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Numerous mechanical biomarkers derived from pulse wave analysis (PWA) have been proposed to predict cardiovascular outcomes. However, whether these biomarkers carry independent prognostic value and clinical utility beyond traditional cardiovascular risk factors hasn't been systematically evaluated. We aimed to investigate the additive utility of PWA-derived biomarkers in two independent population-based cohorts.PWA on central arterial pressure waveforms obtained from subjects without a prior history of cardiovascular diseases of two studies was conducted based on the wave transmission and reservoir-wave theory: firstly in the Kinmen study (1272 individuals, a median follow-up of 19.8years); and then in the Cardiovascular Disease Risk Factors Two-Township Study (2221 individuals, median follow-up of 10years). The incremental value of the biomarkers was evaluated by net reclassification index (NRI).In multivariate Cox analyses accounting for age, gender, body mass index, systolic blood pressure, fasting glucose, high-density- and low-density-lipoprotein cholesterol, and smoking, only systolic (SC) and diastolic rate constant (DC) of reservoir pressure could independently and consistently predict cardiovascular mortality in both cohorts and the combined cohort (SC: hazard ratio 1.18 [95% confidence interval 1.08-1.28, p0.001; DC: 1.18 [1.09-1.28], p0.001]. Risk prediction estimates in traditional risk prediction models were significantly more accurate when incorporating peak of reservoir pressure (NRI=0.049, p=0.0361), SC (NRI=0.043, p=0.0236) and DC (NRI=0.054, p=0.047).Of all PWA-derived biomarkers, SC and DC were consistently identified as valuable parameters for incremental cardiovascular risk prediction in two large prospective cohorts.

BACKGROUND The prognostic value of the short-term blood pressure variability (BPV) from the 24-hour ambulatory blood pressure monitoring (ABPM) remains controversial. The present study aimed to investigate the long-term prognostic value of a high BPV in normotensive and hypertensive subjects from a community-based population. METHODS A cohort of 624 normotensive and 633 untreated hypertensive Taiwanese participants (overall 669 men, aged 30-79 years) with baseline ABPM and 20-year all-cause and cardiovascular mortality data was drawn from a community-based survey. BPV was assessed by the read-to-read average real variability of the 24-hour diastolic and systolic blood pressure (SBP) (ARVd and ARVs, respectively). RESULTS In Cox proportional hazards analysis, ARVd predicted cardiovascular mortality independently of office SBP (hazard ratios (HRs) and 95% confidence intervals (CIs) per 1 SD: 1.31 (1.10-1.55), respectively, bivariate analysis), 24-hour SBP (HR: 1.19, 95% CI: 1.00-1.43), and conventional risk factors (age, sex, smoking, total cholesterol, high-density lipoprotein cholesterol, and fasting blood glucose, HR: 1.40, 95% CI: 1.18-1.67). In subjects with hypertension, a high vs. low ARVd (median: 8.8mm Hg) significantly predicted cardiovascular mortality (HR: 2.11, 95% CI: 1.23-3.62 and HR: 2.04, 95% CI: 1.19-3.51, respectively), when the conventional risk factors plus office SBP or 24-hour SBP were accounted for, respectively. Similar but less significant results were obtained with ARVs. A high ARVd or ARVs did not significantly predict cardiovascular mortality in the normotensive subjects. CONCLUSIONS A high short-term BPV is significantly predictive of long-term cardiovascular mortality in untreated hypertensive but not normotensive community-based subjects, independently of office or 24-hour SBP.

Pulsatile fluid shear stress and circumferential stretch are responsible for the axial alignment of vascular endothelial cells and their actin stress fibers in vivo. We studied the effect of cyclic alterations in axial stretch independent of flow on endothelial cytoskeletal organization in intact arteries and determined if functional alterations accompanied morphologic alterations. Rat renal arteries were axially stretched (20%, 0.5 Hz) around their in vivo lengths, for up to 4h. Actin stress fibers were examined by immunofluorescent staining. We found that cyclic axial stretching of intact vessels under normal transmural pressure in the absence of shear stress induces within a few hours realignment of endothelial actin stress fibers toward the circumferential direction. Concomitant with this morphologic alteration, the sensitivity (log(EC(50))) to the endothelium-dependent vasodilator (acetylcholine) was significantly decreased in the stretched vessels (after stretching -5.15+/-0.79 and before stretching -6.71+/-0.78, resp.), while there was no difference in sodium nitroprusside (SNP) sensitivity. There was no difference in sensitivity to both acetylcholine and SNP in time control vessels. Similar to cultured cells, endothelial cells in intact vessels subjected to cyclic stretching reorganize their actin filaments almost perpendicular to the stretching direction. Accompanying this morphological alteration is a loss of endothelium-dependent vasodilation but not of smooth muscle responsiveness.

We have assessed the functional correlates of common carotid artery (CCA) arterial geometry, derived by combining a measure of vascular mass (VM) with the wall-to-lumen (W/L) ratio in both untreated hypertensive (HT) and normotensive (NT; blood pressure

Arterial aging may link cardiovascular risk to white coat hypertension (WCH). The aims of the present study were to investigate the role of arterial aging in the white coat effect, defined as the difference between office and 24-hour ambulatory systolic blood pressures, and to compare WCH with prehypertension (PH) with respect to target organ damage and long-term cardiovascular mortality. A total of 1257 never-been-treated volunteer subjects from a community-based survey were studied. WCH and PH were defined by office and 24-hour ambulatory blood pressures. Left ventricular mass index, carotid intima-media thickness, estimated glomerular filtration rate, carotid-femoral pulse wave velocity, carotid augmentation index, amplitude of the reflection pressure wave, and 15-year cardiovascular mortality were determined. Subjects with WCH were significantly older and had greater body mass index, blood pressure values, intima-media thickness, carotid-femoral pulse wave velocity, augmentation index, amplitude of the backward pressure wave, and a lower estimated glomerular filtration rate than PH. Amplitude of the backward pressure wave was the most important independent correlate of the white coat effect in multivariate analysis (model r 2 =0.451; partial r 2 /model r 2 =90.5%). WCH had significantly greater cardiovascular mortality than PH (hazard ratio, 2.94; 95% confidence interval, 1.09–7.91), after accounting for age, sex, body mass index, smoking, fasting plasma glucose, and total cholesterol/high-density lipoprotein-cholesterol ratio. Further adjustment of the model for amplitude of the backward pressure wave eliminated the statistical significance of the WCH effect. In conclusion, the white coat effect is mainly caused by arterial aging. WCH carries higher risk for cardiovascular mortality than PH, probably via enhanced wave reflections that accompany arterial aging.

In western populations, patients with hypertension who have a nocturnal decrease in blood pressure (BP) may have less left ventricular (LV) hypertrophy and cardiovascular morbidity than those without a diurnal variation in BP. To further examine this association between nocturnal BP reduction and LV mass index, we studied 720 normotensives ( or = 160/95 mm Hg) from Taiwan and Quemoy island by using 24-hour ambulatory BP monitoring and 2-dimensional echocardiography to obtain LV mass index during a community-based cardiovascular survey. After controlling for age, sex, height, weight, daytime BP, and daytime heart rate, the nocturnal reduction of systolic BP was found to associate weakly with LV mass index, for the whole population (partial correlation coefficient = -0.06, p < 0.05), as well as for the patients with hypertension (partial correlation coefficient = -0.09, p < 0.05), but these associations were eliminated when 24-hour BP and heart rate were accounted for. The average and percent nocturnal decrease of systolic BP (mean +/- SD; mm Hg, [%]) of 3.2 +/- 5.9 (2.7 +/- 4.8%); 3.3 +/- 7.3 (2.4 +/- 5.4%); and 4.6 +/- 9.0 (3.0 +/- 6.1%) in normotensives, borderline hypertensives, and hypertensives, respectively, was smaller than that found in previous studies. Hence, in this large Chinese population, a small nocturnal BP drop was found and it was only weakly associated with LV mass index. These results emphasize the general need for ambulatory BP reference values based on internal controls.

