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• Extrinsic factors such as air pollution may influence sudden cardiac death.
  Helen C Routledge
  Published on: 23 November 2015
• SUD: product of an abnormally increased amplitude of synchronised metabolic variations?
  Richard G Fiddian-Green
  Published on: 23 November 2015

• Published on: 23 November 2015

  Extrinsic factors such as air pollution may influence sudden cardiac death.

  • Helen C Routledge, SpR Cardiology
  • Other Contributors:
    • Jonathan N Townend

  Dear Editor,

  We would like to congratulate Struthers and colleagues on their recent paper showing that sudden unexpected death in a small group of patients with heart failure is preceded by changes in both cardiac autonomic nervous control and markers of inflammation. [1]

  Their findings lend support to the hypothesis that changes in inflammatory or autonomic status, might determine on which particular da...

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  Dear Editor,

  We would like to congratulate Struthers and colleagues on their recent paper showing that sudden unexpected death in a small group of patients with heart failure is preceded by changes in both cardiac autonomic nervous control and markers of inflammation. [1]

  Their findings lend support to the hypothesis that changes in inflammatory or autonomic status, might determine on which particular day a person with seemingly stable (or even unrecognized) heart disease dies. Factors such as emotional stress, infection, physical activity and ambient temperature may all be important. In addition, strong recent evidence implicates ambient air pollution. Cardiovascular mortality rates increase during episodes of high air pollution and it is postulated that this association is attributable to either a systemic inflammatory response or an influence of inhaled pollutants on the cardiac autonomic nervous system. [2,3]

  Until now, these hypotheses have been open to the criticism that the supporting information is derived from long term studies showing that baseline measures of cardiac autonomic control and inflammation are of prognostic value over succeeding years. [4,5,6] Struthers has provided important preliminary evidence that these influences may indeed exert short term effects.

  A much larger multi-centre study is required, perhaps with even more frequent sampling, to further examine temporal relationships between markers of cardiac autonomic control and inflammation and cardiovascular mortality and morbidity. Simultaneous collection of data on a range of influences, including environmental data such as temperature and ambient air pollution, might allow another more proximal stage in the process culminating in sudden cardiac death to be identified.

  Thus, we might begin to determine the relative importance of those factors, intrinsic or extrinsic, that by determining day to day levels of inflammation and cardiac autonomic control, increase the immediate risk of sudden cardiac death. This is of more than academic interest; factors such as air pollution are eminently modifiable and for those that are not such as infection or seasonal changes in temperature, treatment could be altered.

  References

  (1). Shehab AM, RJ.. McLaren, M. Tavendale, R. Belch, JJF. Struthers, AD. Sudden unexpected death in heart failure may be preceded by short term, intraindividual increases in inflammation and in autonomic dysfunction: a pilot study. Heart 2004; 90:1263-1268.

  (2). Brook RD, Franklin B, Cascio W, Hong Y, Howard G, Lipsett M, et al. Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association. Circulation 2004; 109:2655-2671.

  (3). Routledge HC, Ayres JG, Townend JN. Why cardiologists should be interested in air pollution. Heart 2003; 89:1383-1388.

  (4). La Rovere MT, Bigger JT, Jr., Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 1998; 351:478- 484.

  (5). Nolan J, Batin PD, Andrews R, Lindsay SJ, Brooksby P, Mullen M, et al. Prospective study of heart rate variability and mortality in chronic heart failure: results of the United Kingdom heart failure evaluation and assessment of risk trial (UK-heart). Circulation 1998; 98:1510-1516.

  (6). Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 2002; 105:2595-2599.

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  SUD: product of an abnormally increased amplitude of synchronised metabolic variations?

  • Richard G Fiddian-Green, FRCS, FACS

  Dear Editor,

  I find this a most interesting study for it gets to the nub, what exactly is it that causes SUD in patients with chronic heart failure.

  "During follow up, nine patients died: five patients had a sudden unexpected death (SUD) and four died of progressive heart failure (PHF). There were significant intraindividual changes in neutrophil counts (p = 0.02), C reactive protein (p = 0.039), and h...

