Ammi Visnaga L., a Potential Medicinal Plant: A Review.

Ammi visnaga L. (Visnaga daucoides Gaertn., Family Apiaceae), also known as Khella Baldi or toothpick weed, is an annual or biennial herb indigenous to the Mediterranean region of North Africa, Asia, and Europe. The plant is known to have been used in traditional medicine a long time ago. Nowadays, it is used in modern medicine to treat many aliments such as renal colic and coronary insufficiency, and is used as an antioxidant, antifungal, and antibacterial, with a larvicidal effect on mosquito larvae. Peer-reviewed studies show that these pharmacological activities are due its valuable chemical constituents that include mainly essential oil, polyphenolic compounds including flavonoids, as well as γ-pyrones, represented mainly by khellin and visnagin. Its essential oil is reported to have antiviral, antibacterial, and larvicidal effects, while its flavonoid content is responsible for its antioxidant activity. Its γ-pyrone content has a powerful effect on facilitating the passage of kidney stones and relieving renal colic, in addition to having a relaxant effect on smooth muscle including that of the coronary arteries. The current review represents the progress in research on A. visnaga in terms of either its chemistry or biological activities. This review represents scientific support material for the use of the plant by the pharmaceutical industry.

Cost-Effectiveness Analysis of Rehabilitation Interventions for Teeth With Extensive Coronary Destruction.

OBJECTIVE: To perform a cost-effectiveness analysis of rehabilitation interventions for management of posterior teeth (molar) with extensive coronary destruction. METHODOLOGY: An economic model by Markov simulated a hypothetical 10-year cohort with 1,000 patients requiring treatment for a molar tooth with pulp necrosis and extensive coronary destruction. This study adopted the perspective of a local manager from Specialized Center in Dentistry, based on the transfer from the Ministry of Health. Treatments were proposed: Tooth Extraction + Removable Partial Denture (TE+RPD); Root Canal Treatment + Intra-Radicular Restoration + Single Crown (RCT+RIR+SC); and Tooth Extraction + Dental Implant + Single Crown (TE+DI+SC). The costs were obtained from the SUS Integrated System of Procedures, Medicines and orthoses; prostheses and special materials table management (SIGTAP). Failure and survival rates were obtained from systematic reviews. The variable "years of survival" was an outcome of effectiveness. The probabilistic simulation considered the confidence interval of 95%, variation of parameters by 5% and annual discount rate of 5%. RESULTS: TE+RPD intervention presented lower cost and effectiveness. The incremental cost-effectiveness ratio (ICER) of RCT+IRR+SC and TE+DI+SC interventions compared to TE+RPD were $13.06 and $9.92 per year of survival. Compared to RCT+IRR+SC, the TE+DI+SC intervention had an ICER=$26.90 per year of survival. The acceptability curve indicates that the choice of intervention depends on the willingness to pay. CONCLUSION: The RCT+IRR+SC intervention presented a balance of cost-effectiveness. Rehabilitation with implants can be considered in view of the higher expectation of longevity and, especially, greater willingness to pay.

Impact of stent deployment procedural factors on long-term effectiveness and safety of sirolimus-eluting stents (final results of the multicenter prospective STLLR trial).

Drug-eluting stent failures were associated with various clinical factors. However, the clinical impact of stent deployment technique was unknown. This study was designed to evaluate the frequency and impact of suboptimal percutaneous coronary intervention on long-term outcomes of 1,557 patients treated with sirolimus-eluting stents (SESs) in 41 US hospitals. All steps of the interventional procedure were scrutinized by an independent core laboratory to determine the occurrence of geographic miss (GM). GM included longitudinal (LGM; injured or diseased segment not covered by SES) or axial GM (balloon-artery size ratio <0.9 or >1.3) mismatches. Patients with and without GM were stratified (GM vs no-GM group). Patients, investigators, and the independent clinical event adjudication committee were blind to study group assignments. The primary end point was 1-year target-vessel revascularization (TVR) rate. Incidences and predictors of GM and safety outcomes were secondary end points. GM occurred in 943 patients (66.5%): 47.6% had LGM, 35.2% had axial GM, and 16.5% had both. One-year TVR rates were 5.1% in the GM group versus 2.5% in the no-GM group (p=0.025). TVR was 6.1% in the LGM versus 2.6% in the no-LGM subgroups (p=0.001). The association of GM with 1-year TVR was independent of clinical or anatomic factors (hazard ratio 2.0, 95% confidence interval 1.0 to 4.02, p=0.05). There was a 3-fold increase in myocardial infarction rates associated with GM (2.4% vs 0.8%; p=0.04). In conclusion, GM occurred frequently during SES implantation and was associated with increased risk of TVR and myocardial infarction at 1 year. These results emphasized the need for improvement in contemporary percutaneous coronary intervention practices and technologies.

