Peter F. Carlyle

Hemodynamic and Hormonal Response to Transdermal Nitroglycerin in Normal Subjects and in Patients With Congestive Heart Failure

The hemodynamic and hormonal responses to nitroglycerin administered transdermally in a gel-like matrix were evaluated in nine patients with severe congestive heart failure and in nine normal subjects. In normal subjects, peripheral vasodilation was accompanied by reflex sympathetic stimulation as reflected by an increase in heart rate and plasma norepinephrine. In patients with heart failure, nitroglycerin produced sustained hemodynamic effects that began 30 minutes after the application and fully persisted for at least 6 hours. A significant decrease in right and left ventricular filling pressures was associated with an increase in stroke index and a significant decrease in forearm and pulmonary vascular resistances. There was no change in heart rate and systemic arterial pressure or in plasma norepinephrine or plasma renin activity. After 24 hours, pressures had partially returned to control levels, but mean pulmonary artery pressure was still significantly lower than in the control period. After removal of the nitroglycerin, each patient exhibited a decrease in cardiac index and an increase, above the control values, in pulmonary and systemic arterial pressures and pulmonary, systemic and forearm vascular resistances. This transient rebound appeared to be unrelated to stimulation of the sympathetic or renin-angiotensin systems. Thus, transdermal absorption of this new form of nitroglycerin appears to provide a nitrate vascular effect that is sustained for 24 hours, but an endogenous vasoconstrictor effect may influence the hemodynamic response over the first 24 hours.

Relative effects of alpha 1-adrenoceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog.

BackgroundProgressive ventricular remodeling after myocardial damage is associated with a poor prognosis. Optimal prevention of the histopathological processes involved in remodeling requires a more complete understanding of the mechanisms involved in initiating and maintaining these structural changes. Since the sympathetic nervous system and the renin-angiotensin system may be involved in the remodeling process, the structural effects of pharmacological inhibitors have been evaluated in a canine model of localized myocardial injury resulting from transmyocardial DC shock. Methods and ResultsThe study is comprised of two protocols run in series. In protocol 1, zofenopril (Z), a converting enzyme inhibitor (CEI), prevented the increase in left ventricular mass (LVM) and end-diastolic volume (LVV) observed in the control group (C) at 16 weeks (Z: LVM, 69.8 ± 3.4 to 65.4 ± 2.6 g, P = NS; LVV, 45.4 ± 2.7 to 51.6 ± 2.7 mL, P = NS; C: LVM, 68.4 ± 3.2 to 91.4 ± 2.9 g, P = .0001; LVV, 56.6 ± 3.0 to 71.9 ± 2.4 mL, P = .0003). Terazosin, an alpha 1- adrenoceptor antagonist, failed to prevent remodeling at 16 weeks despite continued receptor blockade. In protocol 2, the antiremodeling effect of full-dose CEI therapy with ramipril was confirmed. Low-dose ramipril that exerted no hemodynamic effect failed to prevent remodeling (LVM, 89.7 ± 4.6 to 105.7 ± 3.4 g, P = .01; LVV, 61.8 ± 3.8 to 76.8 ± 3.3 mL, P = .002). An angiotensin II subtype 1 receptor blocker also failed to prevent the increase in LVM or LVV (LVM, 89.0 ± 4.6 to 109.7 ± 5.3 g, P = .0001; LVV, 66.0 ± 1.9 to 78.4 ± 3.6 mL, P = .007). ConclusionsHigh-dose CEI therapy can prevent progressive structural changes resulting from localized myocardial damage induced by DC shock. The failure of α1-adrenoceptor blockade and angiotensin II subtype 1 blockade to attenuate remodeling argues against an important direct role for norepinephrine acting through α1-receptors or angiotensin II acting through the type 1 receptor in the remodeling process in this model.

Effect of dilation of the distal coronary bed on flow and resistance in severely stenotic coronary arteries in the dog

Studies were performed to evaluate the hemodynamic response of severely stenotic coronary arteries to dilation of the distal coronary bed. A critical stenosis was produced with an adjustable wire snare on the left anterior descending or circumflex arteries of open chest dogs. Coronary flow, distal coronary pressure and aortic pressure were measured. In one group of experiments, coronary arteriolar dilatation was induced by transient occlusion of the artery distal to the stenosis. After the release of a transient occlusion in vessels without a critical stenosis, flow increased (from 33 +/- 4 to 85 +/- 8 ml/min, P less than 0.01), distal pressure decreased slightly (from 86 +/- 4 to 80 +/- 4 mm Hg, P less than 0.01), and large vessel resistance did not change significantly (from 0.06 +/- 0.02 to 0.08 +/- 0.03 units). After the release of a transient occlusion in vessels with a critical stenosis, flow decreased (from 23 +/- 3 to 12 +/- 2 ml/min, P less than 0.01), distal pressure decreased to persistently low levels (from 63 +/- 2 to 29 +/- 2 mm Hg, P less than 0.01), and large vessel resistance increased (from 1.4 +/- 0.3 to 6.7 +/- 1.8 units, P less than 0.01). In a separate group of experiments, radio-opaque contrast medium was used to dilate the distal coronary bed. In these studies dilation of the distal coronary of arteries with a critical stenosis again resulted in a decrease in coronary blood flow (from 35 +/- 4 to 19 +/- 3 ml/min, P less than 0.01), a decrease in distal coronary pressure (from 84 +/- 6 to 35 +/- 6 mm Hg, P less than 0.01) and an increase in large arterial resistance (from 1.0 +/- 0.2 to 5.5 +/- 1.2 units, P less than 0.02). Therefore, in coronary vessels with severe stenosis, dilation of the distal coronary bed may result in a paradoxical decrease in coronary blood flow.

Angiotensin-converting enzyme inhibition and beta-adrenoceptor blockade regress established ventricular remodeling in a canine model of discrete myocardial damage☆

OBJECTIVES This study was designed to assess the effect of angiotensin-converting enzyme inhibition and beta-adrenoreceptor blockade on established ventricular remodeling. BACKGROUND Angiotensin-converting enzyme inhibitor therapy attenuates the development of ventricular remodeling when given shortly after myocardial infarction. However, regression of established ventricular remodeling after infarction has received little attention. METHODS The relative effects of angiotensin-converting enzyme inhibitor therapy and beta-adrenoceptor blockade on established ventricular remodeling were assessed in a canine model characterized by increased left ventricular mass and chamber dilation as a result of localized myocardial necrosis produced by transmyocardial direct current shock. Dogs were randomly assigned to 3 months of therapy with captopril (25 mg twice daily, n = 7) or metoprolol (100 mg twice daily, n = 7) or to a control group with no intervention (n = 6), 11 +/- 4 (mean +/- SD) months after acute myocardial damage. RESULTS Compared with the control group, dogs in both the captopril and metoprolol groups had reduced left ventricular mass as measured by magnetic resonance imaging (-8.1 +/- 3.8 vs. 1.7 +/- 2.8 g, p = 0.003 and -9.6 +/- 5.6 vs. 1.7 +/- 2.8 g, p = 0.001), respectively. Captopril and metoprolol also produced a reduction in left ventricular end-diastolic volume (-7.6 +/- 6.0 and -6.0 +/- 5.8 ml, respectively) compared with the control value (-1.6 +/- 3.8 ml) (p = 0.14 [NS]). Both agents reduced mean arterial pressure but had disparate effects on pulmonary wedge pressure and right atrial pressure. There was no significant correlation between change in ventricular mass or volume and change in any measured hemodynamic or neurohormonal variable. CONCLUSIONS These data suggest that pharmacologic intervention with angiotensin-converting enzyme inhibition or beta-adrenoceptor blockade can result in regression of established ventricular remodeling. The mechanism of this response will require further study, but these data did not support a close association between regression of remodeling and hemodynamic unloading of the ventricle or systemic neuroendocrine factors.

Effect of coronary arterial pressure on coronary stenosis resistance.

