Scott Holcomb

Vascular mechanisms of cyclosporin-induced hypertension in the rat.

Numerous studies have explored the pathogenesis of cyclosporin A (CysA)-induced hypertension; however, none has assessed the impact of CysA treatment on resistance arteries in the setting of elevated blood pressure. Therefore, we studied the chronic effect of CysA on rat mesenteric artery resistance vessels (ex vivo). CysA (25 mg/kg per d for 7 d), but not vehicle, significantly raised systolic blood pressure (13.4 +/- 2.2 mmHg, P < 0.003, n = 9 per group). The resistance vessels from CysA-treated rats showed a small but significant decrease in norepinephrine sensitivity (P < 0.03) and a pronounced decrease in endothelium-dependent and -independent relaxation (P < 0.001) compared to controls. Endothelin-1 sensitivity tended to be diminished (P = 0.07). The direct (in vitro) effect of CysA was subsequently evaluated in resistance vessels from nontreated animals (n = 8) and exposed to CysA (2 micrograms/ml) for 24 h. As observed in vivo, CysA significantly decreased endothelium-dependent and -independent relaxations (P < 0.05) and attenuated norepinephrine sensitivity (P = 0.06). Methylene blue, a nitric oxide quencher, significantly inhibited the acetylcholine-induced relaxation in control, but not in CysA vessels, suggesting a selective action of CysA on the nitric oxide pathway. We conclude that CysA-induced hypertension is the consequence of a primary effect on resistance vessel relaxation, not increased vasoconstriction, as previously suggested.

Factors affecting blood pressure responses to diet: The vanguard study

To study physiologic factors affecting the blood pressure (BP) response to nonpharmacologic maneuvers, fasting blood glucose, insulin, lipid and mineral levels, urinary mineral excretion, and the calcium regulating hormones parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D (1,25 (OH)2D) were measured in 71 unmedicated hypertensive (26 hypertensive only [HT], 45 hypertensive hyperlipidemic [HTHL]), and 87 normotensive hyperlipidemic (NTHL) control subjects before and during a 10-week multicenter, randomized controlled trial comparing a prepared meal plan (CCNW) with a self-selected diet (SSD) based on nutritionist counseling. Blood pressure fell to a greater extent in hypertensive versus normotensive subjects (-8+/-1/-5+/-1 v -2+/-1/-2+/-1 mm Hg, P < .0001/P < .0001), and on CCNW versus SSD diets (delta systolic BP [SBP]/delta diastolic BP [DBP], P = .033/P = .002). Diet-induced weight change was the strongest correlate of changes in BP (SBP: r = 0.360, P < .0001; DBP: r = 0.414, P < .0001), which, on multivariate analysis for deltaSBP, could partly be accounted for by diet-induced changes in fasting glucose (r = 0.215, P = .009) and cholesterol (r = 0.219, P = .006) levels. Independently of weight, diet-induced changes in SBP also were significantly related to concomitant changes in urinary excretion of potassium (r = -0.285, P = .001), magnesium (r = -0.254, P = .003), and calcium relative to sodium (r = -0.200, P = .021), but not to sodium per se; and to changes in serum potassium (r = -0.249, P = .002), phosphorus (r = -0.279, P = .001), PTH (r = 0.288, P = .0006), and 1,25 D (r = 0.202, P = .017). We conclude that the ability of diet to lower BP successfully may result from the additive contributions of multiple components. Independently of weight loss and the associated changes in circulating glucose and cholesterol, BP is influenced by the increasing provision of minerals such as potassium, magnesium, and calcium, perhaps by virtue of their suppressive effects on circulating vasoactive calcium regulating hormones.