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  Dear Editor,

  I find this a most interesting study for it gets to the nub, what exactly is it that causes SUD in patients with chronic heart failure.

  "During follow up, nine patients died: five patients had a sudden unexpected death (SUD) and four died of progressive heart failure (PHF). There were significant intraindividual changes in neutrophil counts (p = 0.02), C reactive protein (p = 0.039), and heart rate variability (p 0.018) in those who died of SUD and PHF. SUD "may be preceded by intraindividual increases in both inflammation and autonomic dysfunction [presumably meaning heart rate variability]. Both may be causal in genesis but, even if they are not, intraindividual increases in either may be convenient markers to identify patients at high risk of impending SUD"[1].

  In an earlier electronic communication I concluded that, "metabolic decompensation in humans will occur when the delivery and uptake of nutrient can no longer keep pace with the rate of ATP hydrolysis dictated by the body temperature"[2] as might have occurred with the inflammatory responses in the patients with SUD in this study. A mechanism, I suggested, might be the putative "exercise factor, IL-6, produced by contracting muscles and released into the blood. "IL-6 stimulates cortisol production, induces lipolysis, and increases temperature presumably by uncoupling oxidative phosphorylation".

  The variable which I have since considered in greater depth [3] is the tissue pH which I have proposed might modulate fluid distribution and balance, partly by modulating renal tubular energetics, and hence myocardial workload. In short a fall in tissue pH might protect the heart by increasing intracellular fluid (ICF)volume, decreasing extracellular fluid (ECF) volume [which should decrease the area of the ventricular pressure-volume loop (P-VL]), and opening the K+(atp) channels [which should also decrease the area of the P-VL further]. Should the cytoprotective effect of cytosolic acidification be compromised, either because a impairment of the residual ATP pool size and/or the resynthesis upon which it it depends, the cytosolic pH should rise and/or not fall as much as it should and the likelihood that the demand for ATP outstripping the capacity for ATP resynthesis increased. Indeed in limiting the opening or inducing the closing of the K+ (atp) channels myocardial workload might also be inappropriately increased.

  Cardiac behaviour is classically defined in terms of the Frank- Starling law which states that "the force of contraction of the cardiac muscle is proportional to its initial length. The energy set free at each contraction is a simple function of cardiac filling. When the diastolic filling of the heart is increased or decreased with a given volume, the displacement of the heart increases or decreases with this volume". A rise in systemic tissue pH might, therefore, be expected to "improve" the Frank -Starling curve or shift it to the left both by limiting the opening of the K+(atp) channels and by increasing ECF volume. Conversely a fall in systemic tissue pH might be expected to have the opposite effect and make the curve "worse" by opening K+(atp) channels and decreasing ECF volume.

  Is not this conventional interpretation back-to-front? In other words is it not better to have to have a low pH, low ECF volume and open K+(atp) channels, the physiological responses to haemorrhagic shock, than a high pH, high ECF volume and closed K+(atp) channels? But hyperkalaemia, which should accompany a fall in tissue pH because of the H+/K+ exchange, increases the risk of developing cardiac arrhythmias and may be cardioprotective if contraction ceases as is well known from the use of potassium cardioplegia. Cardiopulmonary bypass is obviouly needed to maintain peripheral tissue energetics in these circumstances.

  Sympathetic stimulation and/or catecholamine release has in effect the same myocardial actions as a rise in systemic tissue pH in so far as cardiac output is concerned. That is it increases myocardial contractility and cardiac output. If excessive, however, a rise in tissue pH could precipitate tissue eneregtic failure by inhibitng oxidative phosphorylation, stimulating anaerobic glycolysis, and increasing the demand for nutrient dispatch from the heart to sustain a constant level of ATP resynthesis. This could overwhelm the hearts capacity and precipitate an acute fall in availability of the substrate needed to maintain myocardial tissue energetics [5]. The state is analogous to that induced in anaesthetised dogs by a progressive decrease in their FiO2. Cardiac arrest occurred before a gut mucosal intramucosal acidosis developed in these circumstances, but a preterminal fall could have been missed for measurements were only made very 20 minutes[6].

