The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

A 70 percent reduction in the rate of blood flow through the common carotid artery in rabbits caused a 21 percent decrease in the diameter of this artery within 2 weeks. The smooth muscle relaxant papaverine did not attenuate the response; therefore, such reductions in diameter probably reflect a structural modification of the arterial wall rather than sustained contraction of smooth muscle. This arterial response to reduced blood flow was abolished when the endothelium was removed from the vessels. It appears that the endothelium is essential for the compensatory arterial response to long-term changes in luminal blood flow rates.

https://science.sciencemag.org/content/sci/231/4736/405.full.pdf

Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent

Experiments were designed to investigate the importance of vascular endothelium in the vasomotor response to increases in flow as observed in conduit arteries (flow-dependent dilation). The diameter changes of femoral arteries (sonomicrometry) in response to increases in flow before and after endothelial damage procedures were studied in 23 dogs anesthetized with sodium pentobarbital. The functional integrity of the endothelial cells underneath the diameter sensors was tested by intra-arterial acetylcholine (local acetylcholine dilation) applied proximally to the sensors while a constant flow was maintained. Unilateral augmentation of femoral arterial flow (4.6 +/- 1.9-fold) induced by peripheral vasodilation or by arteriovenous shunt, elicited dilation (increase in diameter, 116 +/- 91 microns) in 18 of 23 dogs, whereas the diameter of the contralateral control artery was not affected. Mechanical removal of the endothelial cells by means of a balloon catheter abolished both the flow-dependent dilation and the local acetylcholine dilation, whereas the vasomotor responses to norepinephrine and nitroglycerin were not affected. Brief perfusions (1 minute) of the arteries with cell-free hydrogen peroxide solution (90 mM) also abolished the flow-dependent dilation and attenuated the local acetylcholine dilation (by 27 +/- 19%; p less than 0.02), while the responses to norepinephrine and nitroglycerin were not altered. These results suggest that endothelial cells act as mediators of flow-dependent dilation.

Crucial role of endothelium in the vasodilator response to increased flow in vivo

The introduction of valve replacement surgery in the early 1960s has dramatically improved the outcome of patients with valvular heart disease. Approximately 90 000 valve substitutes are now implanted in the United States and 280 000 worldwide each year; approximately half are mechanical valves and half are bioprosthetic valves. Despite the marked improvements in prosthetic valve design and surgical procedures over the past decades, valve replacement does not provide a definitive cure to the patient. Instead, native valve disease is traded for “prosthetic valve disease,” and the outcome of patients undergoing valve replacement is affected by prosthetic valve hemodynamics, durability, and thrombogenicity. Nonetheless, many of the prosthesis-related complications can be prevented or their impact minimized through optimal prosthesis selection in the individual patient and careful medical management and follow-up after implantation. The purpose of this article is to provide an overview of the current state of knowledge and future perspectives with regard to optimal prosthesis selection and clinical management after valve implantation.

The ideal valve substitute should mimic the characteristics of a normal native valve. In particular, it should have excellent hemodynamics, long durability, high thromboresistance, and excellent implantability. Unfortunately, this ideal valve substitute does not exist, and each of the currently available prosthetic valves has inherent limitations.

### Mechanical Valves

Three basic types of mechanical valve design exist: bileaflet, monoleaflet, and caged ball valves (Figure 1A, 1B, and 1C). 



Figure 1. Different types of prosthetic valves. A, Bileaflet mechanical valve (St Jude); B, monoleaflet mechanical valve (Medtronic Hall); C, caged ball valve (Starr-Edwards); D, stented porcine bioprosthesis (Medtronic Mosaic); E, stented pericardial bioprosthesis (Carpentier-Edwards Magna); F, stentless porcine bioprosthesis (Medtronic Freestyle); G, percutaneous bioprosthesis expanded over a balloon (Edwards Sapien); H, self-expandable percutaneous bioprosthesis (CoreValve).



#### Caged Ball Valves 

Caged ball valves, which consist of a silastic ball with a circular sewing ring and a …

Prosthetic Heart Valves Selection of the Optimal Prosthesis and Long-Term Management

