Left ventricular diastolic dysfunction in chronic kidney disease and anaesthesia implications

Abstract

Left ventricular diastolic dysfunction is frequently noticed in patients with chronic kidney disease. Echocardiography is used to determine the presence and severity of diastolic dysfunction. In left ventricular diastolic dysfunction the ventricular diastolic distensibility, filling or relaxation is abnormal; however, the left ventricular ejection fraction may be normal or decreased. In heart failure with preserved ejection fraction, the patients have symptomatic pulmonary congestion even though the systolic ejection fraction is more than 50%. This condition is commonly associated with ventricular diastolic dysfunction. Increased incidence of major adverse cardiovascular events has been reported in surgical patients having grade III diastolic dysfunction. Peri-operatively haemodynamic instability and fluid overload in this set of patients is known to generate pulmonary oedema.

Key Words: Chronic kidney disease; Diastolic dysfunction; Anaesthesia; Heart failure; 2-Dimensional echocardiography

Core Tip: The extent of diastolic dysfunction in renal failure patients is increasingly gaining interest. Its implications on progress of chronic kidney disease and vice versa are known as cardiorenal syndrome. These patients present with heart failure inspite of adequate ejection fraction. These patients sometimes have pulmonary oedema during weaning of from ventilator. Various pharmcotherapeutic agents have been found useful in preserving contractility of heart.

INTRODUCTION

Patients with chronic kidney disease (CKD) often have cardiovascular disease which accounts for approximately 40% of the deaths in patients with CKD stage 4 and 5[1]. Long standing hypertension, chronic fluid overload and uraemia in these patients lead to diffuse interstitial myocardial fibrosis, abnormal myocardial relaxation and myocyte death[2,3]. This reduction in left ventricular compliance leads to higher left ventricular filling pressures during diastole causing left ventricular diastolic dysfunction. Diastolic dysfunction is considered the underlying pathophysiology for heart failure with preserved ejection fraction[4]. Diastolic dysfunction is sensitive to impaired perfusion and hence is also an indicator of ischaemia in early stages[5]. In the initial stages, diastolic dysfunction is compensated by increased left atrial pressures. As diastolic dysfunction increases the symptoms of exertional dyspnoea and exercise intolerance appear which can be confused with chronic obstructive pulmonary disease. This subset of patients sometimes develop haemodynamic instability and pulmonary oedema postoperatively.

PATHOPHYSIOLOGY AND ASSESSMENT

Ventricular diastole consists of four stages: Isovolumetric relaxation; Passive ventricular filling; Diastasis; Atrial contraction.

Anatomically the duration of diastole is from closing of aortic valve to closure of mitral valve. However, at the molecular level it starts during systole when the actin-myosin cross bridges start dissociating[5]. In diastolic dysfunction there is an increase in activity of phospholamban and reduction in activity of sarcoplasmic/endoplasmic reticulum calcium ATPase 2 at cellular level. This leads to decrease in coupling of beta receptors with intracellular adenylate activity, thereby diminishing the response of heart to endogenous and exogenous catecholamines.

Diastolic dysfunction can be ascertained by Doppler or cardiac catheterization (Table 1). Cardiac catheterization is an invasive method to measure left ventricular pressures. The parameters measured by this technique are pressure/volume curves, the rate of left ventricular pressure decline, time constant of isovolumetric relaxation (τ), left ventricular minimal pressure after opening of mitral valve and left ventricular pressure just before atrial contraction.

Table 1 Grades of diastolic dysfunction based on echocardiography.

Normal diastolic function	Diastolic dysfunction grade 1	Diastolic dysfunction grade 2	Diastolic dysfunction grade 3	Diastolic dysfunction grade 4
	Impaired relaxation	Pseudo normal	Reversible restricted	Fixed restricted
E/A 1.0-1.5	E/A < 1.0	E/A 0.8-1.5	E/A ≥ 2.0	E/A ≥ 2.0
Deceleration time > 160 ms	Deceleration time > 200 ms	Deceleration time 160-200 ms	Deceleration time < 160 ms	Deceleration time < 160 ms
Left atrial pressure	Left atrial pressure	Left atrial pressure	Left atrial pressure	Left atrial pressure
Normal	Normal	↑↑	↑↑↑	↑↑↑↑

Left ventricular pressure/volume relation describes the systolic and diastolic function of ventricle and is represented as pressure/volume loops graphically. In systolic dysfunction the end-systolic slope shifts downwards and rightwards. In diastolic dysfunction the left ventricular end diastolic pressure and τ is significantly increased and the diastolic curve shifts towards left and upwards[6,7]. In patients with preserved ejection fraction heart failure, the pressure volume loops during diastole are normal at rest but altered during exertion[6,8].

2-Dimensional echocardiography (2-D echo) is conventionally used to assess left ventricular systolic function. 2-D echo combined with pulsed- wave Doppler, mitral annular tissue Doppler imaging and M-mode Doppler is used to assess diastolic dysfunction. Pulsed-wave Doppler measures the velocity of blood flow from left atrium to the left ventricle as it crosses the mitral valve. This is used to measure the pressure gradient between left atrium and ventricle. The initial passive diastolic filling is represented by E (early) wave followed by filling due to atrial systole represented by an A (auricular) wave. In a normal healthy heart, E wave is prominent because most of the ventricular filling occurs during early part of diastole. Extent of diastolic dysfunction can be measured based on the peak and duration of these waves. In mild diastolic dysfunction the A wave is greater than the E wave and the E wave has prolonged deceleration time more than 240 milliseconds. This indicates that the majority of ventricular filling is due to atrial contraction. In moderate diastolic dysfunction, the E wave is greater than the A wave but the E wave deceleration time is shortened. Due to decreased left ventricular compliance the atrial pressure is high leading to a false normal pattern of E wave greater than the A wave. In severe diastolic dysfunction the E wave velocity is more than twice the A wave velocity. This indicates very low left ventricular compliance.

Mitral annular tissue Doppler imaging measures myocardial wall movements and its longitudinal velocity above the mitral annulus. The peak systolic velocity (s’), early diastolic velocity (e’) and late diastolic velocity (a’) are studied[9]. Of these the e’ wave is used to assess the left ventricular relaxation and is inversely related to it. Hence E is driving pressure from left atrium to left ventricle and e’ is increase in left ventricular volume, the E/e’ represents the elastance of left ventricle as relation of left ventricular pressure to volume change. High E/e’ indicates diastolic dysfunction. The American society of echocardiography guidelines state that to diagnose left ventricular diastