Israel Medical Association Journal

Background: Endothelial dysfunction is recognized as a major factor in the development of atherosclerosis and it has a prognostic value.

Objectives: To detect the long-term association of peripheral vascular endothelial function and clinical outcome in healthy subjects and patients with cardiovascular disease.

Methods: We prospectively assessed brachial artery flow-mediated dilation in 110 consecutive subjects (46 CVD[1] patients and 64 healthy controls), mean age 57 ± 11 years; 68 were men. After an overnight fast and discontinuation of all medications for ≥ 12 hours, percent improvement in FMD and nitroglycerin-mediated vasodilatation were assessed using high resolution ultrasound.

Results: %FMD[2] but not %NTG[3] was significantly lower in CVD patients (9.5 ± 8.0% vs. 13.5 ± 8.0%, P = 0.012) compared to healthy controls (13.4 ± 8.0% vs. 16.7 ± 11.0%, P = 0.084; respectively). In addition, an inverse correlation between %FMD and the number of traditional CVD risk factors was found among all study participants (r = -0.23, P = 0.015) and healthy controls (r = -0.23, P = 0.036). In a mean follow-up of 15 ± 2 months, the composite CVD endpoints (all-cause mortality, myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting and percutaneous coronary interventions) were significantly more common in subjects with FMD < 6% compared to subjects with FMD > 6% (33.3% vs. 12.1%, P < 0.03, respectively).
Conclusions: Thus, brachial artery %FMD provides important prognostic information in addition to that derived from traditional risk factor assessment

Background: Coronary heart disease and ischemic stroke are among the leading causes of morbidity and mortality in adults, and cerebrovascular disease is associated with the presence of symptomatic and asymptomatic CHD[1]. Several studies noted an association between coronary calcification and thoracic aorta calcification by several imaging techniques, but this association has not yet been examined in stable angina pectoris patients with the use of spiral computed tomography.

Objectives: To examine by spiral CT the association between the presence and severity of CC[2] and thoracic aorta calcification in patients with stable angina pectoris.

Methods: The patients were enrolled in ACTION (A Coronary Disease Trial Investigating Outcome with Nifedipine GITS) in Israel. The 432 patients (371 men and 61 women aged 40–89 years) underwent chest CT and were evaluated for CC and aortic calcification.

Results: CC was documented in 90% of the patients (n=392) and aortic calcification in 70% (n=303). A significant association (P < 0.05) was found between severity of CC and severity of aortic calcification (as measured by area, volume and slices of calcification). We also found an association between the number of coronary vessels calcified and the presence of aortic calcification: 90% of patients with triple-vessel disease (n=157) were also positive for aortic calcification (P < 0.05). Age also had an effect: 87% of patients ≥ 65 years (n=219) were positive for both coronary and aortic calcification (P = 0.005) while only 57% ≤ 65 (n=209) were positive for both (P = 0.081).

Conclusions: Our study demonstrates a strong association between the presence and severity of CC and the presence and severity of calcification of thoracic aorta in patients with stable angina pectoris as detected by spiral CT.

Background: Echocardiographic assessment of left ventricular function includes calculation of ejection fraction and regional wall motion analysis. Recently, speckle imaging was introduced for quantification of left ventricular function.

Objectives: To assess LVEF[1] by speckle imaging and compare it with Simpson’s method, and to assess the regional LV strain obtained by speckle imaging in relation to conventional echocardiographic scores.

Methods: Thirty consecutive patients, 28 with regional LV dysfunction, underwent standard echocardiographic evaluation. LV end-diastolic volume, LV end-systolic volume and EF were calculated independently by speckle imaging and Simpson’s rule. The regional peak systolic strain presented by speckle imaging as a bull's-eye map was compared with the conventional visual estimate of echo score.

