Myocardial ischemia in aortic stenosis: Insights from arterial pulse-wave dynamics after percutaneous aortic valve replacement

TR

E N D S I N

CA

R D I OVA S C U L A R

M

E D I C I N E

23 (2013) 185–191

Available online at www.sciencedirect.com

www.elsevier.com/locate/tcm

Review article

Myocardial ischemia in aortic stenosis: Insights from arterial pulse-wave dynamics after percutaneous aortic valve replacement$, $$ Christopher J. Broyd, Sayan Sen, Ghada W. Mikhail, Darrel P. Francis, Jamil Mayet, and Justin E. Davies International Centre for Circulatory Health, National Heart and Lung Institute, 59-61 North Wharf Road, London W2 1LA, UK

artic le info

abstract

Article history:

Wave-intensity analysis is a technique that can qualify both the direction and magnitude

Received 2 October 2012

of the forces accelerating and decelerating coronary blood flow and is derived from

Received in revised form

simultaneously acquired measures of coronary pressure and velocity using invasive

1 December 2012

intracoronary wires. Using this technique during TAVI, the dominant force (or ‘wave’)

Accepted 3 December 2012

acting to increase the coronary blood flow which originates from microvascular relaxation

Available online 8 February 2013

is shown to be elevated in severe aortic stenosis and decreased post-implantation. Additionally, with increasing heart rate a progressive fall in the magnitude of this wave is noted and after TAVI this effect is reversed (returning towards the physiological norm). The potential causes of myocardial ischemia in aortic stenosis are clearly multi-factorial but this observation suggests a decoupling between the aorta and myocardium in aortic stenosis, the effects of which are magnified during increased heart rate. & 2013 Elsevier Inc. All rights reserved.

Introduction Calcific aortic stenosis (AS) is the most common reason for aortic valve replacement in developed countries and affects 2–3% of individuals by the age of 65 (Lindroos et al., 1993). As the disease state progresses, it is associated with left ventricular hypertrophy (LVH) which is initially a compensatory mechanism to maintain ejection fraction but ultimately results in myocardial ischemia.

Abbreviations: LVH,

The presence of myocardial ischemia has been demonstrated in animal models and humans using both noninvasive and invasive techniques. Until recently, the ‘benchmodel’ for AS in humans has been those patients undergoing conventional aortic valve replacement (AVR) for whom measurements can be taken pre- and post-operatively. However, the recent expansion of transcatheter valve therapy in the treatment of AS has also provided a new potential platform for its investigation.

left ventricular hypertrophy; AS, aortic stenosis; TAVI,

valve replacement; CFR,

coronary flow reserve; LV, left ventricular; TOE,

transcatheter aortic valve implantation; AVR,

aortic

transoesophageal echocardiography; PET, positron

emission tomography; VTI, velocity time integral $ Funding sources: supported by the NIHR Biomedical Research Centre funding scheme. Dr Broyd is funded by the British Heart Foundation. Dr Davies and Dr Francis are British Heart Foundation fellows. Dr Sen is an MRC fellow. $$ Contributorship: all authors contributed to, read and approved this manuscript. Corresponding author. Tel.: þ44 7594 1100; fax: þ44 207 411 8656. E-mail address: [email protected] (C.J. Broyd). 1050-1738/$ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.tcm.2012.12.001

186

T

R E N D S I N

CA

R D I OVA S C U L A R

With the development of coronary wave-intensity analysis, an in vivo assessment of the myocardial contribution to coronary flow has recently been applied to a group of patients with severe AS undergoing transcatheter aortic valve implantation (TAVI) both before and after valve deployment. The requirement of a temporary pacing wire for the procedure also provides the opportunity to physiologically stress the heart. Using pacing wire-generated increases in heart rate, favorable changes in the wave-intensity profile can be seen after TAVI. Ultimately, these objective measures of the burden of aortic stenosis may prove to be useful in timing the surgery or valve implantation.

