Acquired noncompaction?
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Cardiomyopathies↗
Biomedical subjects
Frank Enseleit
Publications and source records attributed to Frank Enseleit.
Images in cardiovascular medicine. The blue man: amiodarone-induced skin discoloration.
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Amiodarone↗
Long-term continuous external electrocardiographic recording: a review.
Ambulatory electrocardiographic (AECG) monitoring is an essential tool in the diagnostic evaluation of patients with cardiac arrhythmias. Recent advances in solid-state technology have improved the quality of the ECG signals and new dedicated algorithms have expanded the clinical application of software-based AECG analysis systems. These advances, in addition to the availability of inexpensive large storage capacities, and very long-term continuous high-quality AECG monitoring, have opened new potential uses for AECG. New digital recorders have the capability of multichannel simultaneous recordings (from 3 to 12 leads) and for telemetred signal transduction. These possibilities will expand the traditional uses of AECG for arrhythmia detection, as arrhythmia monitoring to assess drug and device efficacies has been further defined by new studies. The analysis of transient ST-segment deviation still remains controversial, but considerably more data are now available, especially about the prognostic value of detecting asymptomatic ischaemia. Heart rate variability analysis has shown promise for predicting mortality rates in cardiac patients at high risk. We review recent advances in this field of non-invasive cardiac testing.
Algorithms↗
Continuous wave Doppler signal: a mystery.
Doppler echocardiography is an established noninvasive cardiovascular investigational tool. However, the physical nature of the ultrasound beam may lead to unexpected findings in routine echocardiographic examination, which may lead to misdiagnosis and subsequent wrong clinical decisions.
Aortic Valve Stenosis↗
Simvastatin improves endothelial function in patients with rheumatoid arthritis.
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Arthritis, Rheumatoid↗
Effect of losartan on muscle sympathetic activity and baroreceptor function in systemic hypertension.
Angiotensin II directly stimulates muscle sympathetic nerve activity and facilitates adrenergic sympathetic transmission. The hypotheses that the chronic blockade of angiotensin II receptors (AT(1) type) reduces muscle sympathetic activity and that there is an interaction with baroreceptor function in patients with mild to moderate hypertension were investigated. Muscle sympathetic nerve activity decreased from 51.7 +/- 3.5 to 45.9 +/- 4.2 bursts/min (p = 0.022), and cardiac baroreceptor sensitivity increased from 3.2 +/- 1.3 to 4.9 +/- 1.8 ms/mm Hg (p = 0.007). This study for the first time demonstrates that in hypertensive patients, chronic AT(1) receptor antagonism inhibits muscle sympathetic nerve activity and that baroreceptor function is improved under these conditions.
Angiotensin II Type 1 Receptor Blockers↗
[HIV infection, antiretroviral therapy, and endothelium].
Introduction of antiretroviral combination therapy has profoundly altered both the course and prognosis of the disease in HIV-infected persons. Indeed, protease inhibitor-containing antiretroviral combination therapy dramatically decreased morbidity and mortality and improved quality of life of HIV-infected persons. Recent data, however, have raised concerns that antiretroviral combination therapy is associated with premature manifestation of coronary artery disease. In particular, protease inhibitors have been linked to metabolic changes such as insulin resistance, abnormalities in lipid metabolism and lipodystrophy and increased coronary artery calcification. Previous studies have reached conflicting conclusions whether the incidence of myocardial infarction is indeed increased in this patient population. The most substantial database has recently been provided by the D:A:D study group who demonstrated an increased incidence of myocardial infarction in HIV-infected persons on protease inhibitors or non-nucleoside reverse transcriptase inhibitor-containing therapy in a prospective observational cohort study. Much about the mechanisms involved leading to this finding remain elusive. Surrogate markers such as endothelial function may help to delineate potential mechanisms. Endothelial dysfunction is a key event in the initiation and progression of atherosclerotic vascular disease. It is characterized by decreased nitric oxide (NO) bioavailability. Furthermore endothelial "activation" leading to a pro-inflammatory, proliferative and prothrombotic state of the endothelium occurs. The observed accelerated atherosclerosis could either be caused by the virus infection itself or by a side effect of antiretroviral therapy, protease inhibitors in