  To what degree then might the effects of autonomic stimulation or an inflammatory response be modulated by or even induced by changes in tissue pH?

  Might the metabolic effects of sympathetic stimulation oppose those of an abnormal fall in tissue pH and parasympathetic stimulation oppose those of an abnormal elevation in tissue pH? A rise in temperature caused by an inflammatory response, which appears to be a feature of anaerobic glycolysis rather than oxidative phosphorylation, can be expected to upregulate oxidative phosphorylation by increasing the protonmotive force, downregulate anaerobic glycolysis certainly if stimulated by an abnormal elevation in tissue pH, and increase ATP output unless limited by substrate dispatch from the heart. What of the possibility of sympathetic stimulation, or rather catecholamine release being induced by an abnormal fall in pH and parasympathtic stimulation being induced by an abnormal rise?

  What then of the relevance of inflammation and autonomic dysfunction to the onset of SUD in heart failure? If by autonomic dysfunction is meant variability in heart rate it might be a reflection of a increase in amplitude of the normal fluctuations in tissue pH and, therefore, indicative of metabolic stress.

  The fluctuation in temperature seen an inflammatory response are very similar and indeed can be expected to be inversely related to any fluctuations in tissue pH solely because of their physical relationship [8]. The degree of any leukocytosis present might even change in parallel be they cause or effect. As these are likely to be accompanied by equally rapid and relatively large fluctuations in serum [K+] and degree of K+(atp) opening the stage is clearly set for SUD.

  References

  (1). A M A Shehab, R J MacFadyen, M McLaren, R Tavendale, J J F Belch, and A D Struthers Sudden unexpected death in heart failure may be preceded by short term, intraindividual increases in inflammation and in autonomic dysfunction: a pilot study Heart 2004; 90: 1263-1268

  (2). Oxygen supply dependency: has it any clinical relevance? Richard G Fiddian-Green (8 September 2004) eLetter re: HJ Silverman, J Abrams, and LJ Rubin Effects of interleukin-2 on oxygen delivery and consumption in patients with advanced malignancy Chest 1988; 94: 816-821

  (3). pH-guided management of fluid distribution and balance and myocardial workload.. Richard G Fiddian-Green (4 November 2004) eLetter re: Shehan Hettiaratchy and Remo Papini Initial management of a major burn: II—assessment and resuscitation BMJ 2004; 329: 101-103

  (4). Frank-Starling law of the heart www.whonamedit.com/synd.cfm/1242.html

  (5). Successful evolutionary adaptation to environmental stress? Richard G Fiddian-Green Heart Online, 14 Jul 2004 eLetter re: D A Lawlor, G Davey Smith, R Mitchell, and S Ebrahim Temperature at birth, coronary heart disease, and insulin resistance: cross sectional analyses of the British women’s heart and health study Heart 2004; 90: 381-388

  (6). Grum CM, Fiddian-Green RG, Pittenger GL, Grant BJ, Rothman ED, Dantzker DR. Adequacy of tissue oxygenation in intact dog intestine. J Appl Physiol. 1984 Apr;56(4):1065-9.

  (7). Reciprocal pH-dependence of myocardial protection and dysfunction. Richard G Fiddian-Green (2 August 2004) eLetter re: Satoshi Ohki, Fumio Kunimoto, Yukitaka Isa, Hiroshi Tsukagoshi, Susumu Ishikawa, Akio Ohtaki, Toru Takahashi, Tetsuya Koyano, Noboru Oriuchi, and Yasuo Morishita Changes in gastric intramucosal pH and circulating blood volume following coronary artery bypass grafting Can J Anesth 2000; 47: 516-521

  (8). Severinghaus JW, Astrup P, Murray JF Blood gas analysis and critical care medicine. Am J Respir Crit Care Med. 1998 Apr;157(4 Pt 2):S114-22.

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  Conflict of Interest:
  None declared.

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