Chronic heart failure induced by multiple sequential coronary microembolization in sheep.

OBJECTIVE: Although a large variety of animal models for acute ischemia and acute heart failure exist, valuable models for studies on the effect of ventricular assist devices in chronic heart failure are scarce. We aimed to establish a stable and reproducible animal model of chronic heart failure in sheep. METHODS: Sheep (n=8, 77 +/- 4 kg) were anesthesized and a 5F sheath was implanted into the left carotid artery. The left main coronary artery was catheterized under flouroscopic guidance and bolus injection of polysterol microspheres (90 microm, n=25.000) was performed. Microembolization (ME) was repeated up to three times in two to three week intervals until animals started to develop stable clinical signs of heart failure. Clinical and echocardiographic data were analyzed at baseline (base) and at three months (3 mo) after first ME. All animals were followed for 3 months after first microembolization and then sacrificed for histological examination. Another four healthy sheep (79+/-6 kg) served as control animals. RESULTS: All animals developed clinical signs of heart failure as indicated by increased heart rate at rest (68+/-4 bpm (base) to 93 +/- 5 bpm (3 mo) (p<0.05)), increased respiratory rate at rest (28+/-5 (base) to 38 +/- 7 (3 mo) (p<0.05)) and increased body weight 77 +/- 2 kg to 81 +/- 2 kg (p<0.05) due to pleural effusion, peripheral edema and ascites. Echocardiographic evaluation revealed significantly an increase of left ventricular enddiastolic diameter from 46 +/- 3 mm (base) to 61 +/- 4 mm (3 mo) (p<0.05). Clinically and echocardiographically no significant changes were revealed in healthy control animals. CONCLUSIONS: We conclude that multiple sequential intracoronary microembolization can effectively induce myocardial dysfunction with clinical and echocardiographical signs of chronic ischemic cardiomyopathy. The present model may be suitable in experimental work on heart failure and left ventricular assist devices, e.g. for studying the impact of mechanical unloading, mechanisms of recovery and reverse remodeling.

Effect of collateral flow on epicardial and endocardial lysosomal hydrolases in acute myocardial ischemia.

Early changes in lysosomal enzymes must occur if their role is significant in irreversible myocardial injury. Therefore, we ligated the anterior descending coronary artery in 14 dogs and after 60 min excised epicardial and endocardial samples from the ischemic and adjacent normal heart. The collateral flow measured with radioactive microspheres in the endocardial samples averaged 19% of control. The muscle was disrupted and fractionated by ultracentrifugation into nuclear pellet (NP), heavy lysosomal pellet (HL), light lysosomal pellet (LL), microsomal pellet (M) and supernate (S). Electron microscopy demonstrated changes characteristic of sichemia in whole tissues and sedimented fractions. Acid phosphatase reaction product was present in residual bodies in the HL fraction and membrane-bound vesicles in the LL fraction and in the intact tissue. Significant decreases in the specific activity of N-acetyl-beta-glucosaminidase and beta-glucuronidase occurred in the endocardial LL fraction, while significant increases in both were found in the ts fraction (P less than 0.05). Losses of acid phosphatase occurred in both LL and S fractions. Moreover, decreases of total N-acetyl-beta-glucosaminidase in the HL fraction and of total beta-glucuronidase and acid phosphatase in the LL fraction were positively correlated (P less than 0.01) with the degree of ischemia measured with radioactive microspheres. Only insignificant enzymatic changes were found when the collateral flow was greater than 40%, and the differences were less significant in epicardial samples where the flow averaged 29%. The early loss of enzymes from the lysosomal fractions in severe ischemia suggests a role for lysosomal hydrolases in the necrosis that follows coronary occlusion.