Results: Average EDV[2] obtained by speckle imaging and by Simpson’s method were 85.1 vs. 92.7 ml (P = 0.38), average ESV[3] was 49.4 vs. 48.8 ml (P = 0.94), calculated EF was 43.9 vs. 50.5% (P = 0.08). The correlation rate with Simpson’s rule was high: 0.92 for EDV, 0.96 for ESV, and 0.89 for EF. The peak systolic strain in two patients without wall motion abnormality was 17.3 ± 4.7; in normal segments of patients with regional dysfunction, peak systolic strain (13.4 ± 4.9) was significantly higher than in hypokinetic segments  (10.5 ± 4.5) (P < 0.000001). The strain in hypokinetic segments was significantly higher than in akinetic segments (6.2 ± 3.6) (P < 0.000001).

Conclusions: Speckle imaging can be successfully used for the assessment of LV volumes and EF. Bull's-eye strain map, created by speckle imaging, can achieve an accurate real-time segmental wall motion analysis.

Background: Femoral artery vascular complications are the most common adverse events following cardiac catheterization. Smaller diameter introducer sheaths and catheters are likely to lower the puncture site complication rate but may hinder visualization.

Objectives: To evaluate the safety and angiographic quality of 4 French catheters.

Methods: The study was designed to simulate real-life operator-based experience. Diagnostic angiography was performed with either 4F or 6F diagnostic catheters; the size of the catheter used in each patient was predetermined by the day of the month. Patients undergoing 4F and 6F diagnostic angiography were ambulated after 4 and 6 hours, respectively. The following technical parameters were recorded by the operator: ease of introducer sheath insertion, ease of coronary intubation, ease of injection, coronary opacification, collateral flow demonstration, and overall assessment. Adverse events were recorded in all patients and included minor bleeding, major bleeding (necessitating blood transfusion), minor hematoma, major hematoma, pseudo-aneurysm formation and arteriovenous fistula.

Results: The study group included 177 patients, of whom 91 were in the 4F arm and 86 in the 6F arm. Demographic and procedural data were similar in both groups. Seventy-seven percent of 6F and 50% of 4F procedures were evaluated as excellent (P < 0.05). This difference was attributed to easier intubation of the coronary ostium and contrast material injection, increased opacification of the coronary arteries, and demonstration of collateral flow with 6F catheters. Complications occurred in 22% of patients treated with 6F catheters and 10% of those treated with 4F catheters (P = 0.11). Of the 50 patients who switched from 4F to 6F 12% had complications. In patients undergoing diagnostic angiography, the complication rate was 10% vs. 27% (most of them minor) in the 4F and 6F groups, respectively (P < 0.05).
Conclusions: Patients catheterized with 4F have fewer complications compared with 6F diagnostic catheters even when ambulated earlier. Although 4F had a reduced quality compared to 6F angiographies, they were evaluated as satisfactory or excellent in quality 85% of the time. 4F catheters have a potential for reduced hospitalization stay and are a good option for primary catheterization in patients not anticipated to undergo coronary intervention

Background: The use of the bilateral internal mammary arteries has been reserved mainly for younger and low risk patients.

Aim: To assess the safety and efficacy of BIMA[1] grafting in older patients (≥ 70 years).

Methods: We reviewed the records of all consecutive patients ≥ 70 years old who underwent coronary artery bypass surgery with a BIMA graft in our institute over a 2 year period. Demographic data, operative data, perioperative morbidity and mortality were recorded. Findings were compared with a matched-size group of patients who underwent CABG[2] with a left internal mammary artery graft to left anterior descending artery.

Results: The study sample included 136 patients, of whom 68 underwent BIMA grafting and 68 LIMA[3] grafting. Baseline demographic and clinical characteristics were similar in the two groups. There was no significant difference in operative mortality between the BIMA and LIMA groups (1.5% vs. 0%, P = 0.3) or in mortality during follow-up at a mean of 16 months (4.4% vs. 2.9%, P = 0.4, respectively). There was no difference between the groups in the incidence of perioperative complications, re-admission and re-intervention rates during follow-up. Significant between-group differences were noted for mean cardiopulmonary bypass time (93.2 ± 34.7 BIMA vs. 108.8 ± 40.7 LIMA min, P = 0.02) and for red blood cell transfusion (1.9 ± 1.9 vs. 4.3 ± 2.8 packed cells/patient, P < 0.001).

