaHS partially relaxed endothelium-intact rings pre-contracted by high K+ , as well as phenylephrine-contracted rings in the presence of nifedipine. Additionally, the incubation of HSV rings with NaHS increased NO production. These results demonstrate that NaHS produces the concentration- and endothelium-dependent relaxation of isolated HSV. Vasorelaxation to NaHS probably involves activation of NO/cGMP/PKG pathway and partially prostacyclin. In addition, different K+ channels subtypes, especially SKCa and IKCa , as well as BKCa and KATP channels in high concentrations of NaHS, probably participate in the NaHS-induced vasorelaxation.

Mechanisms of endothelium-dependent vasorelaxation induced by procyanidin B2 in venous bypass graft.

Cardioprotective abilities of procyanidins, might, at least in part, attribute to their vasodilator properties. The present study was undertaken to assess the vasorelaxant effect of procyanidin B2 on isolated human saphenous vein (HSV) and its underlying mechanisms. Procyanidin B2 relaxed phenylephrine-induced contraction of HSV rings in concentration-dependent manner. The relaxation was dependent on the presence of endothelium and was strongly affected by l-NAME, hydroxocobalamin or ODQ, the inhibitors of NO/cGMP pathway. Indomethacin significantly affected only the relaxation produced by the highest concentrations of procyanidin B2. Apamin and TRAM-34 combination, in the presence of l-NAME and indomethacin, did not additionally decreased procyanidin B2-induced relaxation. In the presence of K+ channel blockers, relaxation induced by procyanidin B2 was partially attenuated by 4-aminopyridine, significantly inhibited by glibenclamide and almost abolished by iberiotoxin. Procyanidin B2 also relaxed the contractions induced by phenylephrine or caffeine in Ca2+-free solution. Finally, nifedipine slightly, while thapsigargin strongly antagonized HSV relaxation. Our results indicate that procyanidin B2 induces endothelium-dependent relaxation of HSV, which results primarily from stimulation of NO production, as well K+ channels opening, especially BKCa, and partially KATP and KV. Regulation of the intracellular Ca2+ release and inhibition of Ca2+ influx probably contribute to procyanidin B2-induced relaxation.

Heart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology.

Cardiomyopathies are a heterogeneous group of heart muscle diseases and an important cause of heart failure (HF). Current knowledge on incidence, pathophysiology and natural history of HF in cardiomyopathies is limited, and distinct features of their therapeutic responses have not been systematically addressed. Therefore, this position paper focuses on epidemiology, pathophysiology, natural history and latest developments in treatment of HF in patients with dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies. In DCM, HF with reduced ejection fraction (HFrEF) has high incidence and prevalence and represents the most frequent cause of death, despite improvements in treatment. In addition, advanced HF in DCM is one of the leading indications for heart transplantation. In HCM, HF with preserved ejection (HFpEF) affects most patients with obstructive, and ∼10% of patients with non-obstructive HCM. A timely treatment is important, since development of advanced HF, although rare in HCM, portends a poor prognosis. In RCM, HFpEF is common, while HFrEF occurs later and more frequently in amyloidosis or iron overload/haemochromatosis. Irrespective of RCM aetiology, HF is a harbinger of a poor outcome. Recent advances in our understanding of the mechanisms underlying the development of HF in cardiomyopathies have significant implications for therapeutic decision-making. In addition, new aetiology-specific treatment options (e.g. enzyme replacement therapy, transthyretin stabilizers, immunoadsorption, immunotherapy, etc.) have shown a potential to improve outcomes. Still, causative therapies of many cardiomyopathies are lacking, highlighting the need for the development of effective strategies to prevent and treat HF in cardiomyopathies.

Metastatic cardiac tumors: from clinical presentation through diagnosis to treatment.

BACKGROUND: To evaluate the prevalence of metastatic tumors involving the myocardium and study their presentation in order to increase awareness to their existence. METHODS: Pathological reports from Sheba Medical Center (Israel, January 1, 2010 through December 31, 2015) and medical records from The Institute for Cardiovascular Diseases of Vojvodina, Sremska Kamenica (Serbia, 23 years period) were screened for cases of metastatic cardiac tumors. Medical, radiological and pathological data of identified cases was retrieved and reviewed. RESULTS: Out of thousands of registered cardiac surgeries we found less than a dozen cases of metastatic cardiac tumors classified as melanoma, carcinomas of lung, colon and kidney and sarcomas of uterine origin. We found that metastatic cardiac tumors comprised 15.8% of all the cardiac tumors. CONCLUSIONS: Metastatic cardiac tumors are extremely rare. As new diagnostic technologies and improved survival of oncological patients may increase the incidence of metastatic cardiac tumors in the future, awareness to their existence and knowledge of their presentation are key factors in their timely recognition.