Cortisol awakening response is elevated in acute coronary syndrome patients with type-D personality.

OBJECTIVE: Type-D or "distressed" personality and depression following admission for acute coronary syndrome (ACS) have been associated with poor clinical outcome. The biological pathways underpinning this relationship may include disruption of the hypothalamic-pituitary-adrenocortical (HPA) axis. We therefore assessed cortisol output in patients who had recently suffered from ACS. METHOD: Salivary cortisol was assessed eight times over a 24-h period in 72 patients within 5 days of admission for ACS. Depressive symptoms were measured with the Beck Depression Inventory (BDI), and type-D personality was measured with the Type-D Scale-16. Particular attention was given to cortisol awakening response (CAR), which was measured as the difference in cortisol between waking and peak responses 15-30 min later. RESULTS: Cortisol showed a typical diurnal pattern, with low levels in the evening, high levels early in the day, and CAR averaging 7.58+/-10.0 nmol/l. Cortisol was not related to the severity of ACS or underlying coronary artery disease or to BDI scores. The CAR was positively associated with type-D personality independently of age, gender, and body mass (P=.007). Linear regression showed that type-D personality accounted for 7.9% of the variance in CAR after age, sex, body mass, BDI, cortisol level on waking, and fatigue had been taken into account (P=.008). CONCLUSIONS: Type-D personality may be associated with disruption of HPA axis function in survivors of acute cardiac events and may contribute to heightened inflammatory responses influencing future cardiac morbidity.

Impact of three or more versus a single sirolimus-eluting stent on outcomes in patients who undergo percutaneous coronary intervention.

This retrospective analysis compared clinical outcomes of patients who underwent stenting with > or =3 sirolimus-eluting stents (SESs) with those who received a single SES. SES (Cypher) implantation for single vessels is proved to be effective and durable, but knowledge regarding the safety and effectiveness of multiple stenting with SESs is currently limited. In total, 929 consecutive patients who received SESs were identified; 63 received > or =3 SESs (multi group) and 866 received 1 SES (single group). The multi group had more non-Q-wave myocardial infarctions (MIs) during the index hospitalization (p = 0.02). At 30-day follow-up, death, Q-wave MI, subacute thrombosis, and major adverse cardiac events were higher in the multi group than in the single group. At 6 months, death, Q-wave MI, target lesion revascularization, and major adverse cardiac events continued to be higher in the multi group. Using multivariate analysis, > or =3 SES implantations, American College of Cardiology/American Heart Association type C lesions, and cardiogenic shock were identified as independent predictors for 6-month major adverse cardiac events. In addition, patients in the multi group had a significantly lower survival rate than patients in the single group (p <0.0001). Patients who required > or =3 SES implantations developed increased periprocedural non-Q-wave MI and worse adverse clinical outcomes at 30 days and 6 months compared with patients who required a single SES implantation. In conclusion, when patients present with multiple coronary lesions, percutaneous coronary intervention with multiple SESs should be undertaken with great caution.

Diurnal cortisol decline is related to coronary calcification: CARDIA study.

OBJECTIVE: Chronic stress may be a risk factor for coronary heart disease and is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. We tested the hypotheses that two markers of HPA axis dysregulation, elevated average level (area under the curve, adjusted for time awake) and diurnal decline of salivary cortisol, were associated with presence of coronary calcification (CaC). METHOD: Seven hundred eighteen black and white middle-aged adults enrolled in an ancillary study of Coronary Artery Risk Development in Young Adults provided six salivary cortisol samples throughout one full day and had measurements of CaC. RESULTS: The prevalence of any calcification was low, 8.1% in the participants of the ancillary study, with white men having the highest proportion. Average cortisol did not differentiate groups, means = 2.15 and 2.08. Those with any CaC declined approximately 6% per hour in cortisol over the course of the day, whereas those with no CaC declined more than 8% per hour (p < .003). Those persons with slope scores in the flattest quartile had a greater likelihood of any CaC than did those in the remaining quartiles adjusted for sex-race group, age, smoking, treatment for diabetes, systolic blood pressure, logged triglycerides, average cortisol, and educational attainment (odds ratio = 2.58; 95% confidence interval = 1.26-5.30). CONCLUSIONS: Our results are consistent with the hypothesis that HPA axis dysregulation may affect risk for atherosclerosis.

Pathophysiology of vascular calcification in chronic kidney disease.

Patients with chronic kidney disease (CKD) on dialysis have 2- to 5-fold more coronary artery calcification than age-matched individuals with angiographically proven coronary artery disease. In addition to increased traditional risk factors, CKD patients also have a number of nontraditional cardiovascular risk factors that may play a prominent role in the pathogenesis of arterial calcification, including duration of dialysis and disorders of mineral metabolism. In histological specimens from the inferior epigastric artery of dialysis patients, we have found expression of the osteoblast differentiation factor core binding factor alpha-1 (Cbfa1) and several bone-associated proteins (osteopontin, bone sialoprotein, alkaline phosphatase, type I collagen) in both the intima and medial layers when calcification was present. In cultured vascular smooth muscle cells, the addition of pooled serum from dialysis patients (versus normal healthy controls) accelerated mineralization and increased expression of Cbfa1, osteopontin, and alkaline phosphatase to a similar magnitude as does beta-glycerophosphate alone. However, a lack of inhibitors of calcification may also be important. Dialysis patients with low levels of serum fetuin-A, a circulating inhibitor of mineralization, have increased coronary artery calcification and fetuin-A can inhibit mineralization of vascular smooth muscle cells in vitro. These data support that elevated levels of phosphorus and/or other potential uremic toxins may play an important role by transforming vascular smooth muscle cells into osteoblast-like cells, which can produce a matrix of bone collagen and noncollagenous proteins. This nidus can then mineralize if the balance of pro-mineralizing factors outweighs inhibitory factors.

Susceptibility to pain during coronary angioplasty: usefulness of pulpal test.

OBJECTIVES: This study in patients with coronary artery disease (CAD) sought to 1) determine the dental pain threshold and reaction to tooth pulp stimulation; 2) correlate the clinical, ergometric and angiographic features of patients with and without pain during percutaneous transluminal coronary angioplasty (PTCA) to pulpal test response; 3) verify whether reactivity to dental pulp stimulation could help to identify patients particularly prone to perceiving angina during myocardial ischemia. BACKGROUND: Silent myocardial ischemia is frequently observed in patients with CAD. Higher pain thresholds have been documented in asymptomatic subjects, suggesting a generalized hyposensitivity to pain. METHODS: Eighty-six consecutive male patients with reproducible exercise-induced myocardial ischemia and CAD documented by angiography underwent PTCA. A pulpal test was performed in all patients by means of an electrical tooth pulp stimulator. RESULTS: Seventy-one patients (82.6%) with and 15 (17.4%) without angina during daily life were studied. During the pulpal test, 57 patient (66.2%) reported dental pain, whereas 29 (33.7%) were asymptomatic, even at maximal stimulation of 500 mA. The study cohort was classified into two groups according to the presence (58 patients [group 1]) or absence (28 patients [group 2]) of angina during myocardial ischemia induced by PTCA. Ergometric variables, extent of CAD, presence of ST segment elevation during PTCA, number of inflations, inflation time and maximal inflation pressure were similar in the two patient groups. Dental pain was provoked by pulpal test in 81% of patients with and 36% of patients without symptoms during PTCA (p = 0.0004). The absence of dental pain even at maximal tooth pulp stimulation (500 mA) was observed in 11 (18.9%) patients in group 1 and 18 (64.2%) in group 2. Patients who were asymptomatic during PTCA had a higher mean dental pain threshold, lower mean threshold reaction and lower mean maximal reaction than those who were symptomatic during both PTCA and the pulpal test. CONCLUSIONS: A correlation between the prevalence of symptoms during pulpal test, daily life, exercise-induced myocardial ischemia and PTCA was found. A higher dental pain threshold and lower reactivity characterized those subjects who were prone to silent ischemia both during daily life and during PTCA. Ergometric variables, extent of CAD and techniques used during PTCA were unrelated to the tendency to perceive pain during myocardial ischemia. Response to the pulpal test and the presence of symptoms during daily life were highly related to the presence of angina during PTCA.

A blunted diurnal cortisol response in the lower educated does not explain educational differences in coronary heart disease: findings from the AGES-Reykjavik study.

Lower educational attainment generally is a strong predictor of coronary heart disease (CHD). The underlying mechanisms of this effect are, however, less clear. One hypothesis is that stress related to limitations imposed by lower socioeconomic status elicits changes in hypothalamic-pituitary-adrenal axis functioning, which, in turn, increases risk of CHD. In a large cohort study, we examined whether educational attainment was related to risk of fatal and non-fatal CHD and the extent to which salivary cortisol mediated this relation independent of potential confounders, including lifestyles. Data came from 3723 participants aged 66 through 96 from the Age, Gene/Environment Susceptibility (AGES) - Reykjavik Study. Between 2002 and 2006, data were collected using questionnaires and examinations including morning and evening salivary samples. Hospital admission records and cause of death registries (ICD-9 and ICD-10 codes) were available until December 2009. Linear regression and Cox proportional hazards analyses were performed. Even after adjustment for potential confounders, including lifestyle, persons with lower educational attainment showed a blunted cortisol response and also greater risk of incident CHD. However, our data did not support the role of cortisol as a mediator in the association between education and CHD in an older sample (192).

Local anesthesia with epinephrine is safe and effective for oral surgery in patients with type 2 diabetes mellitus and coronary disease: a prospective randomized study.

OBJECTIVE: To investigate the variations in blood glucose levels, hemodynamic effects and patient anxiety scores during tooth extraction in patients with type 2 diabetes mellitus T2DM and coronary disease under local anesthesia with 2% lidocaine with or without epinephrine. STUDY DESIGN: This is a prospective randomized study of 70 patients with T2DM with coronary disease who underwent oral surgery. The study was double blind with respect to the glycemia measurements. Blood glucose levels were continuously monitored for 24 hours using the MiniMed Continuous Glucose Monitoring System. Patients were randomized into two groups: 35 patients received 5.4 mL of 2% lidocaine, and 35 patients received 5.4 mL of 2% lidocaine with 1:100,000 epinephrine. Hemodynamic parameters (blood pressure and heart rate) and anxiety levels were also evaluated. RESULTS: There was no difference in blood glucose levels between the groups at each time point evaluated. Surprisingly, both groups demonstrated a significant decrease in blood glucose levels over time. The groups showed no significant differences in hemodynamic and anxiety status parameters. CONCLUSION: The administration of 5.4 mL of 2% lidocaine with epinephrine neither caused hyperglycemia nor had any significant impact on hemodynamic or anxiety parameters. However, lower blood glucose levels were observed. This is the first report using continuous blood glucose monitoring to show the benefits and lack of side effects of local anesthesia with epinephrine in patients with type 2 diabetes mellitus and coronary disease.

Susceptibility to pain in hypertensive and normotensive patients with coronary artery disease: response to dental pulp stimulation.

An association between a decreased responsiveness to varying painful stimuli and arterial hypertension both in animals and in humans has been documented. The relationship between essential hypertension and silent myocardial ischemia in coronary artery disease (CAD) populations is not well understood. The aims of this study in CAD patients with and without essential hypertension were (1) to determine dental pain threshold and reaction to tooth pulp stimulation and (2) to ascertain whether hypertensive CAD patients differ from normotensive ones in reactivity to pain. This study involved 182 patients who were affected by mild and moderate hypertension (G1) and 174 normotensive patients (G2). The inclusion criteria were reproducible exercise-induced myocardial ischemia, CAD documented at angiography, and dental formula suitable for pulp test. All patients underwent an ergometric stress test, coronary angiography, and pulp test. Our CAD hypertensive patients showed a lower prevalence of angina during daily life (64.8% in G1 versus 81.6% in G2, P<.05) and a higher incidence of exercise-induced silent myocardial ischemia (60.4% in G1 versus 48.8% in G2, P<.05) than the normotensive group. The mean anginal pain intensity, which was suffered both during spontaneous transitory episodes of ischemia and/or during acute myocardial infarction, was significantly lower in G1 than in G2 patients (P<.05). During pulp test, 31.8% of G1 and 13.7% of G2 referred no symptoms, even at the highest current intensity of 500 mA. The hypertensive patients with symptoms during pulp test had a higher mean dental pain threshold and lower mean threshold reaction and maximal reaction than did the normotensive symptomatic ones. In patients of both groups, a positive correlation between the mean maximal reaction during pulp test and the prevalence of angina during daily life was also found. In conclusion, patients with CAD and essential hypertension differ from normotensive CAD patients in reactivity to pain. Significantly higher pain thresholds and lower reactions to tooth pulp stimulation characterized patients with increased blood pressure values.