Abstract We conducted this study to compare the effects of fosinopril versus atenolol on peripheral blood pressure, central arterial wave reflection, and left ventricular mass in a group of patients with essential hypertension. We conducted a double-blind, randomized trial of fosinopril and atenolol in 79 hypertensive patients (52 men, 27 women; mean age, 45.8±8.5 years; range, 30 to 68 years). Carotid pressure waveforms were recorded noninvasively by applanation tonometry with a Millar micromanometer-tipped probe. The extent of wave reflection was estimated by the augmentation index defined as the ratio of the amplitude of pressure wave above its systolic shoulder to the pulse pressure. The augmentation index, left ventricular mass index by two-dimensional echocardiography, and 24-hour ambulatory blood pressures were determined before and after 8 weeks of daily treatment with fosinopril (10 to 20 mg) or atenolol (50 to 100 mg) with or without diuretics and compared with those values in 79 normotensive control subjects. After 8 weeks of treatment, both drugs lowered 24-hour ambulatory peripheral systolic and diastolic pressures into the normal range to a similar extent (fosinopril, −18/−13 mm Hg; atenolol, −23/−17 mm Hg, both P =NS). On the other hand, whereas the elevated augmentation index in hypertensive patients compared with normotensive subjects (16±11% versus 10±8%) was completely normalized by fosinopril (−9.3±9.8%, P ≤.002), it was lowered by atenolol (−4.8±8.9%, P P =.04). Neither drug affected the slightly elevated left ventricular mass index (fosinopril, 93±13 gm/m 2 ; atenolol, 98±20 gm/m 2 ) compared with normotensive subjects (86±13 gm/m 2 ). At the doses used, fosinopril and atenolol reduced peripheral blood pressure similarly but had different effects on central systolic wave reflections, implying a greater effect of fosinopril than atenolol in reducing central blood pressure than is apparent from measurements of peripheral pressure. Left ventricular mass was only slightly elevated in these mild hypertensive patients and was not altered after 8 weeks of treatment.

Uric acid may be involved in the pathogenesis of hypertension. We investigated the roles of four major hemodynamic parameters of blood pressure, including arterial stiffness, wave reflections, cardiac output (CO), and total peripheral resistance (TPR), in the association between uric acid and central systolic blood pressure (SBP-c).A sample of 1303 normotensive and untreated hypertensive Taiwanese participants (595 women, aged 30-79 years) was drawn from a community-based survey. Study subjects' baseline characteristics, biochemical parameters, carotid-femoral pulse wave velocity (cf-PWV), amplitude of the backward pressure wave decomposed from a calibrated tonometry-derived carotid pressure waveform (Pb), CO, TPR, and SBP-c were analyzed.In multi-variate analyses adjusted for age, waist circumference, body mass index, creatinine, total cholesterol, smoking, and heart rate, uric acid significantly correlated with Pb and cf-PWV in men, and Pb and TPR in women. The correlation between uric acid and Pb remained significant in men and women when cf-PWV was further adjusted. In the final multi-variate prediction model (model r(2)=0.839) for SBP-c, the significant independent variables included uric acid (partial r(2)=0.005), Pb (partial r(2)=0.651), cf-PWV (partial r(2)=0.005), CO (partial r(2)=0.062), TPR (partial r(2)=0.021), with adjustment for age, sex, waist circumference, body mass index, creatinine, total cholesterol, smoking, and heart rate.Uric acid was significantly independently associated with wave reflections, which is the dominant determinant of SBP-c. Uric acid was also significantly associated with SBP-c independently of the major hemodynamic parameters.

Objective: Myocardial contraction shifts the diastolic coronary pressure-flow relationship to lower flows at any given pressure, the amount of shift being determined primarily by the contractile level. A portion of this shift may be attributable to the Gregg effect. The purpose of this study was to quantify the influence of the Gregg effect and thereby demonstrate the pure effect of activation at a constant contractile level on the pressure-flow relationships. Methods: It was first shown in beating canine interventricular septa that transverse stiffness induced by small high frequency indentations transverse to the plane of the tissue was an index of contractility. At constant perfusion pressure and preload, there was an inverse relationship between peak transverse stiffness and contractile level (induced by graded doses of 2,3-butanedione monoxime) for both isotonic and auxotonic contractions. A Gregg effect was next verified by showing a linear dependence between transverse stiffness and perfusion pressure during ryanodine induced tetanizations. Finally, the relationship between changes in flow and transverse stiffness was determined from diastole to tetany at two contractile levels. These relationships suffice to quantify the Gregg effect. Results: Correcting for the Gregg effect from the transverse stiffness measurements obtained concomitantly with previously reported pressure-flow data in six specimens showed the following: using a linear fit to the pressure-flow data, the mean slope of the diastolic pressure-flow relationships decreased from 0.88 to 0.81 and 0.74 ml·min−1·mm Hg−1 during tetanisation at normal and reduced contractile levels, respectively. Correcting for the Gregg effect decreased the tetanised slopes to intermediate values of 0.85 and 0.79 ml·min−1·mm Hg−1, respectively. Conclusions: A small but clearly discernible portion of the shift in tetanised pressure-flow relationships is attributable to the Gregg effect. Similar conclusions pertained when quadratic regressions were fitted to the pressure-flow data. Cardiovascular Research 1994; 28 :228-234

Central systolic (SBP-C) and/or pulse pressure (PP-C) better predicts cardiovascular events than does peripheral blood pressure. The present study compared the prognostic significance of office central blood pressure with multiple measurements of out-of-office ambulatory peripheral blood pressure, with reference to office peripheral systolic (SBP-B) or pulse pressure (PP-B).In a community-based population of 1014 healthy participants, SBP-C and PP-C were estimated using carotid tonometry, and 24-h systolic (SBP-24 h) and pulse pressure (PP-24 h) were obtained from 24-h ambulatory blood pressure monitoring. Associations of SBP-B, PP-B, SBP-C, PP-C, SBP-24 h, and PP-24 h with all-cause and cardiovascular mortalities over a median follow-up of 15 years were examined by Cox regression analysis.In multivariate analyses accounting for age, sex, BMI, smoking, fasting plasma glucose, and total cholesterol/high-density lipoprotein cholesterol ratio, only PP-C (hazard ratio 1.16, 95% confidence interval 1.01-1.32, per one standard deviation increment) was significantly predictive of all-cause mortality, whereas all but PP-B were significantly predictive of cardiovascular mortality. When SBP-B was simultaneously included in the models, SBP-24 h (2.01, 1.42-2.85) and SBP-C (1.71, 1.21-2.40) remained significantly predictive of cardiovascular mortality. When SBP-C was simultaneously included in the models, SBP-24 h (1.71, 1.16-2.52) remained significantly predictive of cardiovascular mortality.Office central blood pressure is more valuable than office peripheral blood pressure in the prediction of all-cause and cardiovascular mortalities. Out-of-office ambulatory peripheral blood pressure (SBP-24 h) may be superior to central blood pressure in the prediction of cardiovascular mortality, but PP-C may better predict all-cause mortality than SBP-24 h or PP-24 h.