Sudden death: Neurogenic causes, prediction and prevention.

Sudden death is a major health problem all over the world. The most common causes of sudden death are cardiac but there are also other causes such as neurological conditions (stroke, epileptic attacks and brain trauma), drugs, catecholamine toxicity, etc. A common feature of all these diverse pathologies underlying sudden death is the imbalance of the autonomic nervous system control of the cardiovascular system. This paper reviews different pathologies underlying sudden death with emphasis on the autonomic nervous system contribution, possibilities of early diagnosis and prognosis of sudden death using various clinical markers including autonomic markers (heart rate variability and baroreflex sensitivity), present possibilities of management and promising prevention by electrical neuromodulation.

(-)-Epicatechin-induced relaxation of isolated human saphenous vein: Roles of K+ and Ca2+ channels.

In this study, we aimed to investigate relaxant effect of flavanol (-)-epicatechin on the isolated human saphenous vein (HSV), as a part of its cardioprotective action, and to define the mechanisms underlying this vasorelaxation. (-)-Epicatechin induced a concentration-dependent relaxation of HSV pre-contracted by phenylephrine. Among K+ channel blockers, 4-aminopyridine, margatoxin, and iberiotoxin significantly inhibited relaxation of HSV, while glibenclamide considerably reduced effects of the high concentrations of (-)-epicatechin. Additionally, (-)-epicatechin relaxed contraction induced by 80 mM K+ , whereas in the presence of nifedipine produced partial relaxation of HSV rings pre-contracted by phenylephrine. In Ca2+ -free solution, (-)-epicatechin relaxed contraction induced by phenylephrine, but had no effect on contraction induced by caffeine. A sarcoplasmic reticulum Ca2+ -ATPase inhibitor, thapsigargin, significantly reduced relaxation of HSV produced by (-)-epicatechin. These results demonstrate that (-)-epicatechin produces endothelium-independent relaxation of isolated HSV rings. Vasorelaxation to (-)-epicatechin probably involves activation of 4-aminopyridine- and margatoxin-sensitive KV channels, BKCa channels, and at least partly, KATP channels. In addition, not only the inhibition of extracellular Ca2+ influx, but regulation of the intracellular Ca2+ release, via inositol-trisphosphate receptors and reuptake into sarcoplasmic reticulum, via stimulation of Ca2+ -ATPase, as well, most likely participate in (-)-epicatechin-induced relaxation of HSV.

Dabigatran - Metabolism, Pharmacologic Properties and Drug Interactions.

BACKGROUND: The superiority of dabigatran has been well proven in the standard dosing regimen in prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and extended venous thromboembolism (VTE) treatment. Dabigatran, an anticoagulant with a good safety profile, reduces intracranial bleeding in patients with atrial fibrillation and decreases major and clinically relevant non-major bleeding in acute VTE treatment. However, several important clinical issues are not fully covered by currently available directions with regard to dabigatran administration. The prominent one is reflected in the fact that dynamic impairment in renal function due to dehydratation may lead to haemorragic complications on the one hand, while on the other hand glomerular hyperfiltration may be a possible cause of dabigatran subdosing, hence reducing the drug's efficacy. Furthermore, limitations of the Cockcroft-Gault formula, considered a standard equation for assessing the renal function, may imply that other calculations are likely to obtain more accurate estimates of the kidney function in specific patient populations. Method and Conclusions: Although not routinely recommended, a possibility of monitoring dabigatran in special clinical settings adds to optimization of its dosage regimens, timely perioperative care and administration of urgently demanded thrombolytic therapy, therefore significantly improving this drug's safety profile. Despite the fact that dabigatran has fewer reported interactions with drugs, food constituents, and dietary supplements, certain interactions still remain, requiring considerable caution, notably in elderly, high bleeding risk patients, patients with decreased renal function and those on complex drug regimens. Additionally, upon approval of idarucizumab, an antidote to dabigatran solution, hitherto being a major safety concern, has been finally reached, which plays a vital role in life-threatening bleeding and emergency interventions and surgery.

Endothelium-dependent vasorelaxant effect of procyanidin B2 on human internal mammary artery.