Existing experimental evidence for myocardial ischemia in AS In patients with severe AS and angiographically unobstructed coronary arteries, angina is reported in 30–40% and is a marker of severity, increasing the risk of sudden death (Kelly et al., 1988). Recent evidence also shows that the risk of sudden cardiac death also exists in those without symptoms and is related to the severity of the stenotic lesion and therefore to the burden of myocardial ischemia (Rosenhek et al., 2010). This microvascular dysfunction may be a major component in the progression to heart failure (Vatner and Hittinger, 1993) and generation of ventricular arrhythmias (Levy et al., 1987) and has been demonstrated by a number of investigative tools. It was initially noted in invasive studies of humans (Fallen et al., 1967) and animals (Griggs et al., 1973) with AS and no angiographic disease where a relative increase in lactic acid production was detected with pharmacological stimulation. Additionally, thallium scans of patients with significant AS and normal coronary arteries often demonstrates perfusion deficits (Kupari et al., 1992). CFR, as obtained from the coronary sinus thermodilution technique, (Julius et al., 1997) or through invasive (Marcus et al., 1982) or non-invasive coronary Doppler (Hildick-Smith and Shapiro, 2000), has been shown to be significantly reduced in patients with severe AS and anginal symptoms compared to both asymptomatic patients with severe AS and controls; this improves when reassessed 12 months after valve replacement (Eberli et al., 1991). Quantitative myocardial contrast echocardiography has shown myocardial blood flow in the subendocardium, but not in the subepicardium, to be reduced in patients with aortic stenosis (Galiuto et al., 2006) with a sustained improvement in subendocardial blood flow after aortic valve replacement (Miyagawa et al., 2009). PET scanning in AS has demonstrated reduced myocardial perfusion and has confirmed it is most severe in the subendocardial layer. The severity of CFR impairment has been linked by PET to aortic valve area, imposed hemodynamic load and diastolic perfusion time rather than left ventricular mass (Rajappan et al., 2002, 2003).

Coronary wave-intensity analysis Despite these interesting findings, there are some limitations to measuring myocardial ischemia in these ways. Whilst

ME

D I C I N E

23 (2013) 185–191

changes in flow patterns can demonstrate and quantify the burden aortic stenosis places on the myocardium, it is unable to qualify the origin of this burden. A more recent technique to investigate coronary artery hemodynamics is waveintensity analysis. This combines simultaneously acquired measures of both coronary pressure and flow, and derives an index that represents the direction and magnitude of energy transferred to the blood within the artery. Therefore, by taking into account changes in pressure as well as flow, wave-intensity analysis quantifies (in terms of magnitude) AND qualifies (in terms of origin of this force) the burden of aortic stenosis. Because of the complex physiology involved in coronary artery flow, where changes in flow velocity can be attributed to either the proximal (aortic) or distal (myocardial) end of the vessel, this technique provides more information than measuring either pressure or velocity in isolation. For example, blood flow may accelerate down the coronary artery either because of a forward traveling force ‘pushing’ blood down the artery or from a backward originating force ‘sucking’ blood toward the myocardium. Likewise, blood flow will decelerate if a retrograde force is applied to it and this may also originate from either the myocardial or aortic end of the artery (Fig. 1). Using this technique in humans, Davies et al. (2006) have previously demonstrated the presence of six waves across a single cardiac cycle (Fig. 2). Of these, two dominate: the forward-traveling ‘pushing’ wave generated by the increase in aortic pressure during systole and the backward-traveling decompression (or suction) wave that occurs with myocardial relaxation in diastole. When these waves are examined in conjunction with their corresponding flow and pressure data, it is clear that the systolic forward-traveling compression wave causes a large increase in coronary pressure but coronary flow is attenuated by a corresponding rise in microcirculatoryoriginating pressure from left ventricular contraction. Conversely, with the backward-traveling suction wave there is a fall in both myocardial and aortic pressures but coronary flow increases. During this phase, the acceleration in coronary blood flow comes from relaxation of the myocardium and is caused by decompression of the microcirculatory vessels previously compressed by systolic ventricular contraction.