Cardiac contraction causes a decrease in coronary flow. Despite many studies, it is still not clear what mechanism or mechanisms are responsible for this flow decrease. The phasic nature of myocardial contraction and the complexities intrinsic to intact heart preparations make it difficult to elucidate the mechanisms. We therefore studied coronary pressure-flow relationships during steady-state (tetanic) contractions in the maximally vasodilated isolated canine interventricular septum to see whether waterfall-type behavior is present. Using ryanodine and electrical stimulation allowed the production of reproducible and reversible tetani. This preparation minimizes the difficulties associated with transmural variations and also the effects of intramyocardial capacitance. Two separate protocols were performed to delineate the pressure-flow relationships in the passive and tetanized states. The first compared diastolic and tetanized pressure-flow relationships. In the second protocol, 2,3-butanedione monoxime was added to obtain an intermediate contractile level, thus allowing the comparison of two contractile states. Both the diastolic and tetanized pressure-flow relationships were curvilinear in the low-pressure range. Linear and nonlinear fits to the data showed that the primary effect of contraction was a shift of the pressure-flow relationships to higher pressures at a given flow. This effect was graded by the level of contractility and was independent of developed stress. Although other mechanisms may also be operative, these results support the presence of waterfall behavior in the coronary vascular bed.

Objective: The effect of coronary perfusion on left ventricular chamber distensibility is only indirect evidence that perfusion alters the mechanical properties of the myocardium. The aim of this study was to demonstrate explicitly the effects of coronary perfusion on these mechanical properties. Methods: The effects of different levels of coronary perfusion were studied both on in-plane stress-strain relations and on transverse stiffness in an isolated, perfused canine interventricular septal preparation. Additionally, to determine the vascular compartment responsible for the mechanical effects of perfusion on tissue properties, we examined the in-plane stress-strain responses and transverse stiffness after embolisation of the vasculature with 15 μm microspheres. Results: The data show a clear dependence of tissue stress-strain properties on perfusion. The in-plane stress-strain relations were shifted to the left and transverse stiffness increased linearly as septal artery perfusion pressure increased. The dependence of both the in-plane stress-strain relations and transverse stiffness on perfusion was significantly decreased following embolisation. Conclusions: Myocardial tissue stiffness is directly related to perfusion. The linear relationship between transverse stiffness and perfusion makes it easier to assess the effects of perfusion on tissue stiffness than with in-plane stress-strain relations. Perfusion of capillaries and/or venules is largely responsible for these alterations in myocardial stiffness. Cardiovascular Research 1993; 27 :403-410

The value of increased arterial wave reflection, usually assessed by the transit time–dependent augmentation index and augmented pressure (Pa), in the prediction of cardiovascular events may have been underestimated. We investigated whether the transit time–independent measures of reflected wave magnitude predict cardiovascular outcomes independent of arterial stiffness indexed by carotid-femoral pulse wave velocity. A total of 1272 participants (47% women; mean age: 52±13 years; range: 30 to 79 years) from a community-based survey were studied. Carotid pressure waveforms derived by tonometry were decomposed into their forward wave amplitudes, backward wave amplitudes (Pb), and a reflection index (=[Pb/(forward wave amplitude+Pb)]), in addition to augmentation index, Pa, and reflected wave transit time. During a median follow-up of 15 years, 225 deaths occurred (17.6%), including 64 cardiovascular origins (5%). In univariate Cox proportional hazard regression analysis, pulse wave velocity, Pa, and Pb predicted all-cause and cardiovascular mortality in both men and women, whereas augmentation index, reflected wave transit time, and reflection index were predictive only in men. In multivariate analysis accounting for age, height, and heart rate, Pb predicted cardiovascular mortality in both men and women, whereas Pa was predictive only in men. Per 1-SD increment (6 mm Hg), Pb predicted 15-year cardiovascular mortality independent of brachial but not central pressure, pulse wave velocity, augmentation index, Pa, and conventional cardiovascular risk factors with hazard ratios of ≈1.60 (all P

To examine the relationship between brachial and central carotid pressures and target organ indices at baseline and their association with future mortality.We examined, cross-sectionally and longitudinally, the relations of baseline systolic and pulse pressures in central (calibrated tonometric carotid pulse) and peripheral (brachial, mercury sphygmomanometer) arteries to baseline left ventricular mass, carotid intima-media thickness, estimated glomerular filtration rate, and 10-year all-cause and cardiovascular mortality in 1272 participants (47% women aged 30-79 years) from a community of homogeneous Chinese.Left ventricular mass was more strongly related to central and peripheral systolic pressures than pulse pressures. Intima-media thickness and glomerular filtration rate were more strongly related to central pressures than peripheral pressures. A total of 130 participants died, 37 from cardiovascular causes. In univariate analysis, all four blood pressure variables significantly predicted all-cause and cardiovascular mortality. Each blood pressure variable was entered into the multivariate models, both individually and jointly with another blood pressure variable. After adjustment for age, sex, heart rate, BMI, current smoking, glucose, ratio of total cholesterol to high-density lipoprotein cholesterol, carotid-femoral pulse wave velocity, left ventricular mass, intima-media thickness, and glomerular filtration rate, only central systolic pressure consistently and independently predicted cardiovascular mortality (hazards ratio, 1.30 per 10 mmHg). No significant sex interactions were observed in all analyses.Systolic and pulse pressures relate differently to different target organs. Central systolic pressure is more valuable than other blood pressure variables in predicting cardiovascular mortality.

BACKGROUND Resistance, pulse wave velocity, and wave reflections have been shown to be increased in patients with essential hypertension compared with normotensive controls. These alterations are completely normalized by nitroprusside infusion but exacerbated during beta-adrenergic blockade, suggesting an enhanced smooth muscle tone that is in part modulated by adrenergically mediated vasodilation. The present study was performed to examine the extent to which this apparently enhanced smooth muscle tone is a result of alpha-adrenergically mediated vasoconstriction. METHODS AND RESULTS Age-matched normotensive and hypertensive Chinese subjects were instrumented with catheter-tipped micromanometers and an electromagnetic flow velocity sensor positioned in the ascending aorta. Aortic impedance and wave reflection properties were obtained from Fourier analysis of the pressure and flow signals during baseline conditions, after beta-blockade with propranolol (0.15 mg/kg i.v.), and after alpha-blockade with intravenous phentolamine (range, 15-80 mg) that was sufficient to either normalize blood pressure or produce a pressure that could not be further lowered. Compared with normotensives, in the baseline state, hypertensives had elevated resistance (1,962 versus 1,268 dyne.sec/cm5, p less than 0.001), total power (1,893 versus 1,568 mW, p less than 0.08), reflected pressure wave component (25.6 versus 13.5 mm Hg, p less than 0.001), ratio of reflected to forward wave (0.65 versus 0.42, p less than 0.001), and pulse wave velocity as determined from the frequency of the first zero-crossing of impedance phase angle (4.6 versus 3.5 Hz, p less than 0.03). During combined alpha- and beta-adrenergic blockade, blood pressure decreased into the normal range (from 162/103 to 131/87 mm Hg) but was still somewhat higher than that in the normotensive subjects. Resistance (1,914 dyne.sec/cm5, p less than 0.03), reflected wave (19.5 mm Hg, p less than 0.01), and ratio of reflected to forward wave (0.61, p less than 0.001) were, however, persistently elevated above normal values. CONCLUSIONS alpha-Adrenergically mediated vasoconstriction cannot account for all of the hemodynamic alterations seen in essential hypertension.