The aim of the present study was to investigate and characterize vasorelaxant effect of procyanidin B2 on human internal mammary artery (HIMA) as one of the mechanisms of its protective effect against vascular risk. Procyanidin B2 induced strong concentration-dependent relaxation of HIMA rings pre-contracted by phenylephrine. Pretreatment with L-NAME, a NO synthase inhibitor, hydroxocobalamin, a NO scavenger, and ODQ, an inhibitor of soluble guanylate cyclase, significantly inhibited procyanidin B2-induced relaxation of HIMA, while indomethacin, a cyclooxygenase inhibitor, considerably reduced effects of low concentrations. Among K+ channel blockers, iberiotoxin, a selective blocker of large conductance Ca2+-activated K+ channels (BKCa), abolished procyanidin B2-induced relaxation, glibenclamide, a selective ATP-sensitive K+(KATP) channels blocker, induced partial inhibition, while 4-aminopyridine, a blocker of voltage-gated K+(KV) channels, and TRAM-34, an inhibitor of intermediate-conductance Ca2+-activated K+(IKCa) channels, slightly reduced maximal relaxation of HIMA. Further, procyanidin B2 relaxed contraction induced by phenylephrine in Ca2+-free Krebs solution, but had no effect on contraction induced by caffeine. Finally, thapsigargin, a sarcoplasmic reticulum Ca2+-ATPase inhibitor, significantly reduced relaxation of HIMA produced by procyanidin B2. These results demonstrate that procyanidin B2 produces endothelium-dependent relaxation of HIMA pre-contracted by phenylephrine. This effect is primarily the result of an increased NO synthesis and secretion by endothelial cells and partially of prostacyclin, although it involves activation of BKCa and KATP, as well as KV and IKCa channels in high concentrations of procyanidin B2.

Mechanisms underlying the vasorelaxation of human internal mammary artery induced by (-)-epicatechin.

Evidences have suggested that flavanol compound (-)-epicatechin is associated with reduced risk of cardiovascular diseases. One of the mechanisms of its cardioprotective effect is vasodilation. However, the exact mechanisms by which (-)-epicatechin causes vasodilation are not yet clearly defined. The aims of the present study were to investigate relaxant effect of flavanol (-)-epicatechin on the isolated human internal mammary artery (HIMA) and to determine the mechanisms underlying its vasorelaxation. Our results showed that (-)-epicatechin induced a concentration-dependent relaxation of HIMA rings pre-contracted by phenylephrine. Among the K(+) channel blockers, 4-aminopyridine (4-AP) and margatoxin, blockers of voltage-gated K(+) (KV) channels, and glibenclamide, a selective ATP-sensitive K(+) (KATP) channels blocker, partly inhibited the (-)-epicatechin-induced relaxation of HIMA, while iberiotoxin, a most selective blocker of large conductance Ca(2+)-activated K(+) channels (BKCa), almost completely inhibited the relaxation. In rings pre-contracted by 80mM K(+), (-)-epicatechin induced partial relaxation of HIMA, whereas in Ca(2+)-free medium, (-)-epicatechin completely relaxed HIMA rings pre-contracted by phenylephrine and caffeine. Finally, thapsigargin, a sarcoplasmic reticulum Ca(2+)-ATPase inhibitor, slightly antagonized (-)-epicatechin-induced relaxation of HIMA pre-contracted by phenylephrine. These results suggest that (-)-epicatechin induces strong endothelium-independent relaxation of HIMA pre-contracted by phenylephrine whilst 4-AP- and margatoxin-sensitive KV channels, as well as BKCa and KATP channels, located in vascular smooth muscle, mediate this relaxation. In addition, it seems that (-)-epicatechin could inhibit influx of extracellular Ca(2+), interfere with intracellular Ca(2+) release and re-uptake by the sarcoplasmic reticulum.

[Contribution of novel anticoagulants fondaparinux and dabigatran to venous thromboembolism prevention].