Fig. 1 – Schematic diagram demonstrating the four potential waves responsible for coronary acceleration and deceleration. The acceleration of blood (A) can be driven either by a compression wave from the aorta or an expansion wave from the myocardium. Likewise, the deceleration of blood (B) can be driven by an aorta-originating expansion wave or a myocardial-originating compression wave. Reproduced with permission from Davies et al. (2006).

TR

E N D S I N

CA

R D I O VA S C U L A R

M

E D I C I N E

23 (2013) 185–191

187

Fig. 2 – Coronary wave-intensity analysis in a normal coronary artery. Six waves are demonstrated: (1) Early backwardtraveling pushing wave—caused by the onset of ventricular contraction and microcirculatory compression. (2) Dominant forward-traveling ‘pushing’ wave—caused by the systolic ejection of blood into the aorta and a rise in aortic pressure. (3) Late backward-traveling pushing wave—continued compression of the microcirculation and wave reflection. (4) Forward-traveling suction wave—slowing of ventricular contraction creates a suction effect from the aorta. (5) Dominant backward-traveling ‘suction’ wave—myocardial relaxation re-opens the microcirculation, generating a suction wave responsible for coronary flow. (6) The late forward-traveling compression wave—caused by closure of the aortic valve. Reproduced with permission from Davies et al. (2006).

Wave-intensity analysis in aortic stenosis during TAVI Wave-intensity analysis has been employed in patients with normal aortic valves and LVH, and the backward-traveling suction wave is attenuated in this scenario (Davies et al., 2006). However, in LVH generated by severe AS the suction wave is markedly increased. This apparent difference between patients with aortic stenosis and those without, with similar degrees of LVH, identifies both increased ventricular contractility (in AS), and detrimental relaxation due to LVH as being distinct (but inseparable) adverse contributors to coronary hemodynamics (Davies et al., 2011). Wave-

intensity analysis during TAVI offers the possibility for the effects of increased afterload with AS to be separated from LVH. Echocardiographic measures of AS severity were also associated with the magnitude of the backward-traveling suction wave (r ¼ 0.59, p ¼ 0.05). With valve implantation and afterload reduction there was an immediate and dramatic reduction in the backward-traveling suction wave (Fig. 3). Additionally, by increasing the patient’s heart rate prior to valve deployment with the temporary pacing wire it is possible to create a model of exercise-induced myocardial stress to further investigate these patients. With a heart rate of 120 bpm, the suction wave falls; this is contrary to that seen in animal models without aortic stenosis (Sun et al., 2000) and

188

T

R E N D S I N

CA

R D I OVA S C U L A R

ME

D I C I N E

23 (2013) 185–191

these proposed concepts are based on studies of LVH induced by obstruction after the origin of the coronary vessels (e.g. aortic banding or hypertension) and as AS produces pressure changes before their origin these results should be interpreted cautiously (although they may still be applicable). For this reason, the TAVI procedure provides one of the most realistic models of AS and allows us to gain novel insights into the etiology of myocardial ischemia in humans, and the separation of increased afterload and left ventricular hypertrophy.

Increased perivascular compression and decoupling of the mechanisms of coronary perfusion In humans, there is a linear correlation between coronary resistance and left ventricular end diastolic pressure (LVEDP) (Opherk et al., 1984). Invasive studies in animals (O’Gorman et al., 1992) and humans (Eberli et al., 1991) have shown an elevated LVEDP and associated higher coronary resistance in severe AS which falls after AVR. However, the reduction in coronary reserve is proportionally greater than the increase in LVEDP thereby reinforcing the multi-factorial nature of this problem. Studies with PET scanning in adults have shown a strong correlation between CFR and the left ventricular load (Rajappan et al., 2002, 2003). Using wave-intensity analysis in the TAVI model, as described previously, Davies et al. (2011) propose a change in the coupling of the normal mechanisms governing coronary flow with severe aortic stenosis. In normal hearts, a delicate balance exists during exercise between the increase in the microcirculation systolic compression and corresponding diastolic suction wave, and a maintained aortic pressure. With severe aortic stenosis, this mechanism is decoupled and with exercise, coronary perfusion pressure is decreased as a result.