particular. Experimental studies demonstrate a direct impact of viral components (gp120, TAT) on the endothelium, as they lead to expression of adhesion molecules (intercellular adhesion molecule [ICAM], E-selectin), a prothrombotic state (increase of von Willebrand factor, plasminogen activator inhibitor-[PAI-]1, tissue plasminogen activator [t-PA], tissue factor). In addition, soluble adhesion molecules (sE-selectin, ICAM) were found to be increased in HIV-infected persons. Impaired flow-mediated dilation can already be detected in HIV-infected children, independent of antiretroviral therapy. Another study showed a correlation between viral load and flow-mediated dilation, supporting the notion of infection/inflammation as a contributor to endothelial dysfunction. The influence of protease inhibitor therapy on the endothelium was investigated in several studies in vitro and in vivo. In experimental studies certain protease inhibitors downregulated eNOS expression, and induced CD36 scavenger receptor expression. Furthermore, apoptosis, radical oxygen species (ROS), proliferation of vascular smooth muscle cells and endothelin-1 were found to be increased. There is conflicting evidence about adhesion molecules, as some investigators detected a decrease by therapy, others did not see an effect. In clinical studies all but one investigator found endothelial function to be impaired in HIV-infected persons on protease inhibitor-containing regimens. An important study to underline the hypothesis of a link between protease inhibitor therapy comes from Dubé et al. showing that in healthy volunteers, indinavir caused impaired endothelial-dependent vasodilation after 4 weeks. In a wide variety of clinical conditions lipid-lowering therapy using statins has shown to improve endothelial function as well as hard clinical endpoints. Drug interactions caused by common metabolism of protease inhibitors and most statins by the P450 3A4 pathway limit the use of these drugs it this setting. Pravastatin, which is being metabolized independently of P450 enzymes, was tested in several studies. In one study a trend toward improvement of endothelial function was observed. In an own similar study the authors recently provided evidence of a significant improvement of endothelium-dependent vasodilation in 30 HIV-infected persons. These studies support current guidelines of treating protease inhibitor-associated dyslipidemia with statins, preferably pravastatin.. Many questions remain unanswered in the context of antiretroviral therapy and cardiovascular risk. Results gained from research of endothelial function have served to delineate certain potential mechanisms, much work is yet to be done.
Anti-Retroviral Agents↗
Anti-inflammatory strategies in hypertension: focus on COX-1 and COX-2.
An increasing body of evidence suggests that elevated levels of blood pressure may induce a proinflammatory response. Indeed, both C-reactive protein and blood pressure are independent determinants of cardiovascular risk, and, in combination, each parameter has additional predictive value. Hence, strategies targeted to lower blood pressure and reduce vascular inflammation may potentially provide clinical benefit. In this review, we discuss the role of chronic low-grade inflammation in the context of cardiovascular disease with a focus on roles of cyclooxygenase-1 and -2 in potential anti-inflammatory treatment strategies.
Cardiovascular Diseases↗
Folic Acid improves baroreceptor sensitivity in hypertension.
In hypertension baroreceptor-mediated modulation of heart rate is impaired, resulting in a decreased vagal control. Reactive oxygen species produced locally in the vasculature decrease baroreceptor sensitivity. Folic acid has antioxidant properties. Therefore, the aim of this study was to test whether folic acid improves baroreceptor function in hypertension. Twenty-one male patients with hypertension not taking any drugs for 2 weeks participated in the study and were randomized to folic acid 5 mg or matching placebo. Cardiac and vascular sympathetic baroreceptor functions were tested before and after a single dose of folic acid or placebo with two different methods: the alpha-coefficient method and the phenylephrine (PE) and sodium nitroprusside (SNP) bolus method. In the folic acid group both methods showed significantly improved cardiac and vascular sympathetic baroreceptor sensitivity compared with placebo. This study provides evidence that folic acid improves cardiac and vascular sympathetic baroreceptor sensitivity in hypertensive patients, which suggests an improved vagal control and an enhanced baroreceptor modulation of sympathetic vasomotor tone. Thus, folic acid may represent a novel treatment for prevention of orthostatic dysregulation and/or arrhythmic complications resulting from baroreceptor dysfunction.
Antioxidants↗
[Rheumatoid arthritis, inflammation, and atherosclerosis].