Direct Measurement of Three-dimensionally Reconstructed Flow Convergence Surface Area and Regurgitant Flow in Aortic Regurgitation In Vitro and Chronic Animal Model Studies

BACKGROUND Evaluation of flow convergence (FC) with two-dimensional (2D) imaging systems may not be sufficiently accurate to characterize these often asymmetric, complex phenomena. The aim of this study was to validate a three-dimensional (3D) method for determining the severity of aortic regurgitation (AR) in an experimental animal model. METHODS AND RESULTS In six sheep with surgically induced chronic AR, 20 hemodynamically different states were studied. Instantaneous regurgitant flow rates were obtained by aortic and pulmonary electromagnetic flow meters. Video composite data of color Doppler flow mapping images were transferred into a TomTec computer after computer-controlled 180 degrees rotational acquisition. Direct measurement of the 3D reconstructed FC surface areas as well as measurements of FC areas estimated with 2D methods with hemispherical and hemielliptical assumptions were performed, and values were multiplied by the aliasing velocity to obtain peak regurgitant flow rates. There was better agreement between 3D and electromagnetically derived flow rates than there was between the 2D and the reference values (r=.94, y=1.0x-0.16, difference=0.02 L/min for the 3D method; r=.80, y=1.6x-0.3, difference=1.2 L/min for the 2D hemispherical method; r=.75, y=0.90x+0.2, difference=-0.20 L/min for the 2D hemielliptical method). CONCLUSIONS Without any geometrical assumption, the 3D method provided better delineation of the FC zones and direct measurements of FC surface areas, permitting more accurate quantification of the severity of AR than the 2D methods.

Effective Regurgitant Orifice Area by the Color Doppler Flow Convergence Method for Evaluating the Severity of Chronic Aortic Regurgitation An Animal Study

BACKGROUND The aim of the present study was to evaluate dynamic changes in aortic regurgitant (AR) orifice area with the use of calibrated electromagnetic (EM) flowmeters and to validate a color Doppler flow convergence (FC) method for evaluating effective AR orifice area and regurgitant volume. METHODS AND RESULTS In 6 sheep, 8 to 20 weeks after surgically induced AR, 22 hemodynamically different states were studied. Instantaneous regurgitant flow rates were obtained by aortic and pulmonary EM flowmeters balanced against each other. Instantaneous AR orifice areas were determined by dividing these actual AR flow rates by the corresponding continuous wave velocities (over 25 to 40 points during each diastole) matched for each steady state. Echo studies were performed to obtain maximal aliasing distances of the FC in a low range (0.20 to 0.32 m/s) and a high range (0.70 to 0.89 m/s) of aliasing velocities; the corresponding maximal AR flow rates were calculated using the hemispheric flow convergence assumption for the FC isovelocity surface. AR orifice areas were derived by dividing the maximal flow rates by the maximal continuous wave Doppler velocities. AR orifice sizes obtained with the use of EM flowmeters showed little change during diastole. Maximal and time-averaged AR orifice areas during diastole obtained by EM flowmeters ranged from 0.06 to 0.44 cm2 (mean, 0.24 +/- 0.11 cm2) and from 0.05 to 0.43 cm2 (mean, 0.21 +/- 0.06 cm2), respectively. Maximal AR orifice areas by FC using low aliasing velocities overestimated reference EM orifice areas; however, at high AV, FC predicted the reference areas more reliably (0.25 +/- 0.16 cm2, r = .82, difference = 0.04 +/- 0.07 cm2). The product of the maximal orifice area obtained by the FC method using high AV and the velocity time integral of the regurgitant orifice velocity showed good agreement with regurgitant volumes per beat (r = .81, difference = 0.9 +/- 7.9 mL/beat). CONCLUSIONS This study, using strictly quantified AR volume, demonstrated little change in AR orifice size during diastole. When high aliasing velocities are chosen, the FC method can be useful for determining effective AR orifice size and regurgitant volume.

Regulation of parathyroid hormone and vitamin D in essential hypertension.