Decreased density of coronary vessels in hypertrophied myocardium

Fig. 3 – Wave-intensity analysis before and after TAVI at resting heart rate. The backward-traveling ‘suction’ wave is increased pre-TAVI compared to individuals without aortic stenosis. After TAVI this wave is dramatically decreased reflecting the reduction in myocardial work required to eject blood past a stenosed aortic valve. Reproduced with permission from Davies et al. (2011).

in humans during exercise (Lockie et al., 2012). Immediately after TAVI, this situation is reversed and the suction wave increases in response to an increasing heart rate. Correspondingly, the volume of coronary blood flow per cardiac cycle (coronary VTI) before TAVI is also seen to decrease with pacing; after TAVI, the coronary VTI remains constant.

On a macroscopic level, the size of the large coronary arteries, as seen at quantitative angiography in humans, increases with LVH and after AVR the artery size returns to normal (Villari et al., 1992). At the microvascular level, changes in the vascular bed do not appear to parallel myocyte growth in LVH. In pig (Breisch et al., 1986) and dog (Mueller, 1978) models of LVH with impaired CFR, anatomical studies showed that hypertrophy causes a reduction in endomyocardial capillary density, although this is less evident at one year (Bishop et al., 1996). A similar relative reduction in cardiac vessel growth during hypertrophy has also been demonstrated in rats by assessing cardiac cyclic-GMP (cGMP) kinase levels (which is involved in the regulation of vascular smooth muscle tone) (Ecker et al., 1989). In humans, autopsy studies of patients with LVH secondary to AS have shown a decrease in coronary capillary density in comparison with controls (Rakusan et al., 1992).

Cause of myocardial ischemia in aortic stenosis

Prolongation of systole with shortening of diastole

Using the above experimental models, several potential mechanisms have been suggested in the etiology of myocardial ischemia in AS. It is important to acknowledge that some of

AS results in an increased LV ejection time and the severity of aortic stenosis is proportional to this (Bache et al., 1973). As most coronary flow occurs in diastole, increasing the ratio of

TR

E N D S I N

CA

R D I O VA S C U L A R

systole to diastole causes a reduction in the time available for oxygen delivery. PET scans of patients with LVH pre- and post-AVR for AS have confirmed this change and conclude that the improvement in the coronary microcirculation after aortic valve replacement is, at least partly, due to an increase in diastolic perfusion time (Rajappan et al., 2002, 2003).

Increased diffusion distance from capillary to centre of hypertrophied myocardial cells Because the increase in myocardial mass is mediated through hypertrophy and not hyperplasia, the blood supply to individual muscle cells is also altered by LVH. Several studies have shown an increased diffusion distance from individual capillaries to the centre of the cell (Just et al., 1996; Zhu et al., 1996). The pressure within these myocardial cells is also increased (Carpeggiani et al., 2008) and these factors will impair oxygen transfer. However, these findings are not supported in all studies (Anversa et al., 1986).

Relatively low aortic pressures Classical teaching on aortic stenosis states that the severity of the disease is linked with a narrow and low pulse pressure. It has therefore been suggested that the reduced coronary pressure during diastole would reduce coronary flow in severe aortic stenosis (Skalidis and Vardas, 2008). However, an abnormal pulse pressure as a marker, or association, of severity has been refuted in some studies: between 22% and 40% of the patients requiring valve replacement have a systolic blood pressure of more than 130 mm Hg (Das et al., 2000) and diastolic blood pressure is not seen to change after TAVI (Gotzmann et al., 2010). More extensive work has recently shown that pulse pressure in severe aortic stenosis does not differ from age-matched controls and only falls in these patients as systolic function declines (Lodge et al., 2011).

Endothelial dysfunction Structural changes in coronary vasculature may not fully account for the reduction in coronary reserve and there may, in fact, be a change at the endothelial level as well. For example, coronary reserve has been shown to be reduced in hypertensive patients (Antony et al., 1993; Brush et al., 1988) and animal models (Rodriguez-Porcel et al., 2006) prior to the development of LVH. Rats with LVH produce less coronary nitric oxide synthase, another reflection of endothelial dysfunction (Crabos et al., 1997). Guinea pigs with LVH (induced by aortic banding) have impaired coronary relaxation in response to endothelial-dependent and -independent agents (McGoldrick et al., 2007).