Cardiovascular adaptation to orthostatic stress during vasodilator therapy.

BACKGROUND: Orthostatic hypotension is a dangerous problem in elderly patients, often exacerbated by vasodilator medications. Age- and disease-related impairments in cardioacceleration and diastolic ventricular function may make older patients particularly vulnerable to the hypotensive effects of these drugs. Therefore we aimed to determine mechanisms of postural blood pressure regulation in elderly patients with coronary artery disease and to compare the effects of isosorbide dinitrate and nicardipine hydrochloride on postural blood pressure homeostasis in these patients. METHODS: Twenty elderly subjects with stable coronary artery disease (age, 76 +/- 4 [SD] years) underwent a baseline evaluation followed by a double-blind, randomized crossover comparison of nicardipine (20 mg by mouth t.i.d.) versus isosorbide (20 mg by mouth t.i.d.). Doppler echocardiography and a 15-minute 60-degree head-up tilt test were conducted on no study medications and then after successive 3-week treatment periods with nicardipine or isosorbide. Blood pressure, heart rate, vascular resistance, cardiac output, and spectral characteristics of heart rate and blood pressure variability were measured before and during each tilt. RESULTS: Isosorbide treatment was associated with a higher prevalence of symptoms of cerebral hypoperfusion and a failure to increase systemic vascular resistance during tilt. While taking isosorbide subjects were able to preserve cardiac output and maintain upright blood pressure through enhanced cardioacceleration. During nicardipine treatment systemic vascular resistance and low-frequency blood pressure variability were reduced, but the ability to increase systemic vascular resistance during tilt was preserved. CONCLUSIONS: Although nicardipine may decrease vascular responsiveness to sympathetic activation, the baroreflex-mediated vasoconstrictor response to upright tilt remains intact. In contrast, isosorbide impairs the systemic vascular response to orthostatic stress in elderly patients with stable coronary artery disease.

Early and late assessment of stenosis geometry after coronary arterial stenting.

Early and late modifications of stenosis geometry after stenting of coronary arteries were assessed. Morphologic changes were evaluated by quantitative coronary angiography (automated edge-detection) and theoretical pressure drop across the dilated and stented stenosis was calculated from the Poiseuille formula, with turbulent resistances assuming a coronary blood flow of 1 or 3 ml/s. Eleven patients (ages 41 to 69 years, mean 55) were studied before and after angioplasty, and immediately after stent implantation. The stented coronary artery was the left anterior descending artery in 9 patients and the left circumflex in 2. Following stent implantation, an additional increase in minimal luminal cross-sectional area of the dilated vessel was observed, suggesting that the self-expanding stainless-steel endoprosthesis used had a dilating function in addition to its stenting role. Repeat angiography in 6 patients 3 months after stent implantation showed a decrease in the minimal luminal cross-sectional area without a significant change in theoretic pressure decrease. This slight reduction in vessel caliber had no hemodynamically significant repercussions. Thus, stenting of coronary arteries following dilatation is a potentially valuable technique for preventing both abrupt closure and late reduction in lumen diameter.

Nutrient intake and progression of coronary artery disease.