The effects of coronary pressure on coronary stenosis resistance were studied in 13 open-chest dogs. A noncircumferential stenosis was produced in the circumflex coronary artery by placing sutures into either side of the artery and invaginating a portion of the arterial wall by tying the sutures. Coronary pressure both proximal and distal to the stenosis and coronary flow were measured. Coronary pressure was lowered by 1) hemorrhage and 2) placing a snare proximal to the noncircumferential stenosis and tightening the snare. After hemorrhage, mean proximal coronary pressure fell from 100 ± 5 to 56 ± 6 mm Hg (p < 0.01) and resistance across the noncircumferential stenosis increased from 0.56 ± 0.13 to 1.3 ± 0.26 units (p < 0.05). After the snare was tightened, mean proximal coronary pressure fell from 110 ± 4 to 58 ± 4 mm Hg (p < 0.01) and resistance across the noncircumferential stenosis increased from 0.43 0.05 to 1.1 ± 0.25 units (p < 0.02). In a series of experiments, coronary pressure was raised by inflating a balloon in the proximal aorta. After the balloon was inflated, mean proximal coronary pressure increased from 95 ± 7 to 129 5 mm Hg (p < 0.01) and resistance across the noncircumferential stenosis decreased from 2.34 0.56 to 2.05 + 0.46 units (p < 0.05). These changes in stenosis resistance were consistent with passive narrowing and distension of the stenotic segment caused by the changes in coronary pressure. Alterations in coronary pressure may therefore affect the severity of a coronary stenosis.

Early redistribution of thallium-201 after temporary ischemia.

To define the time course of redistribution of thallium-201 (251TI), ischemia was induced in seven pigs by temporary occlusion of the circumflex coronary artery. After 1½ min of occlusion 201T1 and labeled microspheres were injected into the left atrium. Flow was re-established 4 min after occlusion. Prior to reflow, the relative activities of 201TI and microspheres in the ischemic area were similar, but as early as 5 min after reflow the relative 201fT activity was considerably higher than the relative microsphere activity and from 15 to 105 min after reflow, relative 201TI activity (average 69% of that in normal myocardium) continued to be higher than relative microsphere activity (average 6% of normal). Myocardial arteriovenous differences for 201TI were followed sequentially after 201Tl injection in normal dogs and in dogs with temporary coronary occlusions. The results suggested both loss of 201TI from normal myocardium beginning 10 min after 205TI injection and increased extraction of 201TI from the blood pool immedately after release of a transient occlusion. Redistribution of 201TI therefore begins very soon after relief of myocardial ischemia and even a short delay in initiating myocardial imaging may decrease the sensitivity of the technique for detecting transient ischemia.

Hemodynamic, left ventricular structural and hormonal changes after discrete myocardial damage in the dog☆

Transmyocardial direct-current (DC) shock produces localized left ventricular myocardial necrosis without obstruction to coronary blood flow. In 43 dogs sequential measurements of hemodynamic, neuroendocrine and myocardial structural changes were made at baseline and for 16 weeks after DC shock. Six dogs (14%) died in the peri-shock period. By 1 week after shock, left ventricular mass, as measured by nuclear magnetic resonance imaging, had increased from a mean value +/- SD of 67.9 +/- 10.1 to 82.5 +/- 12.9 g (p = 0.0001). Left ventricular end-diastolic volume was unchanged at 1 week but increased at 16 weeks from 56.1 +/- 10.3 to 70.3 +/- 10.7 ml (p = 0.0003). Left ventricular mass demonstrated a further increase at 12 months (107.8 +/- 14.8 g). Rest cardiac output was significantly decreased at 4 months (3.67 +/- 1.23 to 3.18 +/- 0.81 liters/min, p less than 0.01) as was stroke volume (43 +/- 9 to 37 +/- 7 ml, p less than or equal to 0.01). Left ventricular ejection fraction decreased progressively from 73% to 38% at 1 year. At 4 months there were increases in mean pulmonary artery pressure (18 +/- 4 to 23 +/- 4 mm Hg, p less than 0.01), pulmonary capillary wedge pressure (9 +/- 3 to 15 +/- 3 mm Hg, p less than 0.01) and right atrial pressure (5 +/- 4 to 9 +/- 3 mm Hg, p less than 0.01). Plasma norepinephrine was increased at 4 months (318 +/- 190 to 523 +/- 221 pg/ml, p = 0.0003), whereas plasma renin activity was not significantly changed (4.3 +/- 2.6 vs. 5.2 +/- 3.4 ng/ml per h). Microsphere regional blood flow studies demonstrated a 50% reduction in skeletal muscle blood flow at 4 months (0.06 +/- 0.06 ml/min per g compared with 0.12 +/- 0.09 in normal dogs, p = 0.05), and a reduction in the endocardial/epicardial blood flow ratio (1.11 +/- 0.13 compared with 1.24 +/- 0.13 in normal dogs, p = 0.02). Therefore, in this model of acute left ventricular damage, left ventricular hypertrophy precedes progressive left ventricular dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular hemodynamic impedance in congestive heart failure.