Patients with rheumatoid arthritis (RA) have a two to five times increased risk of developing premature cardiovascular disease that shortens life expectancy by 5-10 years. Traditional risk factors known to promote and accelerate the progression of atherosclerotic lesions however, are often absent in patients with RA. Many similarities have emerged between the paradigm of inflammation in the pathogenesis of atherosclerosis and the well-established mechanisms of inflammation in the pathogenesis of RA. Hence it is intriguing to speculate that inflammation in RA is not confined to the joints but also present in the vessel wall. Indeed, low-grade inflammation and endothelial dysfunction play pivotal roles in the initiation, progression and propagation of the atherosclerotic process. While the healthy endothelium prevents adhesion of mononuclear cells, the defence mechanisms cease under the influence of cardiovascular risk factors and inflammation and they express adhesion molecules (selectins, vascular adhesion molecule-([VCAM-]1, intercellular adhesion molecule-[ICAM-]1) that promote the adherence of monocytes. This expression is induced by pro-inflammatory cytokines such as interleukin-(IL-)1beta and tumor necrosis factor-(TNF-)alpha, by C-reactive protein (CRP), and CD40/CD40 ligand interactions. As all of these factors are present at increased levels in the systemic circulation in RA, it appears possible that they might impact the endothelium as well. Further similarities include proteolytic enzymes such as matrix metalloproteinases (MMPs) that play a role in joint destruction as well as in destabilization and rupture of vulnerable atherosclerotic plaques. In addition, coagulation factors such as increased levels of tissue factor (TF), van Willebrand factor (vWF) and plasminogen activator inhibitor-(PAI-)1 are important in both, RA and CAD. Endothelial dysfunction has shown to correlate with cardiovascular prognosis in several studies, which indicates its clinical relevance. Endothelial function measurement is performed in the coronary or peripheral circulation (by venous occlusion plethysmography or flow-mediated dilation). Recent studies have demonstrated impaired endothelial function in patients with RA, already at early stages of the disease. Similar results are found in patients with systemic lupus erythematosus (SLE), indicating that inflammation per se may impair altering vascular function. This and more evidence supports the notion that inflammation plays a pivotal role in vascular dysfunction and may by these mechanisms explain at least part of the excess morbidity and mortality observed in RA and SLE. In light of the growing evidence of increased cardiovascular morbidity and mortality mostly independent of traditional risk factors, treatment strategies in RA should not only aim at relieving symptoms and inhibiting joint destruction but should have a beneficial effect on the vasculature to reduce cardiovascular events. Indeed, an improvement in endothelial function in RA was recently demonstrated by anti-TNF-alpha therapy and statins. Whether and to what degree the effects of anti-inflammatory strategies to improve endothelial function, which although clinically well established is still a surrogate, translate into clinical benefit for our patients with rheumatologic diseases needs to be determined in large-scale clinical trials some of which are now already under way.
Animals↗
A rare cause of complete heart block after transdermal botanical treatment for psoriasis.
We report the case of a 59-year-old man with a new 3 degrees AV block with a history of psoriasis. After implantation of a definitive DDDR pacemaker, the patient reported a transdermal self-medication with an extract of Nerium oleander for the treatment of his psoriasis. The pharmacological, epidemiological, and clinical features are discussed in brief.
Administration, Cutaneous↗
Selective COX-2 inhibition improves endothelial function in coronary artery disease.
