The Vicious Cycle of Dialysis-induced Cardiac Injury—Are Dynamic Changes in Diastolic Function Involved?

Abstract

Related Article, p. 549 Related Article, p. 549 Cardiac dysfunction is a major contributor to the high mortality rates seen in patients with kidney failure treated by hemodialysis.1Sarnak M.J. Levey A.S. Epidemiology of cardiac disease in dialysis patients.Semin Dial. 1999; 12: 69-76Crossref Scopus (68) Google Scholar From a patient's point of view, the attendant symptoms of dyspnea, fatigue, and exercise intolerance, which negatively affect quality of life, are equally important. The development of uremic cardiomyopathy is complex, but is characterized by structural remodeling at macroscopic and cellular levels that results in changes in ventricular function.2Gross M.L. Ritz E. Hypertrophy and fibrosis in the cardiomyopathy of uremia—beyond coronary heart disease.Semin Dial. 2008; 21: 308-318Crossref PubMed Scopus (131) Google Scholar Eventually these processes lead to systolic contractile dysfunction, often with attendant changes in cardiac gross anatomy. However, abnormalities of diastolic function occur much earlier in the natural history of uremic cardiomyopathy.3Levin A. Singer J. Thompson C.R. Ross H. Lewis M. Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention.Am J Kidney Dis. 1996; 27: 347-354Abstract Full Text PDF PubMed Scopus (643) Google Scholar, 4Silberberg J.S. Barre P.E. Prichard S.S. Sniderman A.D. Impact of left ventricular hypertrophy on survival in end-stage renal disease.Kidney Int. 1989; 36: 286-290Crossref PubMed Scopus (746) Google Scholar Diastolic dysfunction encompasses a variety of morphologic and functional abnormalities that are characterized best by left ventricular (LV) hypertrophy (LVH) and myocardial fibrosis, which increase ventricular stiffness and impair its ability to relax during diastole. The resultant increase in ventricular pressure has important consequences. This increased pressure is transmitted to the pulmonary capillary bed and may result in symptoms of heart failure despite a normal ejection fraction. The leftward shift in the LV pressure-volume curve means that relatively small increases in volume status (typically seen with the inevitable interdialytic accumulation of salt and water) can precipitate pulmonary congestion. Although systolic dysfunction confers a particularly bleak prognosis, abnormalities of diastolic function and the presence of LVH are also strongly associated with poor patient outcomes and characteristically are present in the setting of advanced chronic kidney disease.5Iwabuchi Y. Ogawa T. Inoue T. Otsuka K. Nitta K. Elevated E/E' predicts cardiovascular events in hemodialysis patients with preserved systolic function.Intern Med. 2012; 51: 155-160Crossref PubMed Scopus (23) Google Scholar Ventricular filling during diastole is critical to efficient cardiac function and is determined by the relationship between LV filling pressures and the physical properties of the ventricle. These properties include ventricular compliance, the ability of the myocardium to relax, and diastolic “untwisting” (torsional recoil). The latter is linked directly to the “twisting” of the ventricle (torsion) during systole. The release of this potential energy and untwisting during diastole creates a suction effect that promotes ventricular filling,6Torrent-Guasp F. Ballester M. Buckberg G.D. et al.Spatial orientation of the ventricular muscle band: physiologic contribution and surgical implications.J Thorac Cardiovasc Surg. 2001; 122: 389-392Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar as well as producing the transmural strain gradient essential for providing the suction to drive myocardial perfusion.7Davies J.E. Whinnett Z.I. Francis D.P. et al.Evidence of a dominant backward-propagating “suction” wave responsible for diastolic coronary filling in humans, attenuated in left ventricular hypertrophy.Circulation. 2006; 113: 1768-1778Crossref PubMed Scopus (306) Google Scholar Most obviously, structural changes such as LVH or myocardial fibrosis reduce compliance and lead to increased intraventricular pressures. However, there are several other processes that may interfere with diastolic functioning. Dyssynchronous relaxation between different ventricular regions can further contribute to a delay in overall relaxation time.8Yu C.M. Zhang Q. Yip G.W. et al.Diastolic and systolic asynchrony in patients with diastolic heart failure: a common but ignored condition.J Am Coll Cardiol. 2007; 49: 97-105Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar Extrinsic factors (eg, pericardial disease) and reductions in torsion/torsional recoil may also be important. Demand or chronic ischemia and the effects of reperfusion can impair relaxation by triggering changes at a cellular level that interfere with myocyte inactivation (possibly mediated by slower cytosolic calcium removal).9Carroll J.D. Hess O.M. Hirzel H.O. Krayenbuehl H.P. Exercise-induced ischemia: the influence of altered relaxation on early diastolic pressures.Circulation. 1983; 67: 521-528Crossref PubMed Scopus (123) Google Scholar, 10McKenney P.A. Apstein C.S. Mendes L.A. et al.Increased left ventricular diastolic chamber stiffness immediately after coronary artery bypass surgery.J Am Coll Cardiol. 