The objective of this study was to determine whether pulse-contour analysis could provide a measure of the differences in peripheral vascular state between patients with congestive heart failure (CHF) and healthy persons. Vascular hemodynamic impedance parameters were determined from brachial artery pressure waveforms recorded in 14 patients with CHF, aged 20 to 55 years (mean 36 +/- 12) and in 7 healthy control subjects, aged 22 to 55 years (mean 33 +/- 12). Cardiac output, heart sounds and electrocardiogram were also monitored. Cardiac output was 32% lower (p less than 0.01) and heart rate was 43% higher (p less than 0.001) in the CHF group than in the control group. The mean arterial pressure did not differ between groups. Systemic vascular resistance was 47% higher (p less than 0.05) and distal vascular compliance 73% lower (p less than 0.001) in the CHF group than in control group. Proximal vascular compliance was unchanged. These studies suggest that distal compliance assessed from pulse-contour analysis is a more sensitive and specific index than systemic vascular resistance to the vascular changes in CHF.

Pressure pulse contour analysis in determining the effect of vasodilator drugs on vascular hemodynamic impedance characteristics in dogs

The effects of three vasodilators on the shape of the arterial pressure contour in the dog were investigated. A modified Windkessel model of the arterial vasculature was used as a guide in interpreting the observed contour changes. The pressure curve during diastole has been viewed as the transient response of the arterial system and can be fit accurately to the equation The parameters in this equation and peripheral resistance were used to define the components of the third order Windkessel model consisting of proximal (C1) and distal (C2) compliances, an inertance term (L), and peripheral resistance (R). This model describes the gross mechanical behavior seen in the arterial system during diastole. The arterial pressure pulse, mean pressure, and cardiac output responses to intravenous administration of sodium nitroprusside (NP), nitroglycerin (NTG), and hydralazine (H) were studied using computerized parameter estimating techniques to determine the ai parameters in the pressure equation and their relationship to the Windkessel components. All three drugs caused C1 to decrease, but not significantly. NTG increased inertance from 0.076 to 0.134 mm. Hg/ml./sec.2, with a p value < 0.05. NP increased C2 from 0.027 to 0.046 ml./mm. Hg. (p < 0.01); NTG also increased C2, from 0.030 to 0.060 ml./mm. Hg (p < 0.05). Hydralazine had no significant effect on C2, but it did reduce R from 3.10 to 2.16 mm. Hg/ml./sec. (p < 0.01). Neither NP nor NTG showed a significant decrease in R. Thus, the three vasodilators apparently have different vascular effects, as demonstrated by the pulse contour analysis. Such an analysis may be a useful way to evaluate vasodilator therapy.

M-mode and two-dimensional echocardiographic analysis of the septum in experimental right ventricular infarction: Correlation with hemodynamic alterations

We investigated the changes that occur in the shape and the motion of the ventricular septum in experimental right ventricular (RV) infarction with M-mode and two-dimensional echocardiography. The echocardiographic findings were correlated with the hemodynamic alterations. Right ventricular infarction was produced by mercury embolization of the right coronary artery in five anesthetized closed-chest dogs. After embolization, the transseptal end-diastolic left-right ventricular pressure gradient reversed (3 +/- 1) to -1 +/- 1 mm Hg, p less than 0.001). The septal shape was altered by the flattening of the septum at end-diastole and a return to the normal septal shape during systole. Systolic septal motion was reversed after embolization (1 mm toward the left ventricle before embolization to 3 mm toward the RV after embolization, p less than 0.01). Septal thickening was not altered. We concluded that isolated RV free wall infarction results in the reversal of the transseptal end-diastolic pressure gradient and is associated with the flattening of the septum at end-diastole. During systole, the septum returns to its normal shape and moves toward the RV. In addition, systolic septal thickening is preserved. The motion of the septum toward the RV, together with normal septal thickening, may provide mechanical assistance to RV ejection with RV free wall infarction.