BACkgROuNd Aortic root diameter (AoD) increases with aging and is related to body size. AoD is also presumed to increase in hypertension. In prior studies, however, after adjusting for age and body size, AoD did not differ between hypertensive and normotensive (NT) individuals. Hypertension is a heterogeneous condition with various subtypes that differ in pathophysiology and age distribution. We assessed whether AoD differs among subjects with the various subtypes of hypertension and nonhypertensive individuals. METhOdS In 1,256 volunteers aged 30–79 years (48% women, 48% hypertensive; all untreated), AoD was measured at the sinuses of Valsalva with transthoracic echocardiography. Using cutoff values based on the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, subjects were identified as NT (23%), or prehypertensive (PH, 29%), or as having isolated diastolic (IDH, 6%), isolated systolic (ISH, 12%), or systolic–diastolic (SDH, 30%) hypertension. Groups were compared using analysis of variance with Bonferroni’s correction. RESul TS AoD increased with age and body surface area (BSA) in both men (r = 0.25 and 0.19, respectively) and women (r = 0.30 and 0.22, respectively) (all P < 0.0001). In men, those identified as having IDH, ISH, and SDH each had a 6% larger AoD than NT individuals (all P < 0.05). In women, those identified with ISH and SDH had a 10 and 8% larger AoD than NT individuals, respectively (all P < 0.05). In both sexes, after indexing to BSA, only ISH individuals exhibited larger AoD compared with NT individuals (both P < 0.05). But, with further adjustment for age, these differences were no longer observed. CONCluSiONS Even when the subtypes of hypertension are examined separately, age and BSA, not hypertension status, account for the AoD differences between NT and hypertensive subjects.

The effects of stretch on coronary pressure-flow relations are not well understood. To examine the role of wall stretch per se on coronary hemodynamics, we studied arterially perfused isolated canine interventricular septa in a noncontracting state with vasodilated vessels. We compared the hemodynamic parameters of zero-flow pressure and resistance during passive stretching in the circumferential and the base-to-apex directions alone as well as during simultaneous biaxial stretching in both directions. Even in the unloaded state the zero-flow pressure was positive. Any type of stretching significantly increased the zero-flow pressure and the resistance from their unloaded values. The pressure-flow responses also showed directional dependence. When stretches with matched strains or stresses in each direction were applied sequentially, the resistance increases corresponded to the direction of higher stress. Conversely, the zero-flow pressure response increase corresponded to the direction of greater strain. However, neither response correlated with a measure of global tissue stiffness. Thus there is a complex and tight mechanical interaction between the vessels and the surrounding tissue. These interactions, but not the tissue stiffness, are important determinants of coronary pressure-flow responses during stretch.

Study objective – The aim was to compare regional wave transmission and reflection properties along the aorta in age matched normotensive and hypertensive subjects. Design – Simultaneous upstream and downstream micromanometer pressures were recorded at five regions from the ascending aorta to the iliac artery. Recordings were made in the baseline condition in both groups and during sustained isometric handgrip exercise in the normotensives to see if increasing the blood pressure to hypertensive levels would eliminate baseline differences between the two groups. Subjects – Only subjects who had no coronary or valvular heart disease were studied. Normotensive subjects (n = 8) were selected from those undergoing electrophysiological testing whose blood pressures were consistently in the normal range (systolic

Hypertension accelerates the age-associated increase in aortic root diameter (AoD), likely because of chronically elevated distending pressures. However, the pulsatile component of blood pressure may have a different relationship with AoD. We sought to assess the relationship between AoD and pulse pressure (PP) while accounting for left ventricular and central arterial structural and functional properties, which are known to influence PP. The study population was composed of 1256 individuals, aged 30 to 79 years (48% women and 48% hypertensive), none of whom were on antihypertensive medications. Blood pressure was measured in the sitting position with conventional sphygmomanometry. PP was calculated as the difference between systolic and diastolic blood pressures. AoD was measured at end diastole at the level of the sinuses of Valsalva with echocardiography. The relationship between AoD and PP was evaluated with multiple regression analyses. PP was 50±14 mm Hg in men and 54±18 mm Hg in women, and AoD was 31.9±3.5 mm in men and 28.9±3.5 mm in women. After adjusting for age, age 2 , height, weight, and mean arterial pressure, AoD was independently and inversely associated with PP in both sexes. After further adjustments for central arterial stiffness and wall thickness, reflected waves, and left ventricular geometry, AoD remained inversely associated with PP in both men (coefficient=−0.48; P =0.0003; model R 2 =0.51) and women (coefficient=−0.40; P =0.01; model R 2 =0.61). Thus, AoD is inversely associated with PP, suggesting that a small AoD may contribute to the pathogenesis of systolic hypertension. Longitudinal studies are needed to examine this possibility.

We previously showed that deformation of the cardiac tissue surrounding a dilated coronary artery changes its hydraulic resistance depending on the direction of stretch. Stretch parallel, but not perpendicular, to the vessel axis increased the hydraulic resistance. This asymmetric dependence of resistance on the direction of stretch was found at a low perfusion pressure only, presumably because this was the state in which surrounding fibers were sufficiently stretched to be able to exert their effects. When the vessel is vasoconstricted and its diameter decreases, this might alter the coupling between tissue and vessel. On the other hand, the stiffer vessel wall would be more difficult to deform, making the coupling less evident. The aim of this study was to test the hypothesis that, at this low perfusion pressure, the asymmetric resistance response to strain differs between the vasodilated and vasoconstricted states. We compared how the hydraulic resistance of an in situ segment of a vasodilated and then vasoconstricted epicardial coronary artery was affected by stretching the surrounding tissue by 10% in a direction parallel and then perpendicular to the vessel axis. Vasoconstriction increased the unstretched resistance of the vessel, demonstrating that the vessel diameter was decreased. In both vasomotor states the relative resistance changes to parallel and perpendicular tissue stretches were found to be similar. Thus, the effects of subtle differences in vessel cross-sectional shape underlying the resistance changes to tissue stretch in the vasodilated state — that should have been altered by vasoconstriction — were seemingly counterbalanced by increased vessel wall stiffness that decreased the manifestation of coupling between the vessel and the surrounding tissue.

Objective: Since muscles, vessels and interstitial spaces are in close physical proximity in the heart wall, interstitial (i.e., intramyocardial) pressure (IMP) should be affected by the stresses of the vessels and/or the muscular tissue surrounding the interstitial spaces. Thus, we tested the hypothesis that increasing the stresses (or stiffness) of the surrounding tissues by muscle contraction or stretching—produced externally by stretching the LV cavity or internally by increasing coronary perfusion pressure—has a greater effect than LV cavity pressure per se on IMP. Methods: In isolated rabbit hearts we measured IMP with small (

Background Central aortic pressures and waveform convey important information about cardiovascular status, but direct measurements are invasive. Peripheral pressures can be measured noninvasively, and although they often differ substantially from central pressures, they may be mathematically transformed to approximate the latter. We tested this approach, examining intersubject and intrasubject variability and the validity of using a single averaged transformation, which would enhance its applicability. Methods and Results Invasive central aortic pressure by micromanometer and radial pressure by automated tonometry were measured in 20 patients at steady state and during hemodynamic transients (Valsalva maneuver, abdominal compression, nitroglycerin, or vena caval obstruction). For each patient, transfer functions (TFs) between aortic and radial pressures were calculated by parametric model and results averaged to yield individual TFs. A generalized TF was the average of individual functions. TFs varied among patients, with coefficients of variation for peak amplitude and frequency at peak amplitude of 24.9% and 16.9%, respectively. Intrapatient TF variance with altered loading (>20% variation in peak amplitude) was observed in 28.5% of patients. Despite this, the generalized TF estimated central arterial pressures to ≤0.2±3.8 mm Hg error, arterial compliance to 6±7% accuracy, and augmentation index to within −7% points (30±45% accuracy). Individual TFs were only marginally superior to the generalized TF for reconstructing central pressures. Conclusions Central aortic pressures can be accurately estimated from radial tonometry with the use of a generalized TF. The reconstructed waveform can provide arterial compliance estimates but may underestimate the augmentation index because the latter requires greater fidelity reproduction of the wave contour.

