Effect of l-Arginine on Human Coronary Endothelium-Dependent and Physiologic Vasodilation

AbstractObjectives. We hypothesized that l-arginine would improve abnormal coronary vasodilation in response to physiologic stress in patients with atherosclerosis and its risk factors by reversing coronary endothelial dysfunction.Background. Studies have demonstrated that physiologic coronary vasodilation correlates with endothelial function and that l-arginine, the substrate for nitric oxide synthesis, improves the response to acetylcholine (Ach).Methods. Changes in coronary blood flow and epicardial diameter response to Ach, adenosine and cardiac pacing were measured in 32 patients with coronary atherosclerosis or its risk factors and in 7 patients without risk factors and normal coronary angiograms.Results. Intracoronary l-arginine did not alter baseline coronary vascular tone, but the epicardial and microvascular responses to Ach were enhanced (both p < 0.001). The improvement after l-arginine was greater in epicardial segments that initially constricted with Ach; similarly, l-arginine abolished microvascular constriction produced by higher doses of Ach. Thus, there was a negative correlation between the initial epicardial and vascular resistance responses to Ach and the magnitude of improvement with l-arginine (r = −0.55 and r = −0.50, respectively, p < 0.001). d-Arginine did not affect the responses to Ach, and adenosine responses were unchanged with l-arginine. Cardiac pacing-induced epicardial constriction was abolished by l-arginine, but microvascular dilation remained unaffected.Conclusions. Thus, l-arginine improved endothelium-dependent coronary epicardial and microvascular function in patients with endothelial dysfunction. Prevention of epicardial constriction during physiologic stress by l-arginine in patients with endothelial dysfunction may be of therapeutic value in the treatment of myocardial ischemia

Comparative effects of verapamil and nitroprusside on left ventricular function in patients with hypertension

AbstractThe effects of verapamil were compared with those of nitroprusside at matched mean arterial pressures and heart rates in 10 symptomatic hypertensive patients during cardiac catheterization. Simultaneous radionuclide angiography and micromanometer pressure measurements were obtained to assess left ventricular pressure-volume relations. Compared with control conditions, verapamil increased left ventricular end-diastolic volume index from 57 ± 16 to 70 ± 28 ml/m2 (p = 0.05) without a significant increase in left ventricular end-diastolic pressure (from 10 ± 4 to 13 ± 6 mm Hg). Despite a downward and rightward shift in the end-systolic pressure-volume relation indicating negative inotropic effects, ejection fraction did not decrease significantly (from 52 ± 9% to 46 ± 9%); cardiac index and stroke volume index remained unchanged. The change in stroke volume index with verapamil was directly related to the magnitude of change in end-diastolic volume index (r = 0.82, p < 0.005), suggesting that the increase in enddiastolic volume did not arise purely from negative inotropic effects. Systemic vascular resistance index decreased from 42 ± 8 to 34 ± 7 mm Hg-min-m2/liter (p < 0.05).In contrast, nitroprusside decreased left ventricular end-diastolic volume index from 57 ± 16 to 41 ± 10 ml/m2 (p < 0.05), cardiac index from 3.2 ± 0.7 to 2.8 ± 0.6 liters/min per m2 (p < 0.05) and stroke volume index from 28 ± 6 to 24 ± 5 ml/m2 (p < 0.01), with no change in systemic vascular resistance index (40 ± 10 mm Hg·min·m2). The end-systolic pressure-volume relation shifted downward and leftward in all patients, stemming from altered left ventricular loading.Thus, in equihypotensive doses, verapamil and nitroprusside have markedly different effects on left ventricular function. The peripheral vasodilation and apparent improvement in left ventricular filling during verapamil balanced the negative inotropic effects, resulting in maintenance of stroke volume and cardiac index. The primary hypotensive effect of verapamil was a decrease in systemic vascular resistance, whereas that of nitroprusside was a decrease in cardiac index stemming from reduced left ventricular preload

Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with nonobstructive hypertrophic cardiomyopathy

Fifty patients with hypertrophic cardiomyopathy underwent invasive study of coronary and myocardial hemodynamics in the basal state and during the stress of pacing. The 23 patients with basal obstruction (average left ventricular outflow gradient, 77 ± 33 mm Hg; left ventricular systolic pressure, 196 ± 33 mm Hg, mean ± 1 SD) had significantly lower coronary resistance (0.85 ± 0.18 versus 1.32 ± 0.44 mm Hg min/ml, p < 0.001) and higher basal coronary flow (106 ± 20 versus 80 ± 25 ml/min, p < 0.001) in the anterior left ventricle, associated with higher regional myocardial oxygen consumption (12.4 ± 3.6 versus 8.9 ± 3.3 ml oxygen/min, p < 0.001) compared with the 27 patients without obstruction (mean left ventricular systolic pressure 134 ± 18 mm Hg, p < 0.001).Myocardial oxygen consumption and coronary blood flow were also significantly higher at paced heart rates of 100 and 130 beats/min (the anginal threshold for 41 of the 50 patients) in patients with obstruction compared with those without. In patients with obstruction, transmural coronary flow reserve was exhausted at a heart rate of 130 beats/min; higher heart rates resulted in more severe metabolic evidence of ischemia with all patients experiencing chest pain, associated with an actual increase in coronary resistance. Patients without obstruction also demonstrated evidence of ischemia at heart rates of 130 and 150 beats/min, with 25 of 27 patients experiencing chest pain. In this group, myocardial ischemia occurred at significantly lower coronary flow, higher coronary resistance and lower myocardial oxygen consumption, suggesting more severely impaired flow delivery in this group compared with those with obstruction. Abnormalities in myocardial oxygen extraction and marked elevation in filling pressures during stress were noted in both groups.Thus, obstruction to left ventricular outflow is associated with high left ventricular systolic pressure and oxygen consumption and therefore has important pathogenetic importance to the precipitation of ischemia in patients with hypertrophic cardiomyopathy. Patients without obstruction may have greater impairment in coronary flow delivery during stress