Patients with essential hypertension have been reported to have a higher serum concentration of parathyroid hormone (PTH) than normotensive individuals although this finding is not universal among studies. To further characterize the status of the calcium regulating hormones in essential hypertension, we measured the parathyroid gland response to acute EDTA-induced hypocalcemia and the renal response of 1,25(OH)2-vitamin D to dietary calcium deprivation in 16 hypertensive (H) and 15 normotensive (N) men. The average mean arterial blood pressure once all antihypertensive medications were discontinued was 108 +/- 7 mm Hg for the hypertensive group and 89 +/- 4 mm Hg for the normotensive group (P < .01). There were no group differences in baseline serum concentrations of ionized calcium, creatinine, intact PTH, and 1,25(OH)2-vitamin D, urinary calcium excretion, and creatinine clearance. After a 1-h infusion of EDTA at 12.5 mg/kg/h, the serum concentration of ionized calcium fell (H: 1.25 +/- .03 to 1.17 +/- .04 mmol/L, N: 1.26 +/- .04 to 1.18 +/- .04 mmol/L, P = NS) and PTH increased (H: 36 +/- 9 to 91 +/- 30 pg/mL, N: 40 +/- 14 to 85 +/- 28 pg/mL, P = NS). With an additional hour of EDTA at a dose of 25 mg/kg/h, serum ionized calcium concentration fell further (H: 1.01 +/- .05 mmol/L, N: 1.03 +/- .06 mmol/L, P = NS) and PTH increased to 150 +/- 58 pg/ml in patients and 130 +/- 32 pg/ml in controls (P < .001). The response suggested an increased maximal parathyroid gland secretory capacity in the hypertensive patients relative to the controls. There was no group difference in the serum concentration of 1,25(OH)2-vitamin D at baseline (H: 32 +/- 6 pg/ml, N: 32 +/- 8 pg/ml, P < .90) and following dietary calcium deprivation for three days (H 50 +/- 12, N 48 +/- 14 P < 0.76). The maximal stimulated PTH level was significantly higher in hypertensive than normotensive subjects in the absence of measured differences in serum ionized calcium concentration, serum 1,25(OH)2-vitamin D concentration, and creatinine clearance. These findings suggest an intrinsic alteration of PTH regulation in patients with essential hypertension, manifest as increased parathyroid gland secretory capacity.

What Is the Validity of Continuous Wave Doppler Grading of Aortic Regurgitation Severity? A Chronic Animal Model Study☆☆☆★★★

Continuous wave Doppler methods have been widely used clinically for evaluating the severity of aortic regurgitation; however, there have been no studies comparing these continuous wave Doppler methods with a strictly quantifiable reference for regurgitant severity. The purpose of this study was to test the applicability of continuous wave Doppler methods (deceleration slope and pressure half-time) for evaluation of chronic aortic regurgitation in an animal model. Eight sheep were studied 8 to 20 weeks after surgery to create chronic aortic regurgitation. Twenty-nine hemodynamically different states were obtained pharmacologically. A Vingmed 775 system was used for recording continuous wave Doppler traces with a 5 MHz annular array transducer directly placed on the heart near the apex. The aortic regurgitation was quantified as peak and mean regurgitant flow rates, regurgitant stroke volumes and regurgitant fractions determined with pulmonary and aortic electromagnetic flow probes and meters balanced against each other. Peak regurgitant flow rates varied from 1.8 to 13.6 L/min (6.3 +/- 3.2 L/min) (mean +/- SD), mean regurgitant flow rates varied from 0.7 to 4.9 L/min (2.7 +/- 1.3 L/min), regurgitant stroke volume varied from 7.0 to 48.0 ml/beat (26.9 +/- 12.2 ml/beat), and regurgitant fraction varied from 23% to 78% (53% +/- 16%). Only marginal correlations were obtained between reference indexes and continuous wave Doppler deceleration slope and pressure half-time (r = 0.55 to 0.74). A deceleration slope greater than 3 m/sec2 and pressure half-time less than 400 msec did, however, provide 100% specificity for detecting severe AR (regurgitant fraction > 50%). Our study shows that the continuous wave Doppler deceleration slope and pressure half-time methods have limited use for quantifying aortic regurgitation.

Comprehensive Nutrition Plan Improves Cardiovascular Risk Factors in Essential Hypertension

Increased arterial pressure is known to be influenced by a variety of nutrients. Compliance with dietary recommendations for risk reduction is often limited by the complexity of their implementation. In addition, how improvements in total diet, rather than single nutrients, influence concomitant cardiovascular risk factors has not been thoroughly explored. We assessed the effects of a nutritionally complete prepared meal program, the Campbells Center for Nutrition and Wellness plan (CCNW), compared with dietary therapy in which participants received a structured nutritional assessment and prescription and selected their own foods, in 101 women and men with mild-to-moderate hypertension. Outcome measures included blood pressure (BP), lipids and lipoproteins, glucose, glycosylated hemoglobin (HbA1c), insulin, homocysteine, nutrient intake, compliance, and quality of life. Both dietary interventions significantly lowered BP (P < .0001), while simultaneously improving the overall cardiovascular risk profile. Significantly greater benefits were observed with the CCNW plan as compared with the participant selected diet in cholesterol and LDL levels (both P < .0001), LDL:HDL (P < .001), HbA1c (P < .05), homocysteine (P < .001), total nutrient intake (P < .0001), compliance (P < .0001), and quality of life (P < .001). This study demonstrates that improving the total diet to include the full array of recommended dietary guidelines, rather than focusing on single nutrients, has significant benefits for the cardiovascular risk profile of hypertensive persons beyond BP control. Compared with typical dietary therapy, the comprehensive CCNW meal plan has significantly greater effects on multiple cardiovascular risk factors while yielding greater compliance and improved quality of life.

Early Changes in Defibrillation Threshold Following Implantation of a Nonthoracotomy System in Dogs

Background: Nonthoracotomy systems are rapidly becoming the preferred surgical method for implantation of cardioverter defibrillators. Testing is performed at the time of implantation to insure an adequate margin of safety for defibrillation. However, this safety margin may change with lead maturation. This study evaluated changes in defibrillation threshold following implantation of a nonthoracotomy system. Methods and Results: Ten dogs underwent implantation of a nonthoracotomy system consisting of a single catheter with a distal coil electrode in the right ventricular apex and a proximal coil electrode in the superior vena cava forming a common anode with a subcutaneous patch over tbe left tborax. Defibrillation threshold testing, using a biphasic waveform, was performed on each animal under general anesthesia at implantation (day 1) and subsequently on postoperative days 3, 7, 10, 17, 24, 31, 38, and 45. E50, the energy associated with a 50% likelihood of successful defibrillation, was determined at each setting. The mean E50 was 12.2 ± 1.1 J at the time of implantation, increasing 36% to 16.8 ± 2.0 J by day 38 (P < 0.01). Individual increases in E50 of 10–12 J were observed in four animals. Conclusions: Energy requirements for defibrillation with a nonthoracotomy system increase during the early postoperative period, with the highest defibrillation threshold observed at 38 days. This increase may be applicable to humans and should be considered when selecting an adequate energy safety margin for defibrillation at time of implantation.

Analysis of body surface area as a determinant of impedance during radiofrequency catheter ablation in adults and children

Since most radiofrequency (RF) generators used for catheter ablation approximate a constant voltage output, applied power is inversely proportional to the impedance load of the system. Knowledge of the expected impedance load for a patient may facilitate selection of safer and more effective voltage output. Preliminary observations suggest that in adults, impedance is directly proportional to body surface area (BSA), thus prompting this study to determine whether this relation was maintained in smaller patients undergoing RF catheter ablation. Prospective analysis of impedance from 949 RF deliveries in 76 patients (BSA, 0.69-2.3 m2) revealed the mean impedance for all deliveries to be 103 +/- 8 ohms. Two-phase linear regression analysis revealed a significant, direct correlation between impedance and BSA in patients with a BSA > or = 1.5 m2 (P = .001); however, for patients with a BSA < 1.5 m2 there was no correlation. These results indicate that as patient size decreases below 1.5 m2, impedance is constant. Radiofrequency catheter ablation procedures in children may require selection of a voltage output similar to that used in adults in order to produce effective RF lesions.