Conclusions: The performance of mainly arterial revascularization with BIMA grafting in patients 70 years or older is as safe as LIMA grafting, with the added advantage of being a better conduit than saphenous vein graft, requiring fewer blood transfusions, and shorter cardiopulmonary bypass time.

Background: Previous studies found some factors such as physical exertion, anger and heavy meals to be triggers for acute coronary syndrome.

Objectives: To estimate the relative risk of an ACS[1] episode associated with positive and negative emotional experiences and anger as potential work-related triggers.

Methods: A total of 209 consecutive patients were interviewed a median of 2 days after a cardiac event that occurred at work or up to 2 hours later. The case-crossover design was used. Positive and negative emotional experiences and anger episodes in the hours immediately before the onset of ACS were compared with episodes in the comparable hours during the previous workday. For anger the episodes were compared with the usual frequency at work during the previous year. Positive and negative emotional experiences were assessed by the PANAS questionnaire (Positive and Negative Affect Scale), and anger by the Onset Anger Scale.

Results: The relative risks of an acute coronary event during the first hour after exposure to negative and positive emotional experiences were RR[2] = 14.0 (95% confidence interval 1.8–106.5) and RR = 3.50 (95% CI[3], 0.7–16.8) respectively and RR = 9.0 (95% CI, 1.1–71) for an episode of anger. Using conditional logistic regression analysis, the highest relative risk was associated with negative emotional experiences.

Conclusions: Negative emotional experiences and anger at work can trigger the onset of an ACS episode. This could have implications for recognizing a cardiac event as a work accident. The implementation of stress-reduction programs in the workplace or use of preventive medications in workers at high risk for coronary heart disease should be investigated.

Background: The etiology of chest pain with normal epicardial coronary arteries (cardiac syndrome X) seems to be related to endothelial cell dysfunction. Multiple factors are implicated in the pathophysiology, including evelated levels of homocysteine in the blood. Mutations in the MTHFR gene are associated with evelated levels of homocysteine.

Objectives: To test whether abnormal homocysteine metabolism is associated with syndrome X.

Methods: Forty-two women with chest pain, positive stress test and normal coronary arteries (syndrome X) and 100 asymptomatic women (controls) were studied for the C677T mutation. Vitamin B12, folic acid, and plasma levels of homocysteine were also measured. Endothelial cell function was studied in 10 patients with syndrome X and homozygosity for C677T mutation, and in 10 matched healthy controls. Folic acid (5 mg daily) was prescribed to syndrome X patients after initial measurements of ECF[1]. Following 13 weeks of treatment, ECF and blood tests were repeated and compared to baseline measurements.

Results: Homozygosity for C677T mutation was doubled in syndrome X vs. control (33%, 14/42 vs. 16%, 16/100, P < 0.02), and homocysteine levels were increased (9.16 ± 2.4 vs. 8.06 ± 2.6 μmol/L, P = 0.02). In the 10 homozygous patients, homocysteine levels decreased significantly after treatment with 5 mg/day folic acid (10 ± 3.3 vs. 5.4 ± 1.1 µmol/L, P = 0.004). Abnormal baseline ECF improved after treatment with folic acid: flow-mediated dilatation was greater (11.3 ± 7.9% vs. 0.7 ± 4.5%, P < 0.002), as was nitroglycerin-mediated dilatation (15.2 ± 9.0% vs. 5.6 ± 6.4%, P < 0.003). Frequency of chest pain episodes was significantly reduced after 13 weeks of folic acid treatment.

Conclusion: Our findings establish the association between the C677T mutation, endothelial cell dysfunction and cardiac syndrome X, and provide a novel and simple therapy for a subset of patients with syndrome X and homozygosity for the C677T mutation.