The data that episodes and sequels of venous thromboembolism (VTE) are recorded in a significant percentage of patients receiving standard anticoagulants as VTE prophylaxis (unfractionated, low-molecular-weight heparin and vitamin K inhibitors) as well as the fact that these drugs have significant limitations and that they may cause serious side-effects in some patients indicate the need for the introduction of new anticoagulant drugs. Fondaparinux, a selective inhibitor of Factor Xa, administered following major orthopedic surgeries having a high risk for the development of VTE, is more efficient than enoxaparin sodium used in European and North-American approved doses. The increased incidence of major bleeding (excluding fatal) due to fondaparinux could be perhaps lowered by dosage reduction in patients with a mildly decreased creatinine clearance. Dabigatran, a peroral direct thrombin inhibitor, administered for VIE prophylaxis in elective hip and knee surgery, showed in to date studies the efficacv comparable (if dabiqatran is given in both dosage regimes of 150 mg and 220 mg daily) or superior (if dabigatran is given at a dose of 220 mg daily) to enoxaparin administered in European-approved doses, while North American-approved doses of enoxaparin were superior than dabigatran in VTE reduction. No significant differences in bleeding rates were determined in any of the study groups. We consider that the introduction of new anticoagulants, including fondaparinux and dabigatran, will contribute to the establishment of a better safety profile and efficacy, and will also enable adequate therapy individualization for each patient depending on his/hers clinical characteristics. The introduction of novel peroral anticoagulants will, inter alia, significantly contribute to improvement in the quality of life, release the patient from numerous limitations in nutrition, interreaction, frequent laboratory monitoring, and also significantly improve therapeutic predictability.

Nicorandil directly and cyclic GMP-dependently opens K+ channels in human bypass grafts.

As we previously demonstrated the role of different K(+) channels in the action of nicorandil on human saphenous vein (HSV) and human internal mammary artery (HIMA), this study aimed to analyse the contribution of the cGMP pathway in nicorandil-induced vasorelaxation and to determine the involvement of cGMP in the K(+) channel-activating effect of nicorandil. An inhibitor of soluble guanylate cyclase (GC), ODQ, significantly inhibited nicorandil-induced relaxation, while ODQ plus glibenclamide, a selective ATP-sensitive K(+) (KATP) channel inhibitor, produced a further inhibition of both vessels. In HSV, ODQ in combination with 4-aminopyridine, a blocker of voltage-gated K(+) (KV) channels, did not modify the concentration-response to nicorandil compared with ODQ, whereas in HIMA, ODQ plus iberiotoxin, a selective blocker of large-conductance Ca(2+)-activated K(+) (BKCa) channels, produced greater inhibition than ODQ alone. We showed that the cGMP pathway plays a significant role in the vasorelaxant effect of nicorandil on HSV and HIMA. It seems that nicorandil directly opens KATP channels in both vessels and BKCa channels in HIMA, although it is possible that stimulation of GC contributes to KATP channels activation in HIMA. Contrary, the activation of KV channels in HSV is probably due to GC activation and increased levels of cGMP.

[Contemporary approach to primary prophylaxis of venous thromboembolism regarding the impact of risk factors on anticoagulation therapy duration].

Adequate thromboprophylaxis primarily requires timely detection of reversible and irreversible risk factors of venous thromboembolism (VTE) and their categorization. It is important to note that the highest percentage ofVTE episodes occur in non-surgical (medical) patients and that VTE develops in a large number of surgical patients upon hospital discharge; this emphasizes the need for adequate VTE prevention in inflammatory diseases, acute medical illness and other medical diseases as well as for prolonging and optimizing the anticoagulant regimen after surgical intervention in the primary VTE prophylaxis. As almost completely unrecognized and neglected major risk factors of VTE in clinical practice, we particularly point out the chronic obstructive pulmonary disease (COPD) and heart failure, especially in NYHA functional class III and IV patients with significantly reduced left heart ventricle. It is necessary to raise clinicians' awareness of a potential danger from wrongly and one-sidedly interpreted dyspnea and coughing signs in patients with COPD as typical symptoms of basic respiratory disease as well as from ascribing the signs of disease aggravation in heart failure patients exclusively to cardial status worsening, neglecting the possibility of having unrecognized and untreated pulmonary embolism at issue. Contemporary way of life enhances the development of new VTE risk factors such as traveler's thrombosis, in particular during long-haul flights as well as in individuals sitting at a computer for prolonged periods (e-thrombosis). Determining and recognizing VTE risk factors, especially those formerly neglected nonsurgical ones and simultaneous presence of multiple risk factors within a given period is required for defining an adequate anticoagulant regimen in primary VTE prophylaxis for surgical and non-surgical (medical) patients.

Effect of wine polyphenol resveratrol on the contractions elicited electrically or by norepinephrine in the rat portal vein.

