The study by Feistritzer et al. , published in this issue of the Journal of Hypertension, provides some new insights into the mechanisms involved in determining myocardial ischemia. In particular, this study supports the occurrence of an association between aortic stiffness and high-sensitive cardiac troponin (hs-cTnT) concentration at a chronic stage after acute ST-segment elevation myocardial infarction (STEMI). Seventy-four patients with a diagnosis of STEMI and successful reperfusion by primary percutaneous intervention were included in this cross-sectional study.
The introduction of hs-cTnT into clinical practice has allowed the identification of a large proportion of patients with minor cardiac troponin increases. Hs-cTnT indeed has been shown to be able to detect with high accuracy even mild and early cases of myocardial tissue injury [2–4]. It has to be emphasized, however, that the finding of an elevated hs-cTnT indicates myocardial injury, regardless of the cause, that is, not only in case of ischemic injury [5–7]. In fact, although the majority of patients with moderate increase in hs-cTnT do not have myocardial infarction or clinical evidence of coronary artery disease, nevertheless a stepwise rise in mortality with increasing levels of hs-cTnT has been shown, regardless of the underlying cause of cTn increase .
The added value of the study by Feistritzer et al.  is related to the collection of data on the levels of hs-cTnT in patients with coronary artery disease after STEMI, in whom the increase in hs-cTnT could be more likely interpreted as the result of an alteration in myocardial perfusion. This is not the first time that an association between arterial stiffness and myocardial ischemia is reported . Watanabe et al.[9,10] described clear signs of regional myocardial dysfunction and a reduction in coronary reserve flow in the presence of coronary stenosis after mechanical induction of a decrease in aortic compliance. Even in absence of coronary stenoses, decreased aortic compliance was shown to be associated with inadequate subendocardial oxygenation, which could obviously be further deranged in the presence of alterations in coronary circulation.
When considering the factors linking aortic stiffness with an increase in hs-cTnT, it is important to clarify whether the association between myocardial ischemia and aortic stiffness is secondary to an independent action of aortic stiffness on myocardial supply–demand ratio, or rather whether this association depends on the presence of factors able to affect both coronary flow and arterial wall properties. The question, still waiting for an adequate answer, is thus how a stiff aorta might affect myocardial supply flow.
Indeed, a number of studies have shown that aorta and large arteries play a major role in the regulation of blood pressure and peripheral blood flow. It is well known that large arteries have not only a passive function in relation to the transfer of oxygenated blood from the heart to the periphery, but also exert an important buffering function, as they are able to ‘cushion’ left ventricular stroke volume thanks to their viscoelastic properties. In fact, each cardiac cycle includes a left ventricular contraction phase, in which a given amount of blood is forcibly pushed into the arterial system (systole), and a relaxation phase (diastole), in which ventricular filling occurs. Large arteries, therefore, have the task of damping the pulsatile output of the left ventricle and translating the rhythmic, intermittent, and discontinuous activity of the cardiac pump into continuous blood flow. After ejection of stroke volume and closure of the aortic valves, a great quantity of blood remains ‘stored’ in the aorta and large arteries. The potential energy stored in the walls of the aorta in systole then turns into kinetic energy in diastole, pushing the stored blood into the bloodstream (so called ‘Windkessel phenomenon’). Thus the aorta behaves like a sort of ‘pump in diastole’, ensuring the achievement of a proper blood pressure level during the diastolic phase of the cardiac cycle to guarantee adequate flow to the periphery .
A number of conditions such as aging, hypertension, inflammation, media calcifications, and metabolic alterations can change the anatomical, structural, and functional properties of large arteries, thereby degrading their mechanical properties. The resulting alterations in the viscoelastic properties of the arterial system cause a stiffening in the arterial wall and reduced elasticity in the aorta and large arteries. Under these conditions, the amount of stroke volume that is stored by the aorta during the systolic ejection time decreases, even drastically, whereas most of the blood ejected at each systole is ‘pushed’ directly toward the periphery of the vascular system. As a consequence, aortic SBP increases and aortic DBP decreases .
The reduction in DBP in aorta may lead to a reduction in subendocardial diastolic perfusion . Actually subendocardial perfusion occurs mostly during diastole because of the development of extravascular compressive forces during the systolic phase of the cardiac cycle. In the absence of coronary hemodynamically significant stenoses, the diastolic pressure in coronary arteries is equal to diastolic pressure in ascending aorta. Thus, subendocardial coronary flow depends on not only diastolic time, but also aortic diastolic pressure and the pressure gradient in diastole between coronary arteries intravascular pressure and left ventricular pressure.