1994; 24: 1189-1194Abstract Full Text PDF PubMed Scopus (64) Google Scholar Therefore, dynamic changes in ventricular relaxation as a consequence of demand ischemia may impair the diastolic changes that usually promote coronary filling, providing the basis for a vicious cycle of dialysis-induced cardiac ischemia. Interestingly, Casper Franssen's group has demonstrated early changes in myocardial perfusion during a hemodialysis session at a point before significant ultrafiltration had been achieved.11Dasselaar J.J. Slart R.H.J.A. Knip M. et al.Haemodialysis is associated with a pronounced fall in myocardial perfusion.Nephrol Dial Transplant. 2009; 24: 604-610Crossref PubMed Scopus (118) Google Scholar Although clearly of significant clinical relevance, the assessment of diastolic function is particularly challenging in hemodialysis patients due to the load-dependent nature of echocardiographic measurements.12Ie E.H. Zietse R. Evaluation of cardiac function in the dialysis patient—a primer for the non-expert.Nephrol Dial Transplant. 2006; 21: 1474-1481Crossref PubMed Scopus (17) Google Scholar With abnormal diastolic function, Doppler measurements of transmitral flow velocity classically show that early mitral flow velocity (E) is decreased in the face of increased intraventricular pressure, resulting in increased reliance on atrial filling (A) and a reduced E:A ratio. However, volume expansion (as seen immediately before hemodialysis) and the resultant increase in preload can elevate mitral inflow (E) despite supraphysiologic ventricular pressures, which can result in underestimation of diastolic dysfunction. Conversely, hemodialysis with ultrafiltration causes a decrease in effective circulating volume to the extent that cardiac chamber size and stroke volume are reduced by the end of treatment; such dramatic declines in filling pressure will exaggerate reductions of E and E:A ratio. A decrease in early mitral flow velocity (E) after hemodialysis is well described and, along with changes in other measures of diastolic function, usually is attributed solely to changes in volume. Certainly, associations between such measurements and ultrafiltration volumes are well reported.13Pecoits-Filho R. Bucharles S. Barberato S.H. Diastolic heart failure in dialysis patients: mechanisms, diagnostic approach, and treatment.Semin Dial. 2012; 25: 35-41Crossref PubMed Scopus (69) Google Scholar Unfortunately, the hopes that alternative methods such as tissue Doppler imaging, which measures peak tissue velocity around the mitral annulus during early (e′) and late (a′) diastole, would be load-independent have not been borne out.14Hung K.C. Huang H.L. Chu C.M. et al.Evaluating preload dependence of a novel Doppler application in assessment of left ventricular diastolic function during hemodialysis.Am J Kidney Dis. 2004; 43: 1040-1046Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar In this issue of AJKD, Assa et al15Assa S. Hummel Y.M. Voors A.A. et al.Changes in left ventricular diastolic function during hemodialysis sessions.Am J Kidney Dis. 2013; 62: 549-556Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar (with Franssen as senior author) attempt to shed more light on the acute effects of hemodialysis on diastolic function, on a background of the burgeoning evidence of hemodialysis-induced cardiac injury. It is now accepted that the circulatory stress of hemodialysis can induce acute reversible segmental myocardial hypoperfusion that results in regional systolic contractile dysfunction (myocardial stunning). When this process occurs repetitively, the injury is cumulative and leads to permanent systolic dysfunction.16McIntyre C.W. Effects of hemodialysis on cardiac function.Kidney Int. 2009; 76: 371-375Crossref PubMed Scopus (123) Google Scholar, 17McIntyre C.W. Haemodialysis-induced myocardial stunning in chronic kidney disease—a new aspect of cardiovascular disease.Blood Purif. 2010; 29: 105-110Crossref PubMed Scopus (106) Google Scholar, 18Selby N.M. McIntyre C.W. The acute cardiac effects of dialysis.Semin Dial. 2007; 20: 220-228Crossref PubMed Scopus (133) Google Scholar Assa et al15Assa S. Hummel Y.M. Voors A.A. et al.Changes in left ventricular diastolic function during hemodialysis sessions.Am J Kidney Dis. 2013; 62: 549-556Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar now report the results of a study in which diastolic function was measured during hemodialysis (in addition to pre- and postdialysis measurements) and compared with several different markers of volume status (relative blood volume, ultrafiltration rate/volume, and brain natriuretic peptide). More than 100 prevalent patients were studied, among whom diastolic dysfunction was extremely common (present in 71% in predialysis assessments, a time when diastolic dysfunction can be underestimated). Consistent with previous studies, the authors saw significant decreases in early mitral inflow (E and E:A ratio) in response to hemodialysis, but noted that these changes occurred early, within the first hour of treatment. Similar decreases were seen with tissue Doppler measurements of e′. Changes in E were associated significantly with changes in both relative blood volume and brain natriuretic peptide level, confirming that reductions in preload exert important effects. However, despite the similarly large changes in tissue Doppler velocity (e′), associations with markers of volume status were much less apparent, which raises the intriguing possibility that some of the changes in diastolic function seen during hemodialysis may have an alternative cause. This was supported further because only weak associations existed between indexes of diastolic