Left Ventricular Geometry and Hypotension in End-Stage Renal Disease: A Mechanical Perspective
Giovanni de Simone
Laboratory of Echocardiography, Department of Clinical and Experimental Medicine, Federico II University Hospital, School of Medicine, Naples, Italy
Correspondence to Dr. Giovanni de Simone, Laboratory of Echocardiography, Department of Clinical and Experimental Medicine, Federico II University Hospital, School of Medicine via S. Pansini 5, 80131 Naples, Italy. Phone: +39-081-746-2013; Fax: +1-815-346-8802;
ABSTRACT. Hemodynamic and nonhemodynamic factors are implicatedin the maintenance and aggravation of left ventricular (LV)hypertrophy in ESRD. Functional consequences of LV geometryare of substantial importance in patients who undergo dialysisand may contribute to explain the negative outcome related toLV hypertrophy, also in patients without overt coronary heartdisease (CHD). Whereas most patients with eccentric LV hypertrophyhave systolic dysfunction and the underlying CHD imposes progressionof their disease, when overt CHD does not occur to remodel leftventricle, concentric LV geometry is more prevalent in ESRDand functional consequences are different. Concentric LV geometryis very sensitive to abrupt changes of cardiac loading conditionsbecause of increased LV stiffness. Dialysis-related decreasein LV filling pressure reduces Starling forces recruitment andcauses a fall in stroke volume as a result of reduced preload.This fall cannot be compensated by increased contractility,as myocardial mechanics is impaired in concentric LV geometryand no functional reserve can be used. When adequate increasein heart rate is not achieved to compensate reduced stroke volume,cardiac output substantially decreases and hypotension occurs.Occurrence of hypotension in the context of concentric LV geometrymight contribute to reduce repeatedly coronary blood flow supplyin the stiff and thick myocardium and might accelerate myocardialstructural deterioration seen in ESRD. E-mail: simogi@unina.it
Left ventricular (LV) hypertrophy is the most potent markerof cardiovascular risk after aging, as well documented in severallongitudinal studies (1–8). Many factors explain thisclose link (9–12). The predicting power of LV hypertrophyis due to the peculiar characteristics of being both a bioassayof vascular abnormalities (hypertension, increased arterialstiffness, etc.) and a causal risk factor by itself, as it influencescoronary hemodynamics and myocardial oxygen requirement (13).During the evolution of myocardial adaptation to overload, namelypressure overload, LV hypertrophy is also progressively associatedwith structural myocardial abnormalities (14,15), eventuallyresponsible for myocardial dysfunction.
In a scenario surrounding the evolution of cardiovascular disease,from exposition to causal cardiovascular risk factors, up tothe appearance of clinical manifestations of overt adverse event,LV hypertrophy occupies a central position, because it is alreadythe expression of the impending cardiovascular disease, whenthis is not yet clinically evident. To underline this aspect,LV hypertrophy has been nominated as the hallmark of markersof "preclinical cardiovascular disease" (16). Therefore, ascompared with causal risk factors (e.g., arterial hypertension,diabetes, smoking, dyslipidemia, obesity), LV hypertrophy identifiesa condition of disease, which is closer to the end of the naturalevolution of cardiovascular disease (i.e., the clinical appearanceof the adverse event), and, moreover, it directly acceleratesthis evolution.
In addition to hemodynamic determinants, LV hypertrophy hasthe characteristic of being very sensitive to a number of nonhemodynamicstimuli, not necessarily presenting with evident alterationsof BP (17); for instance, the risk of LV hypertrophy in normotensivesubjects clustering obesity, diabetes, and dyslipidemia is similarto, if not higher than, the risk of LV hypertrophy in hypertensivesubjects without other metabolic risk factors (18). This isin part due at least to our inability to determine directlyall aspects of hemodynamic load by the simple measurement ofcuff BP and, possibly, to direct biologic stimuli on the myocardium,which work effectively even independent of hemodynamic overload(19–22).
Hemodynamic and nonhemodynamic factors are implicated in themaintenance and aggravation of LV hypertrophy also in ESRD.Functional implications of LV geometry are of substantial importancein patients who undergo dialysis and may contribute to explainthe negative outcome related to LV hypertrophy, even in patientswithout overt coronary heart disease (CHD). In this review,functional and hemodynamic aspects of LV hypertrophy not associatedwith clinical manifestations of CHD are examined.
From the cardiovascular perspective, in most longitudinal studies,ESRD is considered as one of the possible hard end points inthe evolution of cardiovascular disease (8). Therefore, theprevalence of LV hypertrophy in ESRD is favored by the factthat most patients already have LV hypertrophy as the markerof a severe cardiovascular impairment (7,23–27). Similarto evidence in arterial hypertension (28), the reported highprevalence of LV hypertrophy in ESRD would be even greater ifnormalization of LV mass for body size were done by using heightto the allometric power of 2.7, instead of body surface area(29). Recently, Zoccali et al. (30) showed that normalizationof LV mass for height in m2.7 is significantly more predictiveof cardiovascular outcome in patients with ESRD than normalizationfor body surface area, a measure of body size influenced bybody weight, which fluctuates in dialysis patients.
The peculiarity of ESRD is that this condition adds new stimulito the hemodynamic pattern that generated LV hypertrophy (31).Procedures and consequences of hemodialysis might directly participateto the LV hypertrophy-associated cardiovascular risk in ESRDpatients (26,32–36).
An interesting aspect of LV hypertrophy in ESRD is that prevalenceof LV concentric hypertrophy is remarkably high, despite thesubstantial volume overload (30,37–40). When LV concentricremodeling (i.e., LV concentric geometry without increase inLV mass index over the traditional partition values defininghypertrophy) also is considered as a pathologic modificationof LV geometry, the prevalence of LV concentric pattern mightbe even higher (30). Concentric LV geometry is a natural patternin ESRD that is not always recognized because in most availablestudies, many patients also have overt CHD, which causes myocardiumto remodel to a more eccentric (dilated) geometric pattern.These patients, therefore, present with eccentric LV hypertrophyand systolic dysfunction (41). Evolution in those patients isimposed by the underlying ischemic heart disease. When overtCHD does not occur to remodel the left ventricle, prevalenceof concentric LV geometry has to be higher (41) and the functionalconsequences on LV function different.
In ESRD, hemodynamic pattern is altered by enhancement of bothvolume and pressure overloads. In addition to traditional riskfactors for LV hypertrophy, including arterial hypertension,obesity, diabetes, and, at least indirectly, dyslipidemia, ESRDincreases circulating volume, primarily as a consequence ofrenal failure but also through the fistula and as a consequenceof anemia (26,42). At the same time, ESRD is accompanied, almostinvariably, by increased arterial stiffness (31,43), a potentmarker of arteriosclerotic impairment of arterial walls, whichparticipates, together with the high peripheral resistance,to further increase pressure overload. Eventually, ESRD is aunique condition of exaggerated, combined pressure and volumeoverload that can be controlled only in part. A marked, combinedpressure and volume overload yields the highest degree of LVhypertrophy and structural alteration of myocardium (44,45).
The balance between the two fundamental hemodynamic stimuli(pressure and volume) also determines the predominant type ofgeometric development of the left ventricle. We have identifiedfour different patterns of LV geometry (Figure 1) (46), whichalso correspond to peculiar hemodynamic patterns (44,46). Increasein LV mass can be obtained by increase in LV cavity with symmetricincrease in wall thickness, to maintain the ratio between wallthickness and LV transversal radius (relative wall thickness)normal, producing eccentric LV hypertrophy. For a given BP elevation,under the assumption that myocardial performance is normal,eccentric LV hypertrophy is associated with elevated cardiacoutput and normal total peripheral resistance, BP being sustainedby increased flow output and lack of reduction of (more thanincrease in) peripheral resistance. The two forces, subjectedto Laplace’s principle, end-systolic wall stress (i.e.,myocardial afterload, which is the force that stops LV ejection)and end-diastolic stress (i.e., preload, the diastolic stretchingthat recruits Starling forces) are increased (Figure 2).
Figure 1. Left ventricular (LV) geometric patterns, consequences of different combinations of pressure or/and volume overload. (Bottom Left) The normal condition with normal LV mass and relative wall thickness, normal cardiac output (CO), peripheral resistance (TPR), and end-systolic (ES) and end-diastolic (ED) wall stress (). (Top Left) Concentric LV remodeling. (Bottom Right) Eccentric LV hypertrophy. (Top Right) Concentric LV hypertrophy. Adapted from Ganau et al. (46).
Figure 2. Cascade of events regulating preload. In the top right corner, the Laplace’s principle is schemed.
Increase in LV mass also can be obtained by marked increasein wall thickness with less evident increase in LV cavity thatyields an elevated relative wall thickness and concentric LVhypertrophy (Figure 1). The LV cavity being near normal, inthe presence of normal LV chamber function, cardiac output alsotends to be normal, but total peripheral resistance is elevatedand BP is therefore sustained by increased total peripheralresistance in the presence of normal circulating volume. Becauseof the increased relative wall thickness, wall stress is normal(Figure 2). We also described a pattern called LV concentricremodeling, in which LV walls thicken and LV cavity shrinks,similar to conditions when circulating volume is reduced. Inthis case, cardiac output is reduced and peripheral resistanceis highest, a very unfavorable hemodynamic pattern, associatedwith reduced wall stress (Figure 2), a characteristic that hasbeen recently shown to be associated with high cardiovascularrisk (47).
The functional consequences of LV concentric geometry mightbe particularly important in ESRD, because dialysis might influenceLV pump performance more than normally evaluated, as a resultof rapid changes in loading conditions. LV concentric geometrymight also help in understanding the mechanisms of dialysis-relatedhypotension, a complication reported to be associated with LVhypertrophy (48,49).
In the absence of CHD, as compared with eccentric LV hypertrophy,concentric LV geometry characterizes a more severe impairmentof the cardiovascular system. Concentric LV geometry is in factassociated with more marked vascular alterations in arterialhypertension as well as in ESRD (50,51) and predicts more severeoutcome (52,53).
One of the reasons for the potential harmful effect of concentricLV geometry in patients who have ESRD and undergo dialysis mightbe related to the fact that this geometry is very sensitiveto abrupt change of cardiac loading conditions and thereforecan precipitate severe fluctuations of BP during volume subtraction.Dialysis-induced hypotension is indeed a characteristic of severealteration of LV stiffness, related to the high degree of wallthickening (48).
Role of Myocardial Structural Abnormalities and LV Filling Pressure
In pressure overload hypertrophy, increase in wall thicknessis associated with increased myocardial fibrosis and alterationsof extracellular matrix, impeding normal cardiomyocyte activity(54). These structural alterations are exaggerated in ESRD (55–59).
Many factors participate in the enhanced myocardial fibrosisseen in ESRD; among them, hyperparathyroidism most probablyplays a key role as both an indirect factor, sustaining arterialhypertension, and a direct promoter of fibrosis (56,57,59–62).
As a consequence of severe fibrosis, LV contraction and relaxationbecome harder and slower (15,63–65) and LV compliancedecreases (65). For completing LV filling and achieve a sufficientend-diastolic volume, providing adequate stroke volume, theleft ventricle needs filling pressure higher than normal. Figure 2shows the schematic mechanism of filling. Preload is myocardialend-diastolic stress, subjected to Laplace’s principle,being proportional to LV volume and filling pressure and inverselyrelated to wall thickness.
Patients with ESRD and concentric LV hypertrophy have high fillingpressure and a near normal or mildly increased LV radius, whilemyocardial walls are substantially thicker. Preload, therefore,is about normal, because high end-diastolic pressure compensatesthe increased wall thickness. During dialysis, LV filling pressurevariably decreases because of subtraction of central circulatingvolume (66). The magnitude of such a decrease depends on ultrafiltrationrate (67–69) and may or may not be efficiently compensatedby mechanisms that might tend to increase circulating volume(69–71). Because the left ventricle is stiff, i.e., lesscompliant, the reduction of filling pressure also suggests somevariable decrease in LV end-diastolic volume, which must beassociated with simultaneous and consequent increase in wallthickness (principle of conservation of mass). Figure 3 showsthat in most circumstances, the described morphologic and functionaladaptation to reduced LV filling pressure results in a variabledecrease in preload (end-diastolic stress), with consequentreduction of Starling forces recruitment. If time of volumesubtraction is prolonged enough to allow oncotic forces to restorecirculating volume, then LV preload can be preserved at a levelthat can maintain efficient stroke volume and hypotension canbe prevented. Thus, especially in the presence of concentricLV geometry, slow dialysis sessions are needed to prevent hypotensionfrom occurring. When preload reduction is severe, to preservestroke volume, myocardium might increase contractility (whichresults in a left shift of the Starling curve; Figure 4), butthis might be impossible in the setting of concentric LV geometry.
