Dear Editor

We read Rizvi et al's article on the status of rheumatic heart disease (RHD) in rural Pakistan with considerable interest.[1]

Rizvi and colleagues highlight an extremely important problem facing cardiologists in Pakistan. However, it is possible that the true prevalence of RHD in this population may have been underestimated as echocardiography was only performed in those with an audible murmur. Although the concordance between auscultation by experienced cardiologists (such as the authors) and echocardiography is fairly robust, auscultation is an operator- dependent skill which is difficult to quantify. Furthermore, very early RHD, particularly mitral valve disease, may be missed even by highly experienced auscultators. The economics of performing an echocardiogram in over 9000 subjects is clearly prohibitive; however, a random echocardiographic verification of a prespecified number of patients deemed to have "no RHD" by auscultation would have enhanced the robustness of this estimate.

Rizvi et al. very appropriately point out the lack of initiative at the government level to take measures to both, reduce the prevalence of this disease as well as improve health care delivery to those afflicted with RHD.

Reference

1. S F Rizvi, M A Khan, A Kundi, D R Marsh, A Samad, and O Pasha Status of rheumatic heart disease in rural Pakistan Heart 2004; 90: 394-399.

Dear Editor

Steve Yentis raises relevant discussion points.[1] A detailed discussion of anaesthetic methods was beyond the scope of the article and Steve's comments regarding the safety of low-dose epidural are welcome.

I agree that assisted vaginal delivery is the safest mode of delivery for most women with heart disease. His comments about instrumental vaginal delivery for women with Marfan syndrome underlines the importance of specialist obstetric units for women with heart disease. However aortic disease in Marfan syndrome does carry a significant risk and elective Caesarean section may still be a safer option outside units with particular expertise in this condition.

Reference

1. S A Thorne. Pregnancy in heart disease. Heart 2004; 90: 450-456.

Dear Editor,

These studies do not exclude the possibility that myocardial protection might be induced independently of K+(atp) changes by priming the protonmotive force needed to drive ATP resynthesis by oxidative phosphorylation [1]. It could be an important consideration for the protonmotive force might be more easily and reliably primed in advance of angioplasty by perfusing the occluded vessel being targeted with an acidic buffer than by occluding the coronary artery for a limited period. Indeed the failure to have demonstrated myocardial protection in this study might have been due to the failure of coronary artery occlusion to have had a consisent and even an appreciable effect upon the intramyocardial pH and the K+(atp) channel opening with which a fall in pH may be associated.

Functional recovery was better in neonatal rabbit hearts perfused with an acidic buffered cardioplegic solution than those perfused with a basic buffered cardioplegic solution [2]. Furthermore there was a significant inverse relationship between functional recovery and intramyocardial pH achieved by the three buffers examined in this study.

Coronary artery occlusion in dogs reduces the ability of the myocardium to produce H+ and CO2 and accordingly the magnitude of the protonmotive force needed to replenish ATP stores upon reperfusion [3]. The accumulation of H+ and CO2 diminishes with repeated occlusions. Furthermore the decrement in H+ accumulation between the first and second occlusions correlates with the duration of occlusion and is related to the impairment of anterior wall systolic shortening present after the first reperfusion period [4]. These studies are consistent with the hypothesis [2] that the ability to replenish ATP stores upon reperfusion is a function of the ability to generate a protonmotive force and that during ischaemia this is an active process, possibly one catalysed by reversal of ATP synthase.

At the Mayo Clinic optimal metabolic protection of the heart in cardiac surgery, defined in terms of improved postoperative outcome in patients, is said to occur when the temperature-corrected integrated mean pH is maintained at 6.8 or higher [5]. This implies that there may be a limit to the cardioprotective benefits likely to be conferred by priming the protonmotive force.

Within 30 minutes of storing human atrial samples in low pH (pH<_7 buffers="buffers" apoptosis="apoptosis" was="was" detected="detected" with="with" proapoptotic="proapoptotic" markers="markers" including="including" exposure="exposure" to="to" phosphatidyl="phosphatidyl" serine="serine" cytochrome="cytochrome" c="c" apoptotic="apoptotic" protease-="protease-" activating="activating" factor-1="factor-1" and="and" caspase-3="caspase-3" _6.="_6." the="the" degree="degree" of="of" present="present" correlated="correlated" intramyocardial="intramyocardial" acidosis="acidosis" present.="present." in="in" a="a" complementary="complementary" study="study" pigs="pigs" having="having" open="open" heart="heart" surgery="surgery" postacidotic="postacidotic" reperfused="reperfused" cardiac="cardiac" tissue="tissue" also="also" ph="ph" dependent="dependent" approximately="approximately" threefold="threefold" greater="greater" than="than" precross-clamp="precross-clamp" levels.="levels." this="this" suggests="suggests" that="that" not="not" only="only" might="might" there="there" be="be" limit="limit" cardioprotective="cardioprotective" benefits="benefits" priming="priming" protonmotive="protonmotive" force="force" but="but" risk="risk" inducing="inducing" permanant="permanant" damage="damage" if="if" exceeded.="exceeded." p="p"/> pH 6.90 is close to the pH 6.86 we found to distiinguish sigmoid mucosa that developed severe ischaemic colitis after aortic surgery from that which did not [7,8]. Importantly in our study we found little correlation between the intramucosal pH and the vascular anatomy and stump pressures present. The inference is that it would be impossible to determine how low the intramyocardial pH might have fallen even with complete occlusion of the LAD as in this study. The failure to have demonstrated any myocardial protection in the present study might, therefore, simply be a reflection of the unpredictable effects of coronary artery occlusion upon intramyocardial pH. Our experience with acute and chronic ischaemia suggests that in some instances the pH might not have fallen at all even with complete occlusion [9].

In hepatocytes in which ATP resynthesis was inhibited some 95% with iodoacetate and KCN the formation of plasma membrane blebs accompanied all types of injury [10]. Cell death was a rapid event initiated by rupture of a plasma membrane bleb coincident with the onset of irreversible injury. An increase of cytosolic free Ca2+ was not the stimulus for bleb formation or the final common pathway leading to cell death. The cytosolic pH fell by more than 1 pH unit during this reductive stress and the acidosis was cytoprotective even though the pH fell well below 6.90. Cell death was more likely to occur in the presence than in the absence of oxygen and mitochondrial oxygen radical formation by complex III was involved in the cell killing [11].

How might the apparently beneficial effects of even a pH less than pH 6.86 be reconciled with the risks of apoptosis and free radical damage? Might it be that apoptosis, an ATP-dependent process, is an altruistic sacrifice intended to protect adjacent cells from the harmful effects of the inflammatory response induced by free radical release and cellular necrosis should it occur? [The absence of an inflammatory response in apoptosis is a striking feature distinguishing it from necrosis]. Might apoptosis even be a physiological stimulus for myocyte renewal [12]?

In other words might the beneficial effects of a progressive increase in the magnitude of the protonmotive force be succeeded by apoptosis when the beneficial effects are exceeded and an unacceptable energy demand/supply imbalance develops? Furthermore might the apoptotic cells then be replaced just as they are in the very dynamic process present in the gut mucosa, the development of a inflammatory response possibly compromising cell renewal? [The answer to this question might lie in a comparison between the scarless healing of wounds in utero and the scarred healing of wounds in adults].

Troponin T cross-linking occurs in human cardiac myocytes concomitantly with both apoptosis and autopsy autolysis [13]. This sugests that the troponin T release, used amongst other things to demonstrate the myocardial protection of ischaemia preconditioning in patients having coronary artery surgery [1], is incapable of distinguishing myocyte apoptosis from necrosis. It is conceivable that troponin T release might even be a passive reflection of the increase in cellular permeability that may occur independently of morphological evidence of cellular injury when the pH falls to abnormally low levels(14).