An increase in SBP, related to an increase in left ventricular afterload, leads to a rise in cardiac work and consequently to an increase in left ventricular mass and myocardial oxygen needs. The development of left ventricular hypertrophy, and progression toward the resulting left ventricular failure, predispose to an increase in left ventricular diastolic pressure and to a prolongation in isometric contraction time, further reducing the diastolic subendocardial pressure gradient and perfusion time. The result of all these processes is a decrease in subendocardial oxygen supply.
Moreover, arterial stiffness causes an increased pulse wave velocity through the arterial elastic system. Therefore, if the forward (centrifugal) pressure wave travels faster owing to increased arterial stiffness, similarly, the backward (centripetal) pressure wave goes back to the center at a higher speed. Thus, under reduced arterial viscoelasticity, the earlier superimposition of the two waves, in the protomesosystolic phase of the cardiac cycle, produces a further increase in SBP values and a reduction in diastolic pressure, resulting in an increased pulse pressure.
Another factor affected by arterial stiffness must be considered, however, besides the increase in pulse pressure, that is, an increase in short-term blood pressure variability. Large studies showed a link between increased arterial stiffness and an increase in short-term blood pressure variability . Among other mechanisms, such an association may be partly due to a reduced sensitivity of the arterial baroreflex, that is, of the most important mechanism for short-term control of blood pressure . This reflex system consists of stretch receptors located in the wall of the aortic arch and in the carotid sinus, at the origin of the internal carotid artery, connected through afferent fibers to neurons in the brainstem, from which efferent influences guarantee reflex sympathetic and parasympathetic modulation of cardiac and vascular targets. Arterial baroreceptors respond to the extent of stretching/relaxation of carotid/aortic arterial walls, rather than directly to changes in the blood pressure values themselves. Thus, baroreflex responsiveness will be reduced in individuals with increased arterial stiffness, whose vessels distend less than more elastic vessels in response to blood pressure changes. This means that the arterial baroreflex function is significantly affected by the degree of distensibility/stiffness of arterial walls, which in turn determines the degree of stretching/relaxation of carotid/aortic walls in response to blood pressure fluctuations .
As a result of the pathophysiological changes mentioned earlier, arterial stiffness may cause an ischemic heart injury through a reduction in subendocardial oxygen supply and/or an increase in subendocardial oxygen demand.
All too often ischemic heart disease is considered synonymous of coronary artery disease, as if coronary atherosclerotic phenomena were the only responsible mechanism for myocardial ischemia. On the contrary, a more correct approach to ischemic heart disease would need to consider all the factors potentially responsible for an ischemic myocardial (in particular subendocardial) injury, beside atherosclerotic coronary stenosis. Among them we should consider myocardial oxygen requirements, myocardial (subendocardial) flow supply, as well as the arterial oxygen content. In order to better understand the link between arterial stiffness and myocardial ischemia, it is thus necessary to consider ischemic heart disease through a very broad perspective, namely, as the complex balance between subendocardial oxygen supply and demand.
A useful index in the assessment of cardiac ischemic risk was introduced by Gerald David Buckberg at the beginning of the 1970s [12,15], and named subendocardial viability ratio [SEVR, also known as Buckberg's index or diastolic pressure–time index : systolic pressure–time index (DPTI : SPTI) ratio]. This index reflects the subendocardial oxygen supply–demand ratio and can be defined by analyzing left ventricular and aortic pressure curves (Fig. 1).
The area under the left ventricular (or aortic) pressure curve in systole (SPTI), from the onset of ventricular systole to the dicrotic notch, represents the left ventricle afterload and defines cardiac work [16,17]. If mean arterial pressure during the systolic phase in ascending aorta is high, the left ventricle must contract more energetically to maintain adequate stroke volume. Thus, SPTI directly correlates with myocardial oxygen consumption, and mainly depends on left ventricular ejection time, ejection pressure, and myocardial contractility.
The area between the aortic and left ventricular pressure curves in diastole represents the pressure that affects the coronary blood flow and maintains adequate subendocardial blood supply in the diastolic phase of cardiac cycle (DPTI). During the systolic phase, blood supply to the subendocardial layers is not allowed, owing to the presence of two extravascular compressive forces. The first force is left ventricular intracavity pressure, which is fully transmitted to the subendocardial layers, but which falls off to almost zero at the epicardium. The second one is the force developed during left ventricular contraction itself leading to coronary vascular occlusion. The overall compressive force exerted on coronary blood vessels is higher in the subendocardium, where it is similar to the pressure within the left ventricle. Thus, blood flow to subendocardial fiber layers is virtually absent in systole, even though subepicardial layers remain normally perfused. Along this line, experimental studies clearly showed that a reduction in aortic distensibility alters the transmural myocardial blood flow distribution of left ventricle and decreases the subendocardial/subepicardial flow ratio . During the diastolic phase, the degree of myocardial perfusion largely depends on DPTI, which in turn is a function of the coronary arterial diastolic pressure , the pressure gradient in diastole between coronary arteries and left ventricular pressure, and the duration of diastole .
The DPTI : SPTI ratio thus represents the balance between oxygen subendocardial supply and demand. In the elderly and in the presence of aortic stiffness, these two parameters significantly change (SPTI increases and DPTI decreases) and the subendocardial oxygen supply–demand ratio (DPTI : SPTI) is greatly reduced, as clearly shown in Fig. 1, a finding that highlights the possible usefulness of subendocardial oxygen supply–demand ratio assessment in clinical practice. However, the need in the past of an invasive arterial catheterization for its estimate has for a long time represented a major limitation for its application in a clinical setting.
The introduction of transcutaneous arterial tonometry has provided a new approach to noninvasively determine the subendocardial oxygen supply–demand ratio through a simple and easily implementable test. Actually, applanation tonometry is at present considered the reference method for noninvasive estimation of central blood pressure and central pulse wave analysis. The devices using this method that are currently available provide values of Buckberg's index on the basis of the morphological analysis of the central arterial pressure wave recorded by the tonometer itself. In the context of DPTI : SPTI ratio assessment by transcutaneous tonometry, DPTI represents the area under the diastolic portion of the blood pressure wave, and is obtained by multiplying the mean value of blood pressure during the diastolic phase of cardiac cycle by the diastolic time. Conversely, SPTI represents the area under the systolic portion of the pressure wave, obtained by multiplying the mean value of blood pressure during the systolic phase of cardiac cycle by the left ventricular ejection time (Fig. 2, right panels).
However, the assessment of DPTI : SPTI ratio based only on pulse waveforms recorded by arterial tonometers is affected by a number of important limitations. First, a correct estimation of the oxygen demand by the myocardium cannot ignore the muscle mass or contractility. Actually, an increase in muscular mass, such as in left ventricular hypertrophy, increases the oxygen needs. Thus, in order to improve the estimation of SPTI, recently, Hoffman and Buckberg  suggested to multiply SPTI by the relative left ventricular mass as determined by echocardiography. Second, left ventricular diastolic pressure is not taken into account by this approach. In patients with heart failure or cardiac valve disease, characterized by increase in left ventricular diastolic pressure, this limitation leads to overestimate the DPTI value when only focusing on tonometry data. Finally, only left ventricular ejection time is taken into account when analyzing tonometric pulse waveforms to calculate this ratio, whereas left ventricle isovolumic contraction time is not considered in the determination of systolic left ventricular function, with a consequent underestimation of SPTI (Figs. 1 and 2). On the other hand, left ventricle isovolumic contraction time is considered in DPTI determination, even though this parameter should actually be considered as a component of cardiac workload and not as an oxygen supply time, with the consequent result of an overestimation of DPTI. As the isovolumic contraction time/ejection time ratio increases significantly in the elderly and in heart failure, the tonometry method may overestimate the DPTI : SPTI ratio in these patients by even 80–100% with regard to its real value, as shown in Fig. 2.
These methodological aspects may have affected the studies performed so far on SEVR. Despite tonometric SEVR being calculated in all epidemiological studies estimating arterial stiffness, there are indeed very few articles reporting data on the relationship between SEVR and cardiovascular disease. Likely, this could be at least in part the consequence of the above-reported inaccuracies affecting the measurement of DPTI : SPTI ratio. Conversely, no major interferences are to be expected when considering the result of recent studies reporting significant changes in SEVR after acute exposure at high altitude [21,22], including a report on the possible link between the reduction of SEVR and the appearance of signs and symptoms of a reduced coronary reserve in this setting . In these studies, in fact, only relatively young and overall healthy individuals were evaluated, in whom the contribution of isovolumic contraction time to cardiac work may be considered negligible.
Overall, on the background of the above methodological issues related to the estimate of Buckberg's index based only on arterial tonometry data, the current approach seems to provide a relatively unreliable surrogate assessment of the real subendocardial oxygen supply–demand ratio. Further studies are thus needed in order to improve this noninvasive approach to detection of critical reductions in subendocardial oxygen supply–demand ratio. As an example, a more reliable estimate of SEVR might be achieved by combining use of arterial tonometry with a cardiac ultrasound assessment.
In conclusion, the study of Feistritzer et al.  highlights the contribution given by changes in vascular hemodynamics to the occurrence of ischemic heart injury, providing further evidence on the occurrence of a link between increased arterial stiffness and increased likelihood of ischemic myocardial lesions. Based on these data, aortic stiffness indeed appears to be an important factor affecting subendocardial oxygen supply–demand balance, and thus it should be considered more than just an independent risk factor for coronary artery disease. On the contrary, ischemic heart disease should then be considered not only the result of a vascular atherosclerotic process affecting coronary arteries, but rather the result of a complex interaction among local coronary atherosclerotic damage, changes in vascular hemodynamics, oxygen arterial content, and the oxygen requirements of myocardial cells. According to this suggestion, in daily clinical practice, assessment of aortic distensibility (either through MRI or more simply by measuring carotid–femoral pulse wave velocity) would thus need to be included among the tests recommended to screen for the risk of heart disease. In particular, on the background of these considerations, an imbalance between myocardial flow supply and demand should be always considered in the evaluation of patients with chronic myocardial ischemia.