Increase in coronary vessel wall thickness Structural changes in the vascular bed occurring as a result of left ventricular hypertrophy have been suggested to affect blood flow, oxygen handling and transfer. In guinea pig (Kingsbury et al., 2000; McGoldrick et al., 2007; Mihaljevic et al., 2003) and rat (Brilla et al., 1991; Kalkman et al., 1996;

M

E D I C I N E

23 (2013) 185–191

189

Tomanek et al., 1985) models, the thickness of the coronary vessel wall in relation to the lumen size increases in LVH. However, there are reasons to suggest that this mechanism is less likely to be involved in the generation of myocardial ischemia in AS. Firstly, this histological finding has not been reproduced in ventricular biopsies taken from humans with left ventricular hypertrophy (Opherk et al., 1984) or in pig models (Breisch et al., 1986). More specifically, autopsy specimens from patients with LVH secondary to AS do not show intramyocardial arteriole wall thickening but do in LVH secondary to hypertension. It also remains debatable as to whether medial hypertrophy impairs oxygen transfer as no difference in the relaxation response to pharmacological agents has been seen in hypertrophied mesenteric rat arteries compared to controls (Boonen et al., 1993).

Conclusion Myocardial ischemia is evident in patients with aortic stenosis as demonstrated by a wide variety of investigative tools. The most recent of these employs wave-intensity analysis during the TAVI procedure to provide a novel mechanism for identifying detrimental alterations in coronary hemodynamics with aortic stenosis that are exacerbated by an increasing heart rate. Myocardial ischemia is the cause of angina in AS with normal coronary arteries. It is also involved in the etiology of arrhythmias, heart failure and sudden death associated with severe AS even in asymptomatic patients. However, the presence or development of symptoms in the context of severe aortic stenosis, particularly dyspnea or angina, is notoriously subjective and therefore identifying patients who have developed ‘critical’ myocardial ischemia can be difficult. Wave-intensity analysis is a novel tool that may ultimately provide a more objective complementary measure of myocardial ischemia and may have a future role in timing aortic valve intervention. Additionally, in patients with severe aortic stenosis without symptoms it may quantify cardiac burden and aid in the timing of surgery or implantation, thereby avoiding any detrimental delays in outflow tract relief (Fig. 4). Aortic stenosis leads to the development of LVH which increases the oxygen requirements of the myocardium disproportionately to that of coronary vessel supply. The key mechanisms through which this is mediated are a decoupling of the aortic and microcirculatory hemodynamic forces, an increase in the perivascular compression secondary to increased muscle mass, and prolongation of systole in relation to diastole. This is also reflected in the immediate reduction in morbidity and mortality following aortic valve replacement, despite the relatively slow LVH remodeling that occurs. There is also a relative reduction in the capillary density in the hypertrophied muscle which is likely to be contributory at least in the initial stages of LVH development. Coronary endothelial dysfunction is obvious in hypertension-induced LVH but it is not clear if this can be applied to AS-driven LVH given that the pressure of hypertension originates after the coronary sinuses. There is also some evidence to show thickening within the medial layer of coronary vessels in LVH secondary to hypertension but this is

T

R E N D S I N

CA

R D I OVA S C U L A R

Time

Point of reversed physiological reserve (x intercept)

Optimum operative period

Increasing operative risk

Proposed start of wave-intensity-guided surgical work up

Development of symptoms

Physiological Reserve (Pacedsuction wave– resting suction wave)

190

Fig. 4 – Proposed model demonstrating the use of waveintensity analysis in guiding aortic valve intervention. Currently, patients are usually put forward for aortic valve replacement or implantation when they develop symptoms. However, symptom development only occurs when myocardial ischemia is established and by this time there is a chance that irreversible myocardial damage has occurred or will do so whilst waiting for any proposed intervention. A more useful strategy may involve intervention occurring at the point just prior to the development of myocardial ischemia and this is possible if the wave intensity is measured. The point at which the suction wave measured during increased heart rate (such as during exercise) is equal in intensity to the resting suction wave is the ‘tipping point’ of physiological reserve and just prior to this is the optimum time to approach surgery. unlikely to be involved in the development of myocardial ischemia, if it even occurs in AS. Finally, given that the aortic pressure is often preserved or even elevated in aortic stenosis, particularly in elderly patients with less elastic arteries, it seems debatable that this plays a consistent role in the pathogenesis of myocardial ischemia. In summary, myocardial ischemia in aortic stenosis is a key process involved in the morbidity and mortality of this condition. Its reversal is of paramount importance, particularly in patients who develop symptoms relating to ischemia or heart failure. Ultimately, more accurate measures of myocardial ischemia may allow outcome predictions on an individual basis and perhaps in future will help guide therapeutic interventions. More particularly, the clinical application of wave-intensity analysis could be used to provide an objective measure of physiological significance of AS severity for an individual at the myocardial level.

ref eren ces

Antony I, Nitenberg A, Foult JM, Aptecar E. Coronary vasodilator reserve in untreated and treated hypertensive patients with and without left ventricular hypertrophy. Journal of the American College of Cardiology 1993;22:514–20. Anversa P, Ricci R, Olivetti G. Coronary capillaries during normal and pathological growth. Canadian Journal of Cardiology 1986;2:104–13.

ME

D I C I N E

23 (2013) 185–191

Bache RJ, Wange YANG, Greenfield JC. Left ventricular ejection time in valvular aortic stenosis. Circulation 1973;47:527–33. Bishop SP, Powell PC, Hasebe N, Shen YT, Patrick TA, Hittinger L, et al. Coronary vascular morphology in pressure-overload left ventricular hypertrophy. Journal of Molecular and Cellular Cardiology 1996;28:141–54. Boonen HCM, Daemen MJAP, Eerdmans PHA, Fazzi GE, van Kleef EM, Schiffers PMH, et al. Mesenteric small artery changes after vasoconstrictor infusion in young rats. Journal of Cardiovascular Pharmacology 1993;22:388–95. Breisch EA, White FC, Nimmo LE, Bloor CM. Cardiac vasculature and flow during pressure-overload hypertrophy. American Journal of Physiology—Heart and Circulatory Physiology 1986;251:H1031–7. Brilla CG, Janicki JS, Weber KT. Impaired diastolic function and coronary reserve in genetic hypertension. Role of interstitial fibrosis and medial thickening of intramyocardial coronary arteries. Circulation Research 1991;69:107–15. Brush JE, Cannon RO, Schenke WH, Bonow RO, Leon MB, Maron BJ, et al. Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. New England Journal of Medicine 1988;319:1302–7. Carpeggiani C, Neglia D, Paradossi U, Pratali L, Glauber M, L’Abbate A. Coronary flow reserve in severe aortic valve stenosis: a positron emission tomography study. Journal of Cardiovascular Medicine 2008;9:893–8. Crabos M, Coste P, Paccalin M, Tariosse L, Daret D, Besse P, et al. Reduced basal NO-mediated dilation and decreased endothelial NO-synthase expression in coronary vessels of spontaneously hypertensive rats. Journal of Molecular and Cellular Cardiology 1997;29:55–65. Das P, Pocock C, Chambers J. The patient with a systolic murmur: severe aortic stenosis may be missed during cardiovascular examination. Quarterly Journal of Medicine 2000;93:685–8. Davies JE, Sen S, Broyd C, Hadjiloizou N, Baksi J, Francis DP, et al. Arterial pulse wave dynamics after percutaneous aortic valve replacement/clinical perspective. Circulation 2011;124: 1565–72. Davies JE, Whinnett ZI, Francis DP, Manisty CH, Aguado-Sierra J, Willson K, et al. Evidence of a dominant backwardpropagating ‘‘suction’’ wave responsible for diastolic coronary filling in humans, attenuated in left ventricular hypertrophy. Circulation 2006;113:1768–78. Eberli FR, Ritter M, Schwitter J, Bortone A, Schneider J, Hess OM, et al. Coronary reserve in patients with aortic valve disease before and after successful aortic valve replacement. European Heart Journal 1991;12:127–38. Ecker T, Gobel C, Hullin R, Rettig R, Seitz G, Hofmann F. Decreased cardiac concentration of cGMP kinase in hypertensive animals. An index for cardiac vascularization? Circulation Research 1989;65:1361–9. Fallen EL, Elliott WC, Gorlin RICH. Mechanisms of angina in aortic stenosis. Circulation 1967;36:480–8. Galiuto L, Lotrionte M, Crea F, Anselmi A, Biondi-Zoccai GGL, De Giorgio F, et al. Impaired coronary and myocardial flow in severe aortic stenosis is associated with increased apoptosis: a transthoracic Doppler and myocardial contrast echocardiography study. Heart 2006;92:208–12. Gotzmann M, Hehen T, Germing A, Lindstaedt M, Yazar A, Laczkovics A, et al. Short-term effects of transcatheter aortic valve implantation on neurohormonal activation, quality of life and 6-minute walk test in severe and symptomatic aortic stenosis. Heart 2010;96:1102–6. Griggs DM, Chen CC, Tchokoev VV. Subendocardial anaerobic metabolism in experimental aortic stenosis. American Journal of Physiology—Legacy Content 1973;224:607–12. Hildick-Smith DJR, Shapiro LM. Coronary flow reserve improves after aortic valve replacement for aortic stenosis: an

TR

E N D S I N

CA

R D I O VA S C U L A R

adenosine transthoracic echocardiography study. Journal of the American College of Cardiology 2000;36:1889–96. Julius BK, Spillmann M, Vassalli G, Villari B, Eberli FR, Hess OM. Angina pectoris in patients with aortic stenosis and normal coronary arteries: mechanisms and pathophysiological concepts. Circulation 1997;95:892–8. Just H, Frey M, Zehender M. Calcium antagonist drugs in hypertensive patients with angina pectoris. European Heart Journal 1996;17:20–4. Kalkman EAJ, Bilgin YM, Haren Pv, Suylen RJv, Saxena PR, Schoemaker RG. Determinants of coronary reserve in rats subjected to coronary artery ligation or aortic banding. Cardiovascular Research 1996;32:1088–95. Kelly TA, Rothbart RM, Cooper CM, Kaiser DL, Smucker ML, Gibson RS. Comparison of outcome of asymptomatic to symptomatic patients older than 20 years of age with valvular aortic stenosis. American Journal of Cardiology 1988;61:123–30. Kingsbury MP, Turner MA, Flores NA, Bovill E, Sheridan DJ. Endogenous and exogenous coronary vasodilatation are attenuated in cardiac hypertrophy: a morphological defect? Journal of Molecular and Cellular Cardiology 2000;32:527–38. Kupari M, Virtanen KS, Turto H, Viitasalo M, Manttari M, Lindroos M, et al. Exclusion of coronary artery disease by exercise thallium201 tomography in patients with aortic valve stenosis. American Journal of Cardiology 1992;70:635–40. Levy D, Anderson KM, Savage DD, Balkus SA, Kannel WB, Castelli WP. Risk of ventricular arrhythmias in left ventricular hypertrophy: the Framingham Heart study. American Journal of Cardiology 1987;60:560–5. Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. Journal of the American College of Cardiology 1993;21:1220–5. Lockie TPE, Rolandi MC, Guilcher A, Perera D, De Silva K, Williams R, et al. Synergistic adaptations to exercise in the systemic and coronary circulations that underlie the warm-up angina phenomenon. Circulation 2012;126:2565–74. Lodge F, Broyd CJ, Milton P, Mikhail GW, Mayet J, Davies JE, et al. Low pulse pressure in aortic stenosis indicates poor left ventricular function but not severe aortic stenosis. European Journal of Echocardiography 2011;12(Suppl 2):ii159–90 Ref type: Abstract. Marcus ML, Doty DB, Hiratzka LF, Wright CB, Eastham CL. Decreased coronary reserve—a mechanism for angina pectoris in patients with aortic stenosis and normal coronary arteries. New England Journal of Medicine 1982;307:1362–6. McGoldrick RB, Kingsbury M, Turner MA, Sheridan DJ, Hughes AD. Left ventricular hypertrophy induced by aortic banding impairs relaxation of isolated coronary arteries. Clinical Science 2007;113:473–8. Mihaljevic T, Paul S, Cohn LH, Wechsler A. Pathophysiology of aortic valve disease. In: Cohn LH, editor. Cardiac surgery in the adult. New York: McGraw-Hil; 2003. p. 791–810.