Weight Loss Programs May Have Beneficial or Adverse Effects on Fat Mass and Insulin Sensitivity in Overweight and Obese Black Women

OBJECTIVE: Weight loss interventions have produced little change in insulin sensitivity in black women, but mean data may obscure metabolic benefit to some and adverse effects for others. Accordingly, we analyzed insulin sensitivity relative to fat mass change following a weight loss program. DESIGN AND METHODS: Fifty-four black women (BMI range 25.9 to 54.7 kg/m(2)) completed the 6-month program that included nutrition information and worksite exercise facilities. Fat mass was measured by dual-energy X-ray absorptiometry, and insulin sensitivity index (S(I)) was calculated from an insulin-modified intravenous glucose tolerance test using the minimal model. RESULTS: Baseline S(I) (range 0.74 to 7.58 l/mU(−1)•min(−1)) was inversely associated with fat mass (r = −0.516, p < 0.001), independent of age. On average, subjects lost fat mass (baseline 40.8 ± 12.4 to 39.4 ± 12.6 kg [mean ± SD], P < 0.01), but 17 women (32 %) actually gained fat mass. S(I) for the group was unchanged (baseline 3.3 ± 1.7 to 3.2 ± 1.6, P = 0.67). However, the tertile with greatest fat mass loss (−3.6 kg, range −10.7 to −1.7 kg) improved insulin sensitivity (S(I) +0.3 ± 1.2), whereas the tertile with net fat mass gain (+0.9 kg, range −0.1 to +3.8 kg) had reduced insulin sensitivity (S(I) −0.7 ± 1.3) from baseline values (P < 0.05 by ANOVA). CONCLUSIONS: Black women in a weight loss program who lose fat mass may have improved insulin sensitivity, but fat mass gain with diminished sensitivity is common. Additional support for participants who fail to achieve fat mass loss early in an intervention may be required for success

Markers of inflammation and cardiovascular disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals From the Centers for Disease Control and Prevention and the American Heart Association

In 1998, the American Heart Association convened Prevention Conference V to examine strategies for the identification of high-risk patients who need primary prevention. Among the strategies discussed was the measurement of markers of inflammation.1 The Conference concluded that “many of these markers (including inflammatory markers) are not yet considered applicable for routine risk assessment because of: (1) lack of measurement standardization, (2) lack of consistency in epidemiological findings from prospective studies with endpoints, and (3) lack of evidence that the novel marker adds to risk prediction over and above that already achievable through the use of established risk factors.” The National Cholesterol Education Program Adult Treatment Panel III Guidelines identified these markers as emerging risk factors,1a which could be used as an optional risk factor measurement to adjust estimates of absolute risk obtained using standard risk factors. Since these publications, a large number of peer-reviewed scientific reports have been published relating inflammatory markers to cardiovascular disease (CVD). Several commercial assays for inflammatory markers have become available. As a consequence of the expanding research base and availability of assays, the number of inflammatory marker tests ordered by clinicians for CVD risk prediction has grown rapidly. Despite this, there has been no consensus from professional societies or governmental agencies as to how these assays of markers of inflammation should be used in clinical practice

First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data

Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a fully coherent search, based on matched filtering, which uses the position and rotational parameters obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto- noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have been developed, allowing a fully coherent search for gravitational waves from known pulsars over a fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of 11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial outliers, further studies show no significant evidence for the presence of a gravitational wave signal. Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for the first time. For an additional 3 targets, the median upper limit across the search bands is below the spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried out so far

Reinforcement versus Fluidization in Cytoskeletal Mechanoresponsiveness

Every adherent eukaryotic cell exerts appreciable traction forces upon its substrate. Moreover, every resident cell within the heart, great vessels, bladder, gut or lung routinely experiences large periodic stretches. As an acute response to such stretches the cytoskeleton can stiffen, increase traction forces and reinforce, as reported by some, or can soften and fluidize, as reported more recently by our laboratory, but in any given circumstance it remains unknown which response might prevail or why. Using a novel nanotechnology, we show here that in loading conditions expected in most physiological circumstances the localized reinforcement response fails to scale up to the level of homogeneous cell stretch; fluidization trumps reinforcement. Whereas the reinforcement response is known to be mediated by upstream mechanosensing and downstream signaling, results presented here show the fluidization response to be altogether novel: it is a direct physical effect of mechanical force acting upon a structural lattice that is soft and fragile. Cytoskeletal softness and fragility, we argue, is consistent with early evolutionary adaptations of the eukaryotic cell to material properties of a soft inert microenvironment