Abstract Previous studies have shown some distinct hemodynamic alterations in essential hypertension, including increased resistance, wave reflections, and pulse wave velocity and decreased arterial compliance. These abnormalities are completely normalized by nonspecific smooth muscle dilation with nitroprusside but not by combined α- and β-adrenergic blockade or angiotensin-converting enzyme inhibition, suggesting an enhanced smooth muscle tone that cannot be attributed solely to the sympathetic nervous or renin-angiotensin systems. Since hypertensive patients have an enhanced calcium influx–dependent vasoconstriction, we performed the present study to examine the extent to which the dihydropyridine calcium channel antagonist nifedipine could normalize the hemodynamic abnormalities in essential hypertension. An essential hypertensive patient group was compared with a normotensive group similar in age, body size, and proportion of men and women. During diagnostic cardiac catheterization, ascending aortic micromanometer pressures and electromagnetic flows were measured at baseline and after sufficient sublingual nifedipine (mean, 24 mg) to normalize blood pressure. From the pressures and flows, aortic input impedance, wave reflection magnitude, and compliance were computed. In the hypertensive group, the hemodynamic alterations were indistinguishable from those summarized above. Nifedipine produced sufficient vasodilation to completely normalize all of these hemodynamic alterations, including wave reflections. From these results, together with those reported in our previous studies, it is clear that the various classes of antihypertensive agents affect hemodynamics differently. All are capable of decreasing blood pressure to normotensive levels, but only nitroprusside and nifedipine can also completely normalize all the other pulsatile hemodynamic alterations. Thus, these hemodynamic effects of the different classes of antihypertensive agents should be considered in choosing a therapeutic modality.

Previous studies have shown some distinct hemodynamic alterations in essential hypertension, including increased resistance, wave reflections, and pulse wave velocity and decreased systemic compliance. These abnormalities are completely normalized by nonspecific smooth muscle dilation with nitroprusside but not by combined alpha- and beta-adrenergic blockade. The renin-angiotensin system, acting possibly via both circulating and local tissue effects, is thought to play an important role in essential hypertension, so its role in the altered hemodynamics deserves careful investigation. A hypertensive patient group was compared with a normotensive group similar in age, body size, and proportion of men and women. During diagnostic cardiac catheterization, ascending aortic micromanometer pressures and electromagnetic flows were measured in the baseline state. Intravenous captopril of a sufficient dosage (11 mg) to normalize blood pressure then was given to the hypertensive patients while measurements were repeated. From the pressures and flows, aortic input impedance, wave reflection magnitude, and compliance were computed. In the hypertensive group, the important hemodynamic alterations consisted of increased peripheral resistance, first zero crossing of aortic impedance phase angle, and wave reflections and decreased systemic compliance. Captopril had a pronounced hemodynamic effect. It normalized blood pressure, resistance, and impedance phase angle zero crossing. Compliance, although increased substantially by captopril, was still slightly lower than normotensive levels. The magnitude of wave reflections, although substantially lowered by angiotensin converting enzyme inhibition, was still persistently greater than normal. The present results, together with those previously reported, demonstrate that a complex interplay of factors underlies the increased smooth muscle tone in essential hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid measurements of coronary vascular volume are necessary for a complete understanding of phasic coronary flow. Because no standard method is capable of making these measurements, we developed a method that uses digital subtraction angiography to image an intravascular contrast agent. The method is capable of measuring vascular volume in 33 ms and can be repeated three times per second. The method was first validated in phantoms. We then used this method to measure coronary vascular volume in the isolated, perfluorochemical-perfused, interventricular canine septum. The speed of the measurements allowed us, for the first time, to directly measure transients in vascular volume following sudden changes in perfusion pressure. At the steady-state and maximal vasodilation, coronary vascular volume varied from 7.5 +/- 1.2 (SE) ml/100 g at a perfusion pressure of 20 mmHg to 12.1 +/- 1.9 ml/100 g at 90 mmHg, which is similar to other reports. After a sudden change of 40 mmHg in perfusion pressure, vascular volume changed with a time constant of 3.2 +/- 0.3 (SE) s. Increasing ventricular wall stretch had no effect on either the steady-state volumes (P = 0.25) or the time constant for volume changes (P = 0.17). The fact that the time constant is longer than the cardiac cycle, yet much shorter than the time necessary to measure vascular volume using other methods, highlights the need for rapid measurements of vascular volume.

The hypothesis that ventricular in-plane tensile wall stresses are the major determinant of systolic coronary flow was investigated in this study. We measured coronary artery inflow in the maximally vasodilated bed of the isolated beating septum (n = 10) during two modes of contraction characterized by markedly different levels of developed in-plane stress. An increase in contractility was induced by changing from the control steady-state pacing state to a postextrasystolic potentiated state induced by a modified rapid pacing protocol. Over a range of increments of passive stretch, the systolic flow impediment versus the diastolic wall strain was described by an inverse linear relation. Despite the differences in developed in-plane wall stresses between the two modes of contraction (p less than 0.001), the slope and intercept of these relations in both the control and potentiated states were not different for the low versus high developed stress modes. The systolic flow impediment versus diastolic wall strain relation for the potentiated beats, compared with the control beats, was characterized by an increase in the intercept in both the low developed stress beats (p less than 0.05) and the high developed stress beats (p less than 0.05). These data indicate that the impediment to coronary flow during systole is not primarily determined by systolic myocardial in-plane tensile wall stresses but rather by the contractile state of the muscle.

AIM: Although arterial compliance has been estimated by a variety of methods none of them can be directly validated because it is difficult to measure arterial volume. Moreover, because arterial pressure-volume relationships are non-linear, compliance is pressure-dependent. We have developed a method of estimating arterial compliance based on the Windkessel model of the arterial system that can account for the pressure-dependence of compliance. RESULTS: Compared to normotensive humans, compliance was decreased in hypertension and normalized with alpha-blockade, angiotensin converting enzyme inhibition and vasodilators, but not with beta-blockade. Compliance changes with aging, exercise and some diseases were determined. CONCLUSION: The decreased compliance seen in hypertension was due to an intrinsic change in the arterial wall, most likely due to increased smooth muscle tone.