Figure 4. Starling curves showing effect of preload reduction on stroke volume and the possible compensatory mechanism trough increase in myocardial contractility, a mechanism that is blunted in pressure-overload concentric LV geometry.
Concealed Systolic Dysfunction
Despite the occurrence of normal ejection fraction, concentricLV geometry is almost invariably associated with depressed myocardialperformance, measured at the midwall level, suggesting impairedcontractility (72–74). In the setting of concentric LVgeometry, LV chamber function (i.e., ejection fraction) canbe maintained normal by complex interactions (cross-fiber shorteningand thickening) occurring in the thick myocardium, which compensatethe decreased contractile efficiency of cardiomyocytes (75).In the context of such altered physiology of contraction, asymptomatichypertensive patients with concentric LV geometry, normal ejectionfraction, and impaired midwall mechanics (a near constant association)exhibit depressed LV functional reserve (76), i.e., they cannotincrease their myocardial performance if metabolic requirementsincrease, because their contractility is already expressed atthe highest level, in resting conditions.
Thus, patients with ESRD and concentric LV geometry are unlikelyto compensate dialysis-induced reduction of Starling forceswith increasing contractility. With reduced preload, therefore,stroke volume falls. To maintain cardiac output, heart ratemust increase consistently with the decrease in stroke volume,as the result of sympathetic response. However, often, thisincrease in heart rate does not occur (66,77). Given the inabilityto left-shift the Starling curve, if reduced preload matcheswith impaired heart rate response, then drop of cardiac outputwill result and hypotension occurs (48,78).
In a number of patients with preserved midwall mechanics andmyocardial performance, sympathetic activation-associated hypercontractilityof thick myocardial walls, in the presence of small LV chamberdimension, might cause mid-systolic obstruction at the levelof LV outflow tract (79), another potential cause of hypotension(49). The initial cause will always be a nonsustainable reductionof preload producing drop in stroke volume and activation ofsympathetic response.
Thus, in the reported scenario, in most circumstances, hypotensionis more likely to occur in the context of Starling mechanismmismatch when this is associated with impaired heart rate responseand poor contractile reserve, in the context of LV concentricgeometry. This explains, at least in part, why the risk of hypotensionincreases in the presence of LV hypertrophy (48).
Combination among LV concentric geometry, high LV filling pressure,impaired LV relaxation, and recurrent hypotension can yieldprolonged and repeated insult to myocardium. Hypotension abruptlyreduces coronary perfusion pressure in an anatomic context characterizedby almost constant impaired microcirculation (80–83),even when epicardial arteries are normal (84–86). In addition,in the presence of pressure overload LV hypertrophy, coronaryvasodilator ability is depressed (87,88) and the impairmentof the coronary blood flow reserve is even more evident whenLV geometry is concentric (89,90). Paralleling severe myocardialstructural modifications, coronary microcirculation is evenmore impaired in ESRD than in pressure overload hypertrophy,as a result of concomitant anatomic and functional abnormalities,which are characteristic of this condition (33,57,91–95).Thus, coronary microcirculation does not seem to be able tocompensate sudden changes of blood flow, and, during repeatedhypotensive episodes, accelerated myocardial insult might occur,as a result of overexpression of neurohormones and transcriptionalactivation of fibroblasts (96–98).
Hemodynamic mechanisms underlying progression of LV hypertrophy,and consequent abnormal LV relaxation together with sensitivityto changes of filling pressure on one site and hypotension occurringfor impaired mechanisms of compensation (heart rate and contractility)with abnormal coronary microcirculation on the other site, mayexplain accelerated myocardial structural breakdown often associatedwith ESRD. Attention to LV geometry therefore should be paid,especially when CHD is absent and LV chamber function seemsto be normal.
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Abstract
Introduction
). (Top Left) Concentric LV remodeling. (Bottom Right) Eccentric LV hypertrophy. (Top Right) Concentric LV hypertrophy. Adapted from Ganau et al. (