BACKGROUND: There is an ongoing debate as to whether the gastrointestinal safety of COX-2 inhibition compared with nonsteroidal antiinflammatory drugs (NSAIDs) may come at the cost of increased cardiovascular events. In view of the large number of patients at cardiovascular risk requiring chronic analgesic therapy with COX-2 inhibitors for arthritic and other inflammatory conditions, the effects of selective COX-2 inhibition on clinically useful surrogates for cardiovascular disease, particularly endothelial function, need to be determined. METHODS AND RESULTS: Fourteen male patients (mean age, 66+/-3 years) with severe coronary artery disease (average of 2.6 vessels with stenosis >75%) undergoing stable background therapy with aspirin and statins were included. The patients received celecoxib (200 mg BID) or placebo for a duration of 2 weeks in a double-blind, placebo-controlled, crossover fashion. After each treatment period, flow-mediated dilation of the brachial artery, high-sensitivity C-reactive protein, oxidized LDL, and prostaglandins were measured. Celecoxib significantly improved endothelium-dependent vasodilation compared with placebo (3.3+/-0.4% versus 2.0+/-0.5%, P=0.026), whereas endothelium-independent vasodilation, as assessed by nitroglycerin, remained unchanged (9.0+/-1.6% versus 9.5+/-1.3%, P=0.75). High-sensitivity C-reactive protein was significantly lower after celecoxib (1.3+/-0.4 mg/L) than after placebo (1.8+/-0.5 mg/L, P=0.019), as was oxidized LDL (43.6+/-2.4 versus 47.6+/-2.6 U/L, P=0.028), whereas prostaglandins did not change. CONCLUSIONS: This is the first study to demonstrate that selective COX-2 inhibition improves endothelium-dependent vasodilation and reduces low-grade chronic inflammation and oxidative stress in coronary artery disease. Thus, selective COX-2 inhibition holds the potential to beneficially impact outcome in patients with cardiovascular disease.
Aged↗
Detection of a novel exon 4 low-density lipoprotein receptor gene deletion in a swiss family with severe familial hypercholesterolemia.
Familial hypercholesterolemia (FH) is an autosomal dominant disease which results in 2-3-fold elevated cholesterol levels and in accelerated atherosclerosis. FH is caused by small mutations or larger rearrangements in the low-density lipoprotein receptor (LDLR). Here, we report that screening the LDLR gene in a Swiss family (n = 15) with clinical symptoms of FH by combined single strand conformation polymorphism and long-distance PCR identified a novel 1.3 kb deletion in the LDLR. The deletion eliminated exon 4 of the LDLR presumably by recombination between two identical 25 bp repeats present in intron 3 and 4. The 25 bp sequence in intron 3 is part of an Alu repeat, whereas no homology to Alu repeats was found for the intron 4 region. This 1.3 kb LDLR deletion allele cosegregated with elevated cholesterol levels over three generations. Even on high-dose statin therapy, carriers of the deletion averaged 1.6 times higher cholesterol levels and 1.9 times higher apolipoprotein B-100 (apoB-100) levels than non-carriers who had lipid and apoB-100 levels within the range of the Swiss population. Most affected members of the first and second generation of this family had experienced a first myocardial infarction (MI) before the age of 55 years and most LDLR gene deletion carriers older than 40 years showed severe coronary artery disease (CAD). Hence, we conclude that deletion of exon 4 in the LDLR gene drastically decreases low-density lipoprotein binding leading to severe hypercholesterolemia.
Adult↗
Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT).
BACKGROUND: The endothelin (ET-1) system is activated in chronic heart failure (CHF). Whether, what type, and what degree of selective ET blockade is clinically beneficial is unknown. We investigated hemodynamic and neurohumoral effects of 3 weeks of treatment with various dosages of the orally available ET(A) antagonist darusentan in addition to modern standard therapy in patients with CHF. METHODS AND RESULTS: A total of 157 patients with CHF (present or recent NYHA class III of at least 3 months duration), pulmonary capillary wedge pressure > or =12 mm Hg, and a cardiac index < or =2.6 L x min(-1) x m(-2) were randomly assigned to double-blind treatment with placebo or darusentan (30, 100, or 300 mg/d) in addition to standard therapy. Short-term administration of darusentan increased the cardiac index, but this did not reach statistical significance compared with placebo. The increase in cardiac index was significantly more pronounced after 3 weeks of treatment (P<0.0001 versus placebo). Pulmonary capillary wedge pressure, pulmonary arterial pressure, pulmonary vascular resistance, and right atrial pressure remained unchanged. Heart rate, mean artery pressure, and plasma catecholamines remained unaltered, but systemic vascular resistance decreased significantly (P=0.0001). Higher dosages were associated with a trend to more adverse events (including death), particularly early exacerbation of CHF without further benefit on hemodynamics compared with moderate dosages. CONCLUSIONS: This study demonstrates for the first time in a large patient population that 3 weeks of selective ET(A) receptor blockade improves cardiac index in patients with CHF. However, long-term studies are needed to determine whether ET(A) blockade is beneficial in CHF.
Blood Pressure↗
Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis.