Conflicts of interest
P.S. is a consultant for DiaTecne s.r.l., manufacturers of systems for analyzing the arterial pulse.
1. Feistritzer H-J, Klug G, Reinstadler SJ, Mair J, Seidner B, Mayr A, et al. Aortic stiffness is associated with elevated high-sensitivity cardiac troponin T concentrations at a chronic stage after ST-segment elevation myocardial infarction. J Hypertens
2. Reichlin T, Hochholzer W, Bassetti S, Steuer S, Stelzig C, Hartwiger S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med
3. Keller T, Zeller T, Peetz D, Tzikas S, Roth A, Czyz E, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med
4. Melki D, Lugnegard J, Alfredsson J, Lind S, Eggers KM, Lindahl B, et al. Implications of introducing high-sensitivity cardiac troponin T into clinical practice: data from the SWEDEHEART Registry. J Am Coll Cardiol
5. Newby LK, Jesse RL, Babb JD, Christenson RH, De Fer TM, Diamond GA, et al. ACCF 2012 expert consensus document on practical clinical considerations in the interpretation of troponin elevations: a report of the American College of Cardiology Foundation task force on Clinical Expert Consensus Documents. J Am Coll Cardiol
6. Agewall S, Giannitsis E, Jernberg T, Katus H. Troponin elevation in coronary vs. noncoronary disease. Eur Heart J
7. Thygesen K, Mair J, Katus H, Plebani M, Venge P, Collinson P, et al. Recommendations for the use of cardiac troponin measurement in acute cardiac care. Eur Heart J
8. O’Rourke MF. How stiffening of the aorta and elastic arteries leads to compromised coronary flow. Heart
9. Watanabe H, Ohtsuka S, Kakihana M, Sugishita Y. Decreased aortic compliance aggravates subendocardial ischaemia in dogs with stenosed coronary artery. Cardiovasc Res
10. Watanabe H, Ohtsuka S, Kakihana M, Sugishita Y. Coronary circulation in dogs with an experimental decrease in aortic compliance. J Am Coll Cardiol
11. Salvi P. Pulse waves: how vascular hemodynamics affects blood pressure. Milan: Springer; 2012.
12. Hoffman JI, Buckberg GD. The myocardial supply:demand ratio: a critical review. Am J Cardiol
13. Schillaci G, Bilo G, Pucci G, Laurent S, Macquin-Mavier I, Boutouyrie P, et al. Relationship between short-term blood pressure variability and large-artery stiffness in human hypertension: findings from 2 large databases. Hypertension
14. Parati G, Di Rienzo M, Mancia G. How to measure baroreflex sensitivity: from the cardiovascular laboratory to daily life. J Hypertens
15. Buckberg GD, Fixler DE, Archie JP, Hoffman JI. Experimental subendocardial ischemia in dogs with normal coronary arteries. Circ Res
16. Sarnoff SJ, Braunwald E, Welch GH Jr, Case RB, Stainsby WN, Macruz R. Hemodynamic determinants of oxygen consumption of the heart with special reference to the tension-time index. Am J Physiol
17. Gutterman DD, Cowley AW Jr. Relating cardiac performance with oxygen consumption: historical observations continue to spawn scientific discovery. Am J Physiol Heart Circ Physiol
18. Fokkema DS, Van Teeffelen JW, Dekker S, Vergroesen I, Reitsma JB, Spaan JA. Diastolic time fraction as a determinant of subendocardial perfusion. Am J Physiol Heart Circ Physiol
19. Indolfi C, Ross J Jr. The role of heart rate in myocardial ischemia and infarction: implications of myocardial perfusion-contraction matching. Prog Cardiovasc Dis
20. Hoffman JI, Buckberg GD. The myocardial oxygen supply:demand index revisited. J Am Heart Assoc
21. Salvi P, Revera M, Faini A, Giuliano A, Gregorini F, Agostoni P, et al. Changes in subendocardial viability ratio with acute high-altitude exposure and protective role of acetazolamide. Hypertension
22. Caravita S, Faini A, Bilo G, Revera M, Giuliano A, Gregorini F, et al. Ischemic changes in exercise ECG in a hypertensive subject acutely exposed to high altitude. Possible role of a high-altitude induced imbalance in myocardial oxygen supply-demand. Int J Cardiol