We investigated the effects of resveratrol on rat portal vein (RPV) contractility without endothelium. Contractions were produced by electrical field stimulation of perivascular nerves (EFS), norepinephrine (NE), adenosine 5'-triphosphate (ATP), high K(+) solution and by calcium chloride (CaCl2 ) in Ca(2+) -free and high K(+) , Ca(2+) -free solution. The EFS-evoked contractions were more sensitive to resveratrol and to NS1619-selective openers of big calcium-sensitive (BKCa ) channels, than NE-evoked contractions. Effects of resveratrol on the ATP-evoked contractions were weak. Blockers of BKCa channels partly inhibited the effect of resveratrol only in EFS-contracted preparations. Western blotting showed that RPV expressed KCa 1.1 protein. Inhibitors of ATP- and voltage-sensitive K(+) channels did not modify the effects of resveratrol. None of the antagonists of K(+) channels affected the resveratrol inhibition of NE-evoked contractions and effect of high concentrations of resveratrol on the EFS-evoked contractions. Resveratrol more potently inhibited CaCl2 than potassium chloride contractions of RPV. Thus, BKCa channels partly mediate the inhibitory effect of resveratrol on the neurogenic contractions of RPV. The smooth muscle Ca(2+) channels and/or Ca(2+) mobilizing through cells might be involved in the effects of resveratrol on the contractility of RPV. Our results are important for better understanding the impact of resveratrol on the portal circulation.

Pericardial syndromes: an update after the ESC guidelines 2004.

Despite a myriad of causes, pericardial diseases present in few clinical syndromes. Acute pericarditis should be differentiated from aortic dissection, myocardial infarction, pneumonia/pleuritis, pulmonary embolism, pneumothorax, costochondritis, gastroesophageal reflux/neoplasm, and herpes zoster. High-risk features indicating hospitalization are: fever >38 °C, subacute onset, large effusion/tamponade, failure of non-steroidal anti-inflammatory drugs (NSAIDs), previous immunosuppression, trauma, anticoagulation, neoplasm, and myopericarditis. Treatment comprises 10-14-days NSAID plus 3 months colchicine (2 × 0.5 mg; 1 × 0.5 mg in patients <70 kg). Corticosteroids are avoided, except for autoimmunity, as they facilitate the recurrences. Echo-guided pericardiocentesis (±fluoroscopy) is indicated for tamponade and effusions >2 cm. Smaller effusions are drained if neoplastic, purulent or tuberculous etiology is suspected. In recurrent pericarditis, repeated testing for autoimmune and thyroid disease is appropriate. Pericardioscopy and pericardial/epicardial biopsy may clarify the etiology. Familial clustering was recently associated with tumor necrosis factor receptor-associated periodic syndrome (TNFRSF1A gene mutation). Treatment includes 10-14 days NSAIDs with colchicine 0.5 mg bid for up to 6 months. In non-responders, low-dose steroids, intrapericardial steroids, azathioprine, and cyclophosphamide can be tried. Successful management with interleukin-1 receptor antagonist (anakinra) was recently reported. Pericardiectomy remains the last option in >2 years severely symptomatic patients. In constriction, expansion of the heart is impaired by the rigid, chronically inflamed/thickened pericardium (no thickening ~20 %). Chest radiography, echocardiography, computerized tomography, magnetic resonance imaging, hemodynamics, and endomyocardial biopsy indicate the diagnosis. Pericardiectomy is the only treatment for permanent constriction. Predictors of poor survival are prior radiation, renal dysfunction, high pulmonary artery pressures, poor left ventricular function, hyponatremia, age, and simultaneous HIV and tuberculous infection.

A 30-year-single-center experience in atrial myxomas: from presentation to treatment and prognosis.

BACKGROUND: The symptoms of myxoma are atypical, vary greatly, and may mimic numerous conditions. Our aim was to investigate the correlation of localization, size, and consistency of myxoma with its treatment and prognosis. METHODS: Over a span of 30 years, 74 consecutive patients (24 men, mean age 46.7 years) were surgically treated for echocardiography-diagnosed myxomas at our center. RESULTS: Left atrial myxomas were more frequent (89.19%), with the racemous form being predominantly left-sided and having no difference in tumor size regardless of localization. Three patients were asymptomatic; and those who were symptomatic, symptoms appeared 2 to 36 months (mean 13.60 ± 7.52) before diagnosis. Nonspecific symptoms and signs were present in 91.98% of patients, whereas specific symptoms and signs were present in 74.32%. More often, patients with myxomas >5 cm in diameter were symptomatic. Embolic events occurred in 15 patients (9 cerebral, 4 pulmonary, 2 peripheral), more frequently in right atrial myxomas of >5 cm diameter. All patients were surgically treated on diagnoses, with no intraoperative mortality or recurrences. CONCLUSIONS: Symptoms in our cardiac myxoma patients were more pronounced when the myxomas were left-sided, racemous, and over 5 cm in diameter. Even in asymptomatic patients, a high index of suspicion assured timely diagnosis and management.