BACKGROUND: Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis and increased cardiovascular morbidity and mortality. Striking similarities exist in the inflammatory and immunologic response in RA and atherosclerosis. Indeed, adhesion molecules and cytokines, tumor necrosis factor (TNF)-alpha in particular, are key mediators of joint inflammation and of vascular dysfunction and progression of atherosclerotic vascular disease. Hence, the aim of the present study was to assess the effect of chronic antiinflammatory treatment with the anti-TNF-alpha antibody infliximab on disease activity and endothelial function in patients with active RA. METHODS AND RESULTS: Eleven RA patients (mean age 46+/-5 years; disease duration 9+/-2 years) with high disease activity despite treatment with stable doses of methotrexate (<or=25 mg/wk) and prednisone (<or=10 mg/d) were investigated. Clinical status and endothelium-dependent and -independent vasodilation of the brachial artery as assessed by high-resolution ultrasound were measured before and after 12 weeks of infliximab therapy. Flow-mediated vasodilation improved from 3.2+/-0.4% to 4.1+/-0.5% (P=0.018), whereas endothelium-independent vasodilation with nitroglycerin and baseline diameter remained unchanged (13.6+/-1.2% versus 12.8+/-1.4%, P=0.98, and 3.74+/-0.15 versus 3.66+/-0.11 mm, P=0.54, respectively). Disease activity score (DAS28) was significantly reduced, from 5.6+/-0.3 to 3.5+/-0.6 (P=0.002). Erythrocyte sedimentation rate and C-reactive protein were lowered from 34+/-7 to 19+/-5 mm/h (P=0.04) and from 38+/-11 to 15+/-10 mg/L (P=0.08), respectively. CONCLUSIONS: This is the first study to show that anti-TNF-alpha treatment improves endothelial function in RA. The data suggest that in RA, endothelial dysfunction is part of the disease process and is mediated by TNF-alpha.
Antibodies, Monoclonal↗
Mental stress induces prolonged endothelial dysfunction via endothelin-A receptors.
BACKGROUND: Mental stress is a risk factor for atherosclerosis and may precipitate myocardial ischemia and infarction. Because endothelial dysfunction is an early manifestation of atherosclerosis, we investigated the impact of mental stress on endothelial function. Methods and Results- The effects of a 3-minute mental stress task on endothelium-dependent vasodilation were studied in healthy subjects without cardiovascular risk factors. Flow-mediated (FMD) and nitroglycerin (0.4 mg sublingual)-induced vasodilation were studied before and after mental stress by high-resolution ultrasound of the radial artery. Additionally, FMD was assessed before and 10 to 45 minutes after mental stress during intraarterial infusion of a selective endothelin A receptor antagonist (BQ-123, 1 nmol/min) or saline, respectively. Endothelium-dependent vasodilation was reduced by half for about 45 minutes (8.0+/-1.1% versus 4.1+/-1.0%; P<0.002), whereas endothelium-independent vasodilation to nitroglycerin remained unaffected (15.6+/-1.6 versus 14.3+/-1.3%; NS). Intraarterial infusion of BQ-123, a selective endothelin-A receptor antagonist, but not saline prevented the impairment of endothelium-dependent vasodilation (8.6+/-1.2 versus 9.4+/-1.3%; NS). In contrast, intraarterial infusion of norepinephrine of similar duration as mental stress did not inhibit FMD. CONCLUSIONS: Mental stress induces prolonged endothelial dysfunction, which is prevented by selective endothelin-A receptor antagonism. This represents a novel and important link between mental stress and atherosclerotic vascular disease.
Adult↗
Endothelin antagonists and heart failure.
Chronic heart failure (CHF) is characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance, reduced exercise tolerance, and dyspnea. Despite considerable progress in the treatment of CHF, especially in targeting activated neurohumoral systems, mortality in these patients remains high. Therefore, new treatment approaches are warranted. Endothelin-1 (ET-1) plasma levels are elevated in CHF and correlate with both hemodynamic severity and symptoms. Plasma levels of ET-1 are strong independent predictors of mortality in CHF. Combined ET(A/B) selective ET(A) receptor antagonists have been evaluated in patients with CHF showing impressive hemodynamic improvements. These results indicate that ET receptor antagonists indeed have a potential to improve hemodynamics, symptoms, and potentially prognosis in patients with CHF, which still carries a high mortality.
Atrasentan↗