In conclusion,
1. The effects of coronary artery occlusion on intramyocardial pH are unpredictable
2. It would be easier to control the degree of acidosis induced in preconditoning by using an acidic buffer than by using coronary artery occlusion.
3. Perfusing a stenotic coronary artery being targeted for angioplasty with a very acidotic anoxic buffer might be a better way of limiting the risk of developing ischaemia/reperfusion injury in the myocardium than ischaemic preconditioning.
4. The degree of benefit obtained by priming the protonmotive force can be expected to be inversely related to the degree of dysfunction and apoptosis caused.
5. The dysfunction and apoptosis might be benign and even completely reversible events.
6. Troponin T release might not be a reliable measure of irreversible myocardial damage.

References

(1). Fiddian-Green RG. eLetters re: DP Jenkins, WB Pugsley, AM Alkhulaifi, M Kemp, J Hooper, and DM Yellon Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery Heart 1997; 77: 314-318

(2). Iannettoni MD, Bove EL, Fox MH, Groh MA, Bolling SF, Gallagher KP. The effect of intramyocardial pH on functional recovery in neonatal hearts receiving St. Thomas' Hospital cardioplegic solution during global ischemia. J Thorac Cardiovasc Surg. 1992 Aug;104(2):333-43.

(3). Khuri SF, Axford TC, Garcia JP, Khabbaz KR, Dearani JA, Khait I, Zolkewitz M, Healey NA. Metabolic correlates of myocardial stunning and the effect of cardiopulmonary bypass. J Card Surg. 1993 Mar;8(2 Suppl):262-70.

(4). Warner KG, Khuri SF, Marston W, Sharma S, Butler MD, Assousa SN, Saad AJ, Siouffi SY, Lavin PT. Significance of the transmural diminution in regional hydrogen ion production after repeated coronary artery occlusions. Circ Res. 1989 Mar;64(3):616-28.

(5). Dearani JA, Axford TC, Patel MA, Healey NA, Lavin PT, Khuri SF. Role of myocardial temperature measurement in monitoring the adequacy of myocardial protection during cardiac surgery. Ann Thorac Surg. 2001 Dec;72(6):S2235-43;

(6).Thatte HS, Rhee JH, Zagarins SE, Treanor PR, Birjiniuk V, Crittenden MD, Khuri SF. Acidosis-induced apoptosis in human and porcine heart. Ann Thorac Surg. 2004 Apr;77(4):1376-83.

(7). Fiddian-Green RG, Amelin PM, Herrmann JB, Arous E, Cutler BS, Schiedler M, Wheeler HB, Baker S. Prediction of the development of sigmoid ischemia on the day of aortic operations. Indirect measurements of intramural pH in the colon. Arch Surg. 1986 Jun;121(6):654-60.

(8). Schiedler MG, Cutler BS, Fiddian-Green RG. Sigmoid intramural pH for prediction of ischemic colitis during aortic surgery. A comparison with risk factors and inferior mesenteric artery stump pressures. Arch Surg. 1987 Aug;122(8):881-6.

(9). Fiddian-Green RG, Stanley JC, Nostrant T, Phillips D Chronic gastric ischemia. A cause of abdominal pain or bleeding identified from the presence of gastric mucosal acidosis. J Cardiovasc Surg (Torino). 1989 Sep-Oct;30(5):852-9.

(10). Herman B, Gores GJ, Nieminen AL, Kawanishi T, Harman A, Lemasters JJ. Calcium and pH in anoxic and toxic injury. Crit Rev Toxicol. 1990;21(2):127-48.

(11). Dawson TL, Gores GJ, Nieminen AL, Herman B, Lemasters JJ. Mitochondria as a source of reactive oxygen species during reductive stress in rat hepatocytes. Am J Physiol. 1993 Apr;264(4 Pt 1):C961-7

(12). Swynghedauw B Are adult cardiocytes still able to proliferate? Arch Mal Coeur Vaiss. 2003 Dec;96(12):1225-30.

(13). Gorza L, Menabo R, Di Lisa F, Vitadello M. Troponin T cross- linking in human apoptotic cardiomyocytes. Am J Pathol. 1997 Jun;150(6):2087-97.