The relation between nutrient intake and progression of coronary artery disease was examined in 50 men receiving a lipid-lowering diet or usual care in the St. Thomas' Atherosclerosis Regression Study. Nutrient intake was assessed by diet history. Changes in coronary angiograms were measured by quantitative image analysis. In univariate linear regression analysis progression of disease over 39 months, as measured by decrease in minimum absolute width of coronary segments, was directly related to dietary energy (p < 0.001) and to the absolute intakes of total fat (p < 0.001), saturated fat (p < 0.001), monounsaturated fat (p = 0.016) and cholesterol (p = 0.06). No significant associations were seen with polyunsaturated fat, carbohydrate, protein, fiber, alcohol or with the ratio of intakes of polyunsaturated fatty acids to saturated fatty acids. In multiple linear regression analysis the associations of change in minimum absolute width of coronary segments with total or saturated fat persisted when adjusted for plasma low-density lipoprotein cholesterol concentration, age, weight, blood pressure, smoking or treatment group assignment. The findings suggest that in middle-aged men, progression of CAD is strongly influenced by intake of saturated fatty acids, an effect mediated in part by mechanisms other than the influence of this nutrient on plasma cholesterol and low-density lipoprotein cholesterol.

Effect of gemfibrozil +/- niacin +/- cholestyramine on endothelial function in patients with serum low-density lipoprotein cholesterol levels <160 mg/dl and high-density lipoprotein cholesterol levels <40 mg/dl.

We studied endothelial function using the brachial artery ultrasound model in 100 subjects from the Armed Forces Regression Study, a placebo-controlled, angiographic regression trial in subjects with normal or modestly elevated low-density lipoprotein (LDL) cholesterol and low levels of high-density lipoprotein (HDL) cholesterol treated for 30 months with gemfibrozil and (if necessary) niacin and/or cholestyramine to raise HDL by 25% and lower LDL to < 110 mg/dl. Although the treatment group had highly significant improvements in LDL and HDL cholesterol, there was no difference between the 2 groups in flow-mediated dilation (treatment vs control 6.9 +/- 6.5% vs 6.3 +/- 7.3%) or nitroglycerin-induced dilation (12.4 +/- 9.6% vs 11.9 +/- 7.4%, all p = NS). Treatment and control subjects without a history of hypertension had flow-mediated dilation similar to that of a normal reference population (10.6 +/- 8.3% vs 8.4 +/- 4.5%), whereas subjects with a history of systemic hypertension had markedly impaired flow-mediated dilation that was not significantly improved with treatment (treatment vs control, 6.0 +/- 5.5% vs 4.3 +/- 5.9%, p = 0.2). Thus, nonhypertensive subjects with angiographic coronary disease and low HDL cholesterol had normal endothelial function in the brachial artery model. Patients with a history of hypertension had marked endothelial dysfunction despite blood pressure treated to normal levels, and this dysfunction is not attenuated by pharmacologic therapy for dyslipidemia.

Amiodarone. Haemodynamic profile during intravenous administration and effect on pacing-induced ischaemia in man.

The haemodynamic changes during intravenous amiodarone administration in laboratory animals and human studies are reviewed and compared with the results from our investigations. While the results of previous human studies have been rather variable, our investigations suggest that the cardiovascular changes following intravenous amiodarone include an early and usually short reduction of systemic and coronary vascular resistance, which may be partially due to the vasodilating properties of the solvent, polysorbate 80. As a result, a decrease in afterload and cardiac work and increases in cardiac output and coronary blood flow occur. Contrary to the observations in the animal experiments, heart rate increases in man, presumably as a result of the relatively greater fall in afterload which occurs. However, in spite of this increase in heart rate, contractility is reduced at the end of amiodarone administration and remains depressed after the infusion, resulting in a significant increase in left ventricular filling pressure. Neither myocardial oxygen demand nor consumption change during amiodarone administration. Although the intrinsic negative inotropic effects of amiodarone warrant a cautious approach in patients with left ventricular dysfunction, worsening of heart failure or the occurrence of myocardial ischaemia has been reported in only very few cases so far. In contrast, the drug was demonstrated to protect against pacing-induced myocardial ischaemia, in patients with both normal and depressed left ventricular function. These anti-ischaemic properties of amiodarone were investigated in a second study using a double pacing stress test protocol. Overall myocardial oxygen consumption did not change during pacing after amiodarone, but it clearly reduced (regional) myocardial ischaemia, as demonstrated by a reduction of ST-segment changes and anginal pain, and in particular by the absence of myocardial lactate production during pacing after amiodarone. These anti-ischaemic properties are mainly based on a reduction of myocardial oxygen demand, rather than on an improvement in coronary flow. It is concluded then, that amiodarone has significant haemodynamic effects as manifested by an early reduction in vascular resistance and a late negative inotropic effect. Although vasodilatation of short duration caused by its solvent, polysorbate 80, also occurs, the overall cardiovascular changes are caused by the direct, intrinsic haemodynamic effects of amiodarone alone. The important anti-ischaemic properties of amiodarone appear to result primarily from these cardiovascular actions and the inherent reduction in myocardial oxygen demand.