M

E D I C I N E

23 (2013) 185–191

191

Miyagawa S, Masai T, Fukuda H, Yamauchi T, Iwakura K, Itoh H, et al. Coronary microcirculatory dysfunction in aortic stenosis: myocardial contrast echocardiography study. Annals of Thoracic Surgery 2009;87:715–9. Mueller TM. Effect of renal hypertension and left ventricular hypertrophy on the coronary circulation in dogs; 1978. O’Gorman DJ, Thomas P, Turner MA, Sheridan DJ. Investigation of impaired coronary vasodilator reserve in the guinea pig heart with pressure induced hypertrophy. European Heart Journal 1992;13:697–703. Opherk D, Mall G, Zebe H, Schwarz F, Weihe E, Manthey J, et al. Reduction of coronary reserve: a mechanism for angina pectoris in patients with arterial hypertension and normal coronary arteries. Circulation 1984a;69:1–7. Rajappan K, Rimoldi OE, Camici PG, Bellenger NG, Pennell DJ, Sheridan DJ. Functional changes in coronary microcirculation after valve replacement in patients with aortic stenosis. Circulation 2003;107:3170–5. Rajappan K, Rimoldi OE, Dutka DP, Ariff B, Pennell DJ, Sheridan DJ, et al. Mechanisms of coronary microcirculatory dysfunction in patients with aortic stenosis and angiographically normal coronary arteries. Circulation 2002;105:470–6. Rakusan K, Flanagan MF, Geva T, Southern J, Van Praagh R. Morphometry of human coronary capillaries during normal growth and the effect of age in left ventricular pressureoverload hypertrophy. Circulation 1992;86:38–46. Rodriguez-Porcel M, Zhu XY, Chade AR, Amores-Arriaga B, Caplice NM, Ritman EL, et al. Functional and structural remodeling of the myocardial microvasculature in early experimental hypertension. American Journal of Physiology—Heart and Circulatory Physiology 2006;290: H978–84. Rosenhek R, Zilberszac R, Schemper M, Czerny M, Mundigler G, Graf S, et al. Natural history of very severe aortic stenosis. Circulation 2010;121:151–6. Skalidis EI, Vardas PE. Coronary blood flow and flow reserve in aortic stenosis: effect of aortic valve therapy. Hellenic Journal of Cardiology 2008;49:379–81. Sun YH, Anderson TJ, Parker KH, Tyberg JV. Wave-intensity analysis: a new approach to coronary hemodynamics. Journal of Applied Physiology 2000;89:1636–44. Tomanek RJ, Wangler RD, Bauer CA. Prevention of coronary vasodilator reserve decrement in spontaneously hypertensive rats. Hypertension 1985;7:533–40. Vatner SF, Hittinger L. Coronary vascular mechanisms involved in decompensation from hypertrophy to heart failure. Journal of the American College of Cardiology 1993;22:A34–40. Villari B, Hess OM, Meier C, Pucillo A, Gaglione A, Turina M, et al. Regression of coronary artery dimensions after successful aortic valve replacement. Circulation 1992;85:972–8. Zhu YH, Zhu YZ, Spitznagel H, Gohlke P, Unger T. Substrate metabolism, hormone interaction, and angiotensinconverting enzyme inhibitors in left ventricular hypertrophy. Diabetes 1996;45:S59–65.