Aging results in a decrease in the maximum heart rate during exercise. To determine if the age-associated decline in maximal heart rate might be due to a decreased chronotropic response to catecholamines, the maximum heart rate induced by systemic injections of isoproterenol was compared in unanesthetized mature (1–4 year) and senescent (8–12 year) beagle dogs. Maximum rate was also assessed under pentobarbital anesthesia before and after cholinergic blockade with atropine. The unanesthetized baseline heart rates in the mature and senescent groups did not differ [148 ± 6 vs. 147 ± 7 beats/min (bpm)] but the maximum isoproterenol induced heart rate was lower in the senescent compared to the mature group (249 ± 7 vs. 286 ± 13 bpm, P

The relationship between wave reflections and ventricular-vascular coupling has been the subject of considerable speculation. Since we have previously shown that low-dose nitroprusside infusion improved ventricular-vascular coupling (as evidenced by increases in cardiac output and in aortic and pulmonary arterial total external power) in patients with severe left ventricular failure and secondary pulmonary hypertension, we chose to examine the changes in their aortic and pulmonary arterial wave reflections in this study. Wave reflection indexes examined included [1] calculated backward and forward pressure waves and the ratio of their magnitudes (reflection factor), [2] the reflection coefficient spectrum obtained by taking the ratios of the corresponding Fourier harmonics of the backward and forward waves, [3] two terminal reflection coefficients calculated as Γ t =(R-Z c )/R+Z c ) where Z is characteristic impedance and R is either total resistance or vascular resistance, and [4] the difference between the maximum and minimum impedance moduli for frequencies of 4 to 15 Hz. In the systemic vasculature, nitroprusside produced large reductions in the elevated vascular resistances and decreased aortic reflections as indexed by the reflection factor and by both terminal reflection coefficients. In contrast, however, no significant changes were found in the pulmonary artery wave reflection indexes despite large reductions in the pulmonary resistances.

Aortic impedance, wave reflection magnitude, and compliance were measured in patients with Marfan's syndrome during diagnostic cardiac catheterization. Impedance and wave reflections were calculated from standard Fourier series analysis of ascending aorta micromanometer pressure and electromagnetic flow records. Compliance was estimated by a method recently proposed that uses the area under the pressure-time curve assuming a two-element Windkessel model of the circulation. Measurements were made in the baseline state, during vasodilatation with nitroprusside, after beta-adrenergic receptor blockade with intravenous propranolol, and during vasodilatation after beta-blockade. Marfan's syndrome produces alterations from normal in some hemodynamic variables: during baseline conditions, the magnitude of wave reflection was higher than in normal patients. This was normalized by vasodilatation and further increased by beta-blockade. Despite the greatly dilated aortic root, the aortic characteristic impedance was in the normal range, suggesting increased aortic wall stiffness. The baseline total arterial compliance was greatly increased with nitroprusside and was reduced by beta-blockade. beta-Blockade did not decrease the maximum acceleration of blood into the ascending aorta. These are the first detailed measurements of hemodynamic indexes in this disease. The results suggest that acute beta-blockade is not necessarily beneficial in reducing hemodynamic loading on an already dilated aortic root.

The driving force for carotid artery flow during high-intrathoracic-pressure cardiopulmonary resuscitation is a peripheral arteriovenous pressure gradient resulting from differential transmission of the high intrathoracic pressure to the carotid artery but not to the jugular vein. To study the role of carotid artery resistance to collapse in establishing this differential pressure transmission, we manipulated the upstream, downstream, and surrounding pressures and measured the resultant carotid artery flow in both intact dogs and in excised arteries. Stepwise reductions in downstream pressure produced a narrowing near the outlet from the high-pressure chamber (the thorax in vivo), but increments in flow continued despite the presence of a positive (outside--inside) transmural pressure gradient. Flow limitation occurred only when downstream pressure was further decreased. Resistance to collapse was indexed by the transmural pressure at the onset of flow limitation (Pcrit), which was 7.2 +/- 1.6 mmHg in eight intact dogs. After administration of norepinephrine Pcrit increased by 2.6 +/- 0.7 mmHg, P less than 0.001). Seven excised carotid arteries also demonstrated resistance to collapse which was enhanced somewhat with norepinephrine. Thus resistance of the carotid artery to collapse is a critical factor in maintaining forward flow during high intrathoracic pressure. This resistance to collapse is also seen in vitro and can be enhanced by vasoconstricting agents.

measurementsofleft ventricular end-diastolic dimension, left ventricular end-systolic dimension, andvelocity ofcircumferential fibre shortening weremadeatrestandduring 30mmHgincreases insystolic blood pressure induced byhandgrip exercise orphenylephrine infusion. Atrestthere was no agedifference inheart rate,left ventricular end-diastolic dimension, left ventricular end-systolic dimension, orcircumferential fibre shortening. Bothhandgrip andphenylephrine induced significant changes inthese indices inboth agegroupsbutno agedifference intheresponsescould beelicited. Inorder toeliminate theinfluence ofbeta-adrenergic drive, themeasurements wererepeated during propranolol block. Whilethere was no agedifference inventricular responseduring beta-blockade atrest,phenylephrine infusion during beta-blockade induced greater increase inleft ventricular end-diastolic dimension intheelderly group (2.3 i 0-6mm)compared with the younggroup(0.1 ± 05mm, P< 0.01). Thisincrease intheelderly groupoccurred despite a significantly smaller decrease inheart ratethanintheyounggroup.The normal agedhumanheart performs aswell asayoungheart atrestandduring beta-blockade buthasa greater reliance onbeta-adrenergic drive during haemodynamic stress. Previous studies haveshowntheusefulness of M-modeechocardiography inassessing left ventricular function during handgrip exercise (Stefadouros etal., 1974) andphenylephrine infusion (Redwood etal., 1974; Hirshleifer etal., 1975) innormal and diseased hearts. Earlier studies fromthis andother laboratories (Sj6gren, 1971;Gardin etal., 1977; Gerstenblith etal., 1977)havealsoshownthe feasibility ofusingthistechnique todetect age changes inventricular function anddimensions. Therefore, itappeared that echocardiography could beusedasanoninvasive methodofdetermining the effects ofaging ontheability oftheleft ventricle to respond tohaemodynamic stress. Previous studies suggest thattheoldheart functions aswellastheyoungheart undernormal conditions butmay havea diminished response

Intra-aortic balloon counterpulsation is capable of reducing afterload in patients with unstable angina. Whether it is also capable of augmenting coronary blood flow to poststenotic myocardium is controversial. We studied seven patients receiving maximal drug therapy and requiring balloon pumping for unstable angina as balloon volume and assist ratio were altered. All patients had greater than 90% stenosis of the proximal left anterior descending coronary artery. With maximal augmentation (40 cc balloon volume, 1:1 assist ratio) great cardiac vein flow, representing the efflux from the left anterior descending coronary artery bed, rose from a baseline of 52 +/- 20 to 67 +/- 25 ml/min (mean +/- SD, p = .004) and mean aortic diastolic pressure increased from 77 +/- 13 to 99 +/- 33 mm Hg (p = .004). Increased great cardiac vein flow correlated with increased mean aortic diastolic pressure across changes in balloon volumes (off, 20 cc, 30 cc, and 40 cc) and changes in assist ratio (off, 1:4, 1:2, and 1:1) (p = .02). However, the intermediate balloon volumes produced great cardiac vein flows at an intermediate level between full assist and no assist (p less than .05), whereas the intermediate assist ratios did not augment flow. Thus balloon pumping increased flow to a bed fed by collateral vessels or critical stenoses; this increased flow correlated with increased aortic diastolic pressure, indicating probable loss of autoregulatory ability.

To study the usefulness of large V waves in pulmonary capillary wedge tracings in establishing the diagnosis of mitral regurgitation, data on 1,021 consecutive cardiac catheterizations were reviewed. Wedge tracings were obtained by Swan-Ganz catheterization in 208 patients, usually because of suspected valve disease. One hundred two patients had no trace of mitral regurgitation angiographically, 69 had mild to moderate and 37 had severe regurgitation. V waves were graded as trivial (less than 5), intermediate (5 to 10) or large (10 or more mm Hg above mean wedge pressure). Of 50 patients with large V waves, 18 (36 percent) had no or trace mitral regurgitation; these included 5 with mitral stenosis, 3 with a mitral valve prosthesis, 4 with coronary disease and congestive failure, 2 with aortic valve disease and congestive failure and 2 with a ventricular septal defect. Of 37 patients with severe mitral regurgitation, 16 (43 percent) had large and 12 (32 percent) had trivial V waves. Thus, mitral regurgitation is the most common cause of large V waves; however, large V waves are neither highly sensitive nor specific for severe regurgitation. Increased left atrial compliance may be associated with trivial V waves in the presence of severe regurgitation. Mitral obstruction, congestive heart failure and ventricular septal defect may all be associated with large V waves in the absence of significant mitral regurgitation.