Effect of Terplex/VEGF-165 gene therapy on left ventricular function and structure following myocardial infarction. VEGF gene therapy for myocardial infarction.

BACKGROUND: We used a novel lipopolymeric gene delivery system, TeplexDNA, to transfect myocardium with plasmid vascular endothelial growth factor-165 (pVEGF) and evaluated the ability of pVEGF to preserve left ventricular function and structure after coronary ligation in a rabbit model. METHODS: New Zealand white rabbits underwent circumflex coronary ligation after direct intramyocardial injection of either Terplex alone or Terplex + 50 microg pVEGF-165. Serial echocardiography and histologic studies were performed (n = 12/group). Mortality did not differ between groups. The data is reported as the mean +/- standard deviation. RESULTS: Over the 21 days following coronary ligation, pVEGF-165-treated animals demonstrated significant improvement in fractional shortening (20-25%, p = 0.02), long axis two-dimensional ejection fraction (42-51%, p=0.02) and short axis m-mode ejection fraction (46-54%, p = 0.02). No significant improvements were noted in the control group. VEGF-treated animals had a 50% increase in peri-infarct vessel density and a trend towards a smaller infarct size (20% vs. 29%, p = 0.10). In animals receiving pVEGF-165, the diastolic ventricular area increased from 1.87 +/- 0.24 cm2 prior to ligation to 2.19 +/- 0.23 cm2 at 21 days following ligation, compared to an increase from 1.84 +/- 0.38 to 2.54 +/- 0.55 cm2 over the same period in control animals (p = 0.03). Similarly, the systolic ventricular area in VEGF-165 animals increased from 1.06 +/- 0.26 cm2 prior to ligation to 1.50 +/- 0.29 cm2 at 21 days following ligation, compared to an increase from 1.16 +/- 0.30 to 1.86 +/- 0.43 cm2 over the same period in the control animals (p = 0.04). CONCLUSION: TerplexDNA mediated delivery of plasmid VEGF administered at the time of coronary occlusion improves left ventricular function and reduces left ventricular dilation following myocardial infarction.

Cardiovascular changes during mental stress: correlations with presence of coronary risk factors and cardiovascular disease in physicians and dentists.

Stress may play a role in the etiology of cardiovascular disease. Research showing that mental stress administered in laboratory settings causes great change in cardiovascular and hemodynamic functioning supports this hypothesis. In a small sample of physicians and dentists, those who showed greater cardiovascular reactivity (hot reactors) to stress were more likely to be hyperlipidemic or to have had a myocardial infarction or coronary bypass surgery. In addition, some of the nonreactive group were hypertensives taking medication, which may have blunted their response to stress. Persons with higher cholesterol, higher triglyceride levels, and lower HDL levels all showed greater increases in blood pressure (BP) in response to stress. Also, the reactive group reported less emotional support and experienced greater numbers of family-related stressful events in the previous year. The degree of aerobic fitness influenced resting hemodynamics and percentage of body fat but not reactivity to stress. Likewise, smoking did not affect reactivity, but former smokers did have a significantly elevated total systemic resistance at rest. While it is impossible to say whether reactivity causes disease, is the result of the presence of risk factors and disease, or is caused by some other factor which also contributes to disease, these results suggest that the presence of cardiovascular reactivity to mental stress is a sign of potential illness and indicates the need for further medical and risk factor study of the patient.