Flow-mediated vasodilation is endothelium dependent. We hypothesized that flow activates a potassium channel on the endothelium, and that activation of this channel leads to the release of the endogenous nitrovasodilator, nitric oxide. To test this hypothesis, rabbit iliac arteries were perfused at varying flow rates, at a constant pressure of60 mm Hg. Increments in flow induced proportional increases in vessel diameter, which were abolished by LN-mono-methylarginine (the antagonist of nitric-oxide synthesis). Barium chloride, depolarizing solutions ofpotassium, verapamil, calcium-free medium, and antagonists of the Kc. channel (charybdotoxin, iberiotoxin) also blocked flow-mediated vasodilation. Conversely, responses toother agonists of endothelium-dependent and independent vasodilation were unaffected by charybdotoxin or iberiotoxin. To confirm that flow activated a specific potassium channel to induce the release of nitric oxide, endothelial cells cultured on microcarrier beads were added to a flow chamber containing a vascular ring without endothelium. Flow-stimulated endothelial cells released a diffusible vasodilator, the degree of vasorelaxation was dependent upon the flow rate. Relaxation was abrogated by barium, tetraethylammonium ion, or charybdotoxin, but was not affected by apamin, glybenclamide, tetrodotoxin, or ouabain. The data suggest that transmission of a hyperpolarizing current from endothelium to the vascular smooth muscle is not necessary for flow-mediated vasodilation. Flow activates a potassium channel (possibly the Kc. channel) on the endothelial cell membrane that leads to the release ofnitric oxide. (J. Clin.

/pdf/flow-activates-an-endothelial-potassium-channel-to-release-2dmna6xg42.pdf

Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator.

Diameters of the exposed femoral artery of anesthetized dogs were continuously measured with ultrasonic elements of lead zirconate titanate. In 13 of 16 dogs vascular diameters increased following a sudden increment in arterial blood flow induced by the injection of vasodilating agents (acetylcholine, histamine) peripheral to the recording level, by opening an arteriovenous shunt, or after tetanic stimulation of the sciatic nerve. The dilatation response occurred despite slight reductions in femoral blood pressure, and was present after ganglionic blockade, blockade of alpha and beta receptors with phenoxybenzamine and propranolol, atropinization and injection of an antihistamine. The dilatation response was also observed after transsection of the femoral artery distal to the recording level and is therefore not dependent on the retrograde propagation of nervous or myogenous impulses along the vascular wall.

Local Regulation of Vascular Cross Section during Changes in Femoral Arterial Blood Flow in Dogs

Background—Aortic valve replacement (AVR) is the established treatment for severe aortic stenosis. In response to the long-term results of aortic homografts, stentless porcine valves were introduced as an alternative low-resistance valve. We conducted a randomized trial comparing a stentless with a stented porcine valve in adults with severe aortic stenosis. Methods and Results—The primary outcome was change in left ventricular mass index (LVMI) measured by transthoracic echocardiography and, in a subset, by cardiovascular MR. Measurements were taken before valve replacement and at 6 and 12 months. Patients undergoing AVR with an aortic annulus 25 mm in diameter were randomly allocated to a stentless (n93) or a stented supra-annular (n97) valve. There were no significant differences in mean LVMI between the stentless versus stented groups at baseline (17662 and 18263 g/m 2 , respectively) or at 6 months (14249 and 13145 g/m 2 , respectively), although within-group changes from baseline to 6 months were highly significant. Changes in LVMI measured by cardiovascular MR (n38) were consistent with the echo findings. There was a greater reduction in peak aortic velocity (P0.001) and a greater increase in indexed effective orifice area (P0.001) in the stentless group than in the stented group. There were no differences in clinical outcomes between the 2 valve groups. Conclusions—Despite significant differences in indexed effective orifice area and peak flow velocity in favor of the stentless valve, there were similar reductions in left ventricular mass at 6 months with both stented and stentless valves, which persisted at 12 months. (Circulation. 2005;112:2696-2702.) ortic valve replacement (AVR) is the established treatment for patients with severe aortic stenosis. Tissue valves are commonly employed in the elderly, in whom the risk of bleeding complications is high, and in patients whose lifestyle may preclude anticoagulation. Left ventricular (LV) hypertrophy, a known complication of aortic stenosis, is strongly associated with an increased risk of sudden death, congestive heart failure, and stroke, hence the better outcome of patients whose ventricular hypertrophy regresses after AVR. 1 In a large retrospective study, incomplete regression of LV hypertrophy after AVR has been shown to significantly reduce 10-year survival. 2 Persistent hypertrophy may be due

Randomized Comparison of Stentless Versus Stented Valves for Aortic Stenosis Effects on Left Ventricular Mass

Background:

B-type natriuretic peptide (BNP) is synthesized in cardiac tissue in response to increased wall stress and myocardial hypertrophy.



Aims:

In patients with severe aortic stenosis (AS) we examined the effect of aortic valve replacement (AVR) on plasma BNP and association between BNP and left ventricular mass index (LVMI) preoperatively and in the reverse-remodeling phase twelve months postoperatively. We also examined the correlation between BNP and NYHA-class and between BNP and age.



Methods and Results:

Plasma BNP analyses and echocardiographic measurements were performed preoperatively, before discharge after AVR, and at twelve months in twenty-two patients. BNP was additionally measured at six months. Preoperatively, BNP was 283±45 pg/ml (mean±SEM). Following an immediate postoperative increase (441±38 pg/ml), BNP values decreased towards normal values at six and twelve months (139±25 and 130±18 pg/ml, respectively). LVMI was 206.5±15.8 g/m2 preoperatively and decreased to 119.7±7.2 g/m2 at twelve months with a correlation between LVMI and BNP preoperatively only (r=0.45, p<0.05). There was no correlation between BNP and NYHA-class, whereas BNP correlated to age both pre- and post-operatively.



Conclusion:

We report an increase in plasma BNP in patients with AS. Following a further transient increase postoperatively, BNP levels decreased at six and twelve months after AVR. BNP correlated with LVMI preoperatively, and with age both preoperatively and at twelve months.

https://onlinelibrary.wiley.com/doi/pdf/10.1016/j.ejheart.2005.08.004

The effect of aortic valve replacement on plasma B-type natriuretic peptide in patients with severe aortic stenosis--one year follow-up.

Background:

Patients with aortic stenosis (AS) develop left ventricular remodelling with cardiomyocyte hypertrophy and increased fibrosis. Following aortic valve replacement (AVR) reverse remodelling usually takes place.



Aims:

To examine circulating levels of members of the transforming growth factor (TGF) superfamily and matrix metalloproteinases (MMP), known to have important effects on hypertrophy and extracellular matrix, in patients operated for AS.



Methods:

Circulating levels of activin A, GDF-15, TGF-β3, MMP-2, -3, and -9 were measured in twenty-two patients undergoing AVR preoperatively, and 2 days, six months and 12 months postoperatively. Echocardiography and a six minute walking test evaluated reverse remodelling and physical performance.



Results:

Activin A increased at six (1081.00±98.05 pg/ml, p<0.05) and twelve months (1263.09±141.43 pg/ml, p<0.05) compared to the preoperative value (855.00±76.30 pg/ml) and correlated negatively to physical performance. The preoperative value was also increased compared to controls (639.54±63.05 pg/ml, p<0.05). GDF-15, MMP-3 and -9 were all increased at two days postoperatively (p<0.05). MMP-3 correlated with left ventricular end diastolic dimension (p<0.05). MMP-2 did not change during the study period. TGF-β3 was only slightly reduced at six months postoperatively.



Conclusion:

The observed alteration in circulating levels of members of the TGF-β superfamily and MMPs might play a role in the reverse remodelling process following AVR for AS.

https://onlinelibrary.wiley.com/doi/pdf/10.1016/j.ejheart.2008.09.010

Alterations in circulating activin A, GDF‐15, TGF‐β3 and MMP‐2, ‐3, and ‐9 during one year of left ventricular reverse remodelling in patients operated for severe aortic stenosis

Pulmonary function was studied 3 and 12 months after pulmonary resection for lung cancer in 37 patients, ten of whom had undergone pneumonectomy, 19 lobectomy and eight bilobectomy. The resection was right-sided in 25 cases and left-sided in 12. Tumour site and diameter were registered, arterial blood gases measured and spirometry performed. Three months after all types of resection there was significant decrease in forced vital capacity (FVC), and forced expiratory volume/1 second (FEV1), but not in FEV1/FVC%. At 12 months pneumonectomy had reduced FVC to 58% of predicted values, FEV1 to 50% and FEV1/FVC% to 70%. After lobectomy the corresponding figures were 86%, 73% and 67% and after bilobectomy they were 88%, 78% and 70%. Between 3 and 12 months postoperatively, FVC increased in all groups, significantly in those with lobectomy or bilobectomy (p < 0.01 and 0.05, respectively).

Mons Lie

Papers

Local Regulation of Vascular Cross Section during Changes in Femoral Arterial Blood Flow in Dogs

Randomized Comparison of Stentless Versus Stented Valves for Aortic Stenosis Effects on Left Ventricular Mass

The effect of aortic valve replacement on plasma B-type natriuretic peptide in patients with severe aortic stenosis--one year follow-up.

Alterations in circulating activin A, GDF‐15, TGF‐β3 and MMP‐2, ‐3, and ‐9 during one year of left ventricular reverse remodelling in patients operated for severe aortic stenosis

Pulmonary Function 3–12 Months after Pneumonectomy, Lobectomy or Bilobectomy for Lung Cancer