Although it has been proposed that incomplete relaxation explains certain increases in left ventricular end diastolic pressure relative to volume, there has been no clear demonstration that incomplete relaxation occurs in the intact working ventricle. To identify incomplete relaxation, left ventricular pressure-dimension relationships were studied in 10 canine right heart bypass preparations during ventricular pacing. The fully relaxed, exponential diastolic pressure-dimension line for each ventricle was first determined from pressure and dimension values at the end of prolonged diastoles after interruption of pacing. For 167 beats during pacing under widely varying hemodynamic conditions, diastolic pressure-dimension values encountered this line defining the fully relaxed state during the filling period indicating that relaxation was complete before end diastole. The time constant for isovolumic exponential pressure fall (T) was determined for all beats. For this exponential function, if no diastolic filling occurred, 97% of pressure fall would be complete by 3.5 T after maximal negative dP/dt. For the 167 beats the fully relaxed pressure-dimension line was always encountered before 3.5 T. With very rapid pacing rates (170-200 beats/min) and(or) with pharmacologic prolongation of relaxation, incomplete relaxation occurred as evidenced by the fact that the line defining the fully relaxed state was never reached during diastole (n = 15). This evidence of incomplete relaxation occurred only when the subsequent beat began before 3.5 T but did not always occur under these conditions. Thus, an increase in end diastolic pressure relative to diastolic volume may result from incomplete relaxation under conditions of sufficiently rapid heart rate or sufficiently prolonged ventricular relaxation. Incomplete relaxation does not occur when the next beat begins more than 3.5 T after maximum negative dP/dt.

Almost all existing methods for estimating hemodynamic parameters are valid only during steady-state conditions. There is often a need, however, for estimating peripheral resistance and total arterial compliance during beat-to-beat transients such as during atrial fibrillation. During such transients the pressure at the onset and end of a cardiac cycle usually differ. This pressure difference necessitates a modification of usual methods used for estimating these hemodynamic parameters. In this paper we formulate a method for estimating resistance and total arterial compliance during such beat-to-beat transients. For simplicity the expressions are derived for a two-element windkessel model of the circulation. The method is a generalization of one we previously proposed. Rather than using parameter estimation techniques or having to assume a monoexponential pressure decay during diastole, our method uses the areas under the systolic and diastolic portions of the aortic pressure versus time tracing to obtain explicit expressions for compliance; both for the case where it is constant and when it is assumed to be nonlinear (exponential) function of pressure. Aortic pressure and flow data from patients undergoing cardiac catheterization are employed to illustrate the method. Results illustrate the quantitative difference between uncorrected and corrected estimates of both resistance and compliance as a function of the pressure difference between the onset and end of each beat. The uncorrected parameters were found to be linearly and highly correlated with these pressure differences. Regressions of pressure difference against normalized values revealed that the pooled data for all patients defined a single relationship.(ABSTRACT TRUNCATED AT 250 WORDS)

Septal displacement is postulated as an important mediator of ventricular interdependence. During acute right ventricular loading with the Mueller manoeuvre the septum flattens and shifts leftward. To investigate the mechanism of this septal deformation, we measured transseptal pressures in nine patients during Mueller manoeuvres with simultaneous right and left ventricular micromanometers, and left ventricular configuration with two-dimensional echocardiograms. Data were analysed throughout diastole and at end-systole during control and maximum Mueller manoeuvre (-40 to -80 mmHg airway pressure). Leftward septal displacement during the Mueller manoeuvre was evidenced by an increase in septal radius of curvature at end-diastole persisting through end-systole. The left ventricular free wall radius of curvature was unchanged. During the Mueller manoeuvre, the left ventricular cavity area decreased significantly in the cross-sectional view. All Mueller manoeuvres were associated with a decrease in left-to-right ventricular transseptal pressure gradient throughout diastole. There was no significant change in the gradient at end-systole; septal flattening persisted, however, despite a pronounced left to right pressure gradient. Thus, diastolic septal flattening during right ventricular loading is associated with a decreased transseptal pressure gradient but does not require right ventricular diastolic pressure to exceed left ventricular diastolic pressure. The persistence of flattening in systole suggests that once septal shift occurs during diastole, other forces during systole maintain the deformity despite a large intracavitary transseptal gradient.

The diminished cardiac output response to exercise with advancing age may be attributable to intrinsic inability of the old ventricle to respond appropriately and/or to an additional loading imposed upon the ventricle by the aged vascular system. The steady (resistance) and pulsatile (characteristic impedance) load components together comprise the vascular load faced by the ejecting ventricle. To study the effect of exercise on both vascular components of load, the aortic input impedance was measured in chronically instrumented young and old beagle dogs during graded treadmill exercise before and after beta blockade. Ascending aortic flow was measured by a cuff electromagnetic flow probe, and pressure was measured by a high-fidelity semiconductor transducer. At low levels of exercise the old animals demonstrated a striking 20% increase in characteristic impedance and a 28% decrease in peripheral resistance with no increase in stroke volume. This vascular loading and limitation in stroke volume persisted across the higher exercise levels. In contrast, the young group demonstrated no increase in characteristic impedence, a progressive decrease in peripheral resistance, and a progressive increase in stroke volume across the same exercise levels. These age differences in vascular response and ventricular output were abolished by beta blockade. The groups did not demonstrate a difference in heart rate response, but the young had a greater increase in external left ventricular power than the old across exercise. These data demonstrated a profound difference in the response of young and old vasculature to exercise. At low and intermediate exercise levels the pulsatile vascular load appeared to be a major factor in the limitation of stroke volume in old dogs. At high levels of exercise, the limited exercise response in the old dog may be caused in part by a diminished inotropic responsiveness as well as by the vascular loading.

Atrial pacing-induced tachycardia causes increased myocardial oxygen demand and leads to the development of angina in patients with significant coronary arterial narrowing, when the ability to augment coronary flow is limited. This study evaluated the response of coronary flow in a single coronary bed as that bed was rendered ischemic by progressive increases in oxygen demand. Thermodilution measurements of great cardiac vein flow, representing the efflux from the territory of the left anterior descending coronary artery, were obtained in 20 patients as heart rate was increased by incremental atrial pacing until the maximal heart rate was reached or angina developed. Ten of the 20 patients had no significant coronary narrowing on angiography, and 10 had a lesion obstructing more than 50 percent of the diameter of the left anterior descending coronary artery but no other significant coronary narrowing. No significant difference was found between the two groups in resting heart rate, aortic pressure, left ventricular end-diastolic pressure or great cardiac vein flow. With each increment in heart rate throughout the pacing test, the patients without significant coronary stenosis showed a steady increase in great cardiac vein flow. During all submaximal pacing increments, the increase in great cardiac vein flow per increment in heart rate was similar in those with and without significant stenosis (mean ± standard deviation 1.05 ± 0.48 ml/beat versus 0.79 ± 0.31 ml/beat, respectively). However, over the final pacing increment, the patients with coronary stenosis had no increase in great cardiac vein flow, whereas those without disease continued to have increased flow (Δ = 0.10 ± 0.19 ml/beat versus 1.3 ± 0.69 ml/beat, respectively, p < 0.001). This flow limitation phenomenon was observed in all 10 patients with coronary stenosis and was accompanied by angina or S-T segment changes, or both, in all 10. This striking difference in coronary flow patterns between patients with and without significant left anterior descending coronary artery disease may prove useful in (1) further studies of the pathophysiology and therapy of myocardial ischemia in human beings, and (2) clinical evaluation of the hemodynamic importance of left anterior descending coronary arterial lesions in selected patients.

We initially found that the fall in left ventricular pressure during isovolumic relaxation is exponential and therefore characterized by a time constant (T). To the extent that isovolumic pressure fall reflects myocardial events during relaxation, T indexes the time course of relaxation of the left ventricle. In isolated canine hearts sudden beat to beat loading changes from isovolumic to ejection shorten T. In contrast, under stable hemodynamic conditions T is independent of load across a broad, physiologically significant range. For example:(1) in nine isovolumic hearts with end-diastolic pressure from 7±0.5 to 22±0.5 mm Hg and peak left ventricular pressure (LVP) from 95 ± 11 to 155 ± 12 mm Hg, T did not change significantly; (2) in seven ejecting hearts from a stroke volume of 10 to 20 ml and from a peak LVP of 85 to 192 mm Hg, T was not altered. T changed significantly with factors thought to affect the active cardiac relaxing system such as heart rate, catecholamines and recovery from ischaemia. To quantify the extent of incomplete left ventricular relaxation between beats and to identify the time at which relaxation no longer influences the diastolic ventricular pressure-dimension relationships, we measured pressure and endocardial dimension by sonomicrometry in ten working dog hearts. We obtained the fully relaxed pressure-dimension relationship for individual hearts from pressure-dimension values following prolonged diastoles. From the linear relationship between pressure and dimension we predicted the left ventricular dimension which would be present at any observed diastolic pressure if relaxation were complete. At intervals of 0.25 T or less we compared this predicted fully relaxed dimension with the actual dimension. The predicted and actual dimension were not significantly different at end-diastole in any beat where the next beat began > 3.5 T after maximal negative dP/dt. This indicates completion of relaxation prior to end-diastole in all such beats. An end-diastolic difference in predicted v. actual dimension (when the beat began < 3.5 T after maximal negative dP/dt) identified incomplete relaxation. This difference between the predicted fully relaxed dimension and the actual dimension quantified the extent of incomplete relaxation. Earlier in diastole this difference quantified the effect of relaxation on ventricular dimension and thus diastolic filling. Under widely varying hemodynamic conditions, except with severe failure, the time of the end of the effect of relaxation on diastolic pressure-dimension was 2.85 ± 0.33 (s.d.) T after maximal negative dP/dt. Under severe hemodynamic stress this time occurred earlier in diastole. This early end of the influence of relaxation on diastolic pressure-dimension relationships could be predicted from P at maximal negative dP/dl, T, and the fully relaxed diastolic pressure-dimension relationship. Thus, T is a load-independent index of left ventricular pressure fall under stable hemodynamic conditions. Use of T aids in the identification of changes in the relaxation time course, quantification of incomplete relaxation and the time course and extent of the effect of relaxation on pressure-dimension relationships during the diastolic filling period. The extent of incomplete relaxation and/or the effect of relaxation on diastolic dimensions throughout diastole can be quantified by comparing the actual dimension to the fully relaxed dimension at any pressure during diastole.

The mechanism for the therapeutic effect of nitroglycerin in stress-induced angina remains controversial; it has been attributed to both increased blood supply to the ischemic myocardium and decreased myocardial oxygen demand. To investigate the contribution of each of these mechanisms, systemic pressures and great cardiac vein flow were measured in 14 patients with single-vessel disease involving the left anterior descending (LAD) coronary artery during the development of pacing-induced angina and after the administration of nitroglycerin while continuing pacing at the angina-provoking rate. Great cardiac vein flow, measured by thermodilution, represents the venous efflux from the LAD territory and therefore provided an index of flow to the poststenotic myocardium. In 11 patients, nitroglycerin was administered systemically (400 to 800 micrograms sublingually or 200 micrograms intravenously); angina was relieved in 10, concomitant with a decrease in both great cardiac vein flow (from 123 +/- 29 to 98 +/- 29 ml/min, p less than 0.001) and mean aortic pressure (from 118 +/- 22 to 104 +/- 22 mm Hg, p less than 0.001). In contrast, when 75 micrograms of nitroglycerin was administered directly into the left main coronary artery of 7 patients, it produced a small increase in great cardiac vein flow (from 108 +/- 32 to 125 +/- 31 ml/min, p = 0.059), no change in aortic pressure, and no relief of angina. This study suggests that nitroglycerin's major beneficial action in pacing-induced angina is unrelated to direct effects on the coronary circulation and is likely related to its cardiac unloading effect.

Left ventricular contractility can be assessed from the end-systolic pressure-volume relationship (ESPVR). In this study we test the hypothesis that the same ESPVR can be obtained by varying LV loading with different levels of negative intrathoracic pressure as by varying LV filling. In six dogs mean aortic transmural pressure was used to approximate LV end-systolic pressure and LV volume was determined from data gathered from biplane cineradiograms of multiple markers placed in the LV midwall. In each preparation right heart bypass allowed control of cardiac output while the thoracic pressure was varied with a box surrounding a midsternal thoracotomy. Reflex effects were minimized by ganglionic blockade and bilateral vagotomy. ESPVRs were obtained by varying the cardiac output at constant thoracic pressure or by changing intrathoracic pressure at constant cardiac output. The slopes of the ESPVRs were not significantly different. This result implies that LV loading by negative intrathoracic pressure, in this highly controlled preparation, can be used to generate a systolic LV elastance similar to that obtained by varying LV filling.

We studied the effect of nitroprusside on the hydraulic vascular load of the right and left ventricle in seven patients with severe left ventricular failure. At doses of 0.25-0.75 micrograms/kg/min, stroke volume increased progressively from 40.1 to 48.6 ml and left ventricular end-diastolic pressure decreased from 24.5 to 11.2 mm Hg. Accompanying this improvement in left ventricular performance were dose-related decreases in mean ventricular pressures, pulmonic and systemic resistances and the lower-frequency components of input impedance moduli. Characteristic impedance and both total and oscillatory external power were decreased in the pulmonic, but not the aortic, vasculature. In this class of patients, right ventricular unloading is a striking and direct effect of nitroprusside and may account, in part, for improved left ventricular performance through ventricular interdependence.

Aortic compliance in normotensive and hypertensive Chinese subjects undergoing diagnostic cardiac catheterization was compared by using a newly described method that allows for determination of the pressure dependence of compliance if one assumes a value for the exponential coefficient of the pressure-volume relation of the large arteries. Under baseline conditions in the normotensive and hypertensive groups at mean aortic pressures of 96.3 and 128.6 mm Hg, aortic compliance averaged 1.47 and 0.80 ml/mm Hg, respectively. Compliance in the hypertensive group at a diastolic pressure of 99.4 mm Hg (which was nearly equal to the mean normotensive pressure) was 1.072 ml/mm Hg--still significantly lower than in the normotensive group. During nitroprusside infusion, however, the compliances in the hypertensive group increased to levels equal to or greater those in the normotensive group. Thus, these data confirm that aortic compliance is lower in hypertensive than in normotensive humans. They further demonstrate that the lower compliance cannot be attributed entirely to the elevated blood pressure, suggesting that excess smooth muscle tone may be partly responsible.