function and ultrafiltration volume and rate, although the lack of echocardiography at end of hemodialysis (240 minutes) may have affected this. There are some weaknesses of this study. The authors appropriately acknowledge the potential pitfalls of relative blood volume measurements; nonetheless, this study provides a more comprehensive assessment of volume status in relation to this issue than any previous report. Some degree of doubt exists that studying patients during the first hemodialysis session after the 2-day gap is the optimal timing to study these changes because there may be increased effects of volume status on echocardiographic measurements. However, this was a deliberate decision, reflecting the fact that larger ultrafiltration volumes are a major driver of hemodialysis-induced cardiac stress (at least when looking at regional contractile function).16McIntyre C.W. Effects of hemodialysis on cardiac function.Kidney Int. 2009; 76: 371-375Crossref PubMed Scopus (123) Google Scholar, 17McIntyre C.W. Haemodialysis-induced myocardial stunning in chronic kidney disease—a new aspect of cardiovascular disease.Blood Purif. 2010; 29: 105-110Crossref PubMed Scopus (106) Google Scholar, 18Selby N.M. McIntyre C.W. The acute cardiac effects of dialysis.Semin Dial. 2007; 20: 220-228Crossref PubMed Scopus (133) Google Scholar Finally, changes in systolic functioning were not measured in parallel with measurements of diastolic function. This may have provided some interesting insights about the interaction of hemodialysis-induced changes in ventricular function over the entire cardiac cycle because it does not seem sensible to regard diastolic dysfunction in isolation. Although there is little doubt that changes in volume are of prime importance, it is possible to hypothesize that other factors feasibly may affect diastolic function during hemodialysis. Hemodynamic changes are relevant: in addition to effects on pre- and afterload, the increase in heart rate described by Assa et al15Assa S. Hummel Y.M. Voors A.A. et al.Changes in left ventricular diastolic function during hemodialysis sessions.Am J Kidney Dis. 2013; 62: 549-556Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar leads to reduced ventricular filling time. In health, this is combated by increased diastolic “suction” (more torsional recoil and faster relaxation), but the acute changes that hemodialysis exerts on systolic function may prevent such adaptations. Hemodialysis-induced subclinical ischemia has the potential to interfere with relaxation at a cellular level, as well as to reduce synchrony between different ventricular regions. The previously demonstrated early decreases in myocardial perfusion that occur during hemodialysis and mirror the timing of diastolic changes in the present study may be relevant in this regard.11Dasselaar J.J. Slart R.H.J.A. Knip M. et al.Haemodialysis is associated with a pronounced fall in myocardial perfusion.Nephrol Dial Transplant. 2009; 24: 604-610Crossref PubMed Scopus (118) Google Scholar It is also possible that the increase in ionized calcium levels seen during the present study (using a dialysate calcium ion concentration of 1.5 mmol/L) could affect relaxation through effects on myocyte cytosolic calcium. While providing new insights, the study by Assa et al15Assa S. Hummel Y.M. Voors A.A. et al.Changes in left ventricular diastolic function during hemodialysis sessions.Am J Kidney Dis. 2013; 62: 549-556Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar also raises several questions. How do the acute changes in diastolic function relate to hemodialysis-induced regional contractile dysfunction? To what extent is myocardial hypoperfusion responsible? Do acute changes in diastolic function during hemodialysis translate into long-term reductions in cardiac function? To further appreciate the interaction between cardiac relaxation, myocardial ischemia, and segmental systolic function, this important early study will need to be supplemented by additional investigations that use more highly developed imaging techniques able to simultaneously define wall strain, perfusion, and synchrony of contraction and relaxation (such as tagged cardiac magnetic resonance imaging in conjunction with the newly developed contrast-free based perfusion methods).19McIntyre C.W. Odudu A. Eldehni M.T. Cardiac assessment in chronic kidney disease.Curr Opin Nephrol Hypertens. 2009; 18: 501-506Crossref PubMed Scopus (22) Google Scholar, 20Odudu A. Francis S.T. McIntyre C.W. MRI for the assessment of organ perfusion in patients with chronic kidney disease.Curr Opin Nephrol Hypertens. 2012; 21: 647-654Crossref PubMed Scopus (17) Google Scholar However, regardless of the technique employed, it is clear that the deleterious impact of the hemodialysis process on cardiac function is rapidly evolving into a major focus for further study in the quest to improve the lives of hemodialysis patients. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests. Changes in Left Ventricular Diastolic Function During Hemodialysis SessionsAmerican Journal of Kidney DiseasesVol. 62Issue 3PreviewLeft ventricular diastolic dysfunction is common in hemodialysis patients and is associated with worse outcome. Previous studies have shown that diastolic function worsens from pre– to post–dialysis session, but this has not been studied during hemodialysis. We studied the evolution of diastolic function parameters early and late during hemodialysis. Full-Text PDF