Background: Hyperglycemia is common among patients admitted to intensive care units, and carries the risk for complications and prolonged ICU[1] stay. With intensive insulin control of blood glucose, morbidity and mortality can be reduced.

Objectives: To determine whether intensive or conventional insulin control of blood glucose in hyperglycemic ICU patients correlated with the prognosis.

Methods: Following admission to the ICU, hyperglycemic patients were randomly assigned to a group treated intensively with insulin targeting glucose at 110–140 mg/dl, or to a conventional insulin therapy group, where glucose, upon exceeding 200 mg/dl, was controlled at 140–200 mg/dl. Rates of morbidity and mortality, hypoglycemic episodes, and insulin dosage were compared.

Results: In the 41 patients treated intensively with insulin the glucose level was 142 ± 14 mg/dl, as compared to 174 ± 20 mg/dl in the 48 patients on conventional insulin treatment. Both groups were similar in age, acute physiology and chronic health evaluation score. Morbidity was also similar, except for increased vascular damage in the conventional treatment group and slightly shorter ICU stay in the intensive therapy group. Both groups had similar in-ICU, in-hospital, and 28 day mortalities, and similar rates of hypoglycemic episodes. The daily dosage of insulin was significantly higher with the conventional treatment (P = 0.004).

Conclusions: Intensive insulin treatment did not affect the mortality or morbidity rates in ICU patients. The increased insulin dosage of conventional insulin treatment was attributable to the group's higher prevalence of diabetes. Future studies should address this bias and determine the optimal glucose target.  

Background: Ion Channel Innovations has developed a gene transfer product, ftMaxi-K, and has begun clinical trials to investigate the effect of increased expression of Maxi-K channels in the smooth muscle of the penis or bladder in patients with erectile dysfunction and those with overactive bladder. The primary function of K channels is to modulate Ca⁺⁺ influx through Ca-channels (i.e., L-type, voltage-dependent). The amount of Ca⁺⁺ that enters the cell through these channels is a major determinant of the free intracellular calcium levels inside the smooth muscle cell, which in turn determines the degree of smooth muscle cell contraction. Increased Maxi-K channel activity is associated with smooth muscle cell relaxation, resulting in, for example, penile erection and detrussor muscle relaxation. A phase I clinical trial that used dMaxi-K has been completed and a similar trial to assess safety of the transfer for overactive bladder is about to begin.

Objectives: To assess the safety and tolerability of escalating dMaxi-K doses by clinical evaluations and laboratory tests, and to measure efficacy objectives by means of the International Index of Erectile Function scale.

Methods: In the erectile dysfunction trial 11 patients with moderate to severe erectile dysfunction were given a single-dose corpus cavernosum injection of dMaxi-K, a "naked" DMA plasmid carrying the human cDNA encoding for the gene for the a, or pore-forming, subunit of the human smooth muscle Maxi-K channel, hSIo. Three patients each were given 500,1000, and 5000 pg and two patients were given 7500 pg doses of ftMaxi-K and followed for 24 weeks. Patient responses were validated by partner responses.

Results: There were no serious adverse events and no dose-related adverse events attributed to gene transfer for any patient at any dose or study visit. No clinically significant changes from baseline were seen in physical evaluations (general and genitourinary), hematology, chemistry and hormone analyses, or in cardiac events evaluated by repeated electrocardiograms. Importantly, no plasmid was detected in the semen of patients at any time after the injections. Patients given the two highest doses of dMaxi-K had apparent sustained improvements in erectile function as indicated by improved IIEF-EF domain scores over the length of the study. One patient given 5000 (jg and one given 7500 [jg reported EF category improvements that were highly clinically significant and were also maintained through the 24 weeks of study.
Conclusions: Efficacy conclusions cannot be drawn from results of a phase 1 trial with no control group. However, the promising primary safety outcomes of the study and preliminary indications of effectiveness provide evidence that ftMaxi-K gene transfer is a viable approach to the treatment of erectile dysfunction and other smooth muscle diseases with targeted access