(14). A. L. Salzman, H. Wang, P. S. Wollert, T. J. Vandermeer, C. C. Compton, A. G. Denenberg and M. P. Fink Endotoxin-induced ileal mucosal hyperpermeability in pigs: role of tissue acidosis. Am J Physiol Gastrointest Liver Physiol 266: G633-G646, 1994;

Dear Editor,

It would seem, from Boron's [1,2] and our [3,4] data, that the ATP - dependent sodium pump located on the baso-lateral border of most cells might be exquisitely sensitive to the appearance of protons in interstitial fluid coming from contiguous cells under reductive stress. They might even respond by pumping protons into their cytosol and increasing their protonmotive force driving ATP resynthesis by oxidative phosphorylation. In so doing the rate at which protons are removed from their cytosol and ATP is resynthesised will also be increased. Any excess of ATP produced might then become available for diffusion into contiguous myocytes whose capacity to replenish ATP stores might have been compromised.

As the severity of the reductive stress increases the cytoslic, acidois might then increase until a point at which the cells are near maximally stressed. At this point ATP synthase might reverse itself using the energy released by ATP hydrolysis in the mitochondria to increase the degree of cytoslic acidosis further by pumping mitochondrial protons into the cytosol. Temperature may also be increased increasing the rate of ATP resynthesis by increasing the rate of glycolytic turnover, the proportion being resynthesised by anaerobic glycolysis increasing progressively as the degree of dysoxia increases. At some stage a point will be reached with increasing reductive stress further begins to generate free radicals. These may cause myocyte death [5].

Perhaps it is simply the rate and degree of the development of the reductive stress induced by a coronary artery occlusion that precipitates myocyte death. Perhaps its the amount of free radicals produced or both. With increasing degrees of reductive stress survival of the myocytes should become increasingly dependent upon nutrient delivery and uptake as the degree of dysoxia increases until a point is reached at which it can no longer be met by the vasodilated vasculature in amounts that satisfy myocyte needs.

At this point a myocyte buddy system, as in scuba diving, might become operative. In the first instance the more healthy myocytes might assist the less healthy myocytes by providing them with supplementary supplies of ATP or even mopping up the lactate they are producing as their preferred substrate for ATP resyntheisis by oxidative phosphorylation. The healthy cells might also mop up some of the protons and free radicals being produced by the myocytes under stress. If tissue lactate does not accumulate in myocytes under reductive stress anaerobic glycolysis should continue to repleenish ATP stores. Should however, the removal of lactate cease ATP resynthesis in the stressed myocytes should also cease because of a mass action effect. With the apoptosis of myocytes under maximal stress the reverse might occur surving cells cannibalising the apoptotic cells for nutrient that can no longer be delivred in sufficient quantities by blood.

In this manner the onset of apoptosis might first be delayed and then retricted to isolated cells limiting the likelihood of developing dysfunction from large contiguous areas of apoptosis. Isolated apoptotic cells might even be replaced with healthy cells if the blood flow returns to normal levels. Should instead the process proceed too rapidly and be too extensive and/or be irreverible large areas of apoptosis, necrosis and an inflammatory response might develop setting the stage for irreversible myocyte damage and healing by fibrosis.

This is clearly an hyothesis but a credible one based upon accumulated facts addressed in earlier communications to Heart.

References

(1). Boron WF, Waisbren SJ, Modlin IM, Geibel JP Unique permeability barrier of the apical surface of parietal and chief cells in isolated perfused gastric glands. J Exp Biol. 1994 Nov;196:347-60.

(2). Waisbren SJ, Geibel JP, Modlin IM, Boron WF. Unusual permeability properties of gastric gland cells. Nature. 1994 Mar 24;368(6469):332-5.

(3). Dorricott NJ, Fiddian-Green RG, Silen W Mechanisms of acid disposal in canine duodenum. Am J Physiol. 1975 Jan;228(1):269-75.

(4). Fiddian-Green RG, Silen W Mechanisms of disposal of acid and alkali in rabbit duodenum. Am J Physiol. 1975 Dec;229(6):1641-8.

(5). Dawson TL, Gores GJ, Nieminen AL, Herman B, Lemasters JJ. Mitochondria as a source of reactive oxygen species during reductive stress in rat hepatocytes. Am J Physiol. 1993 Apr;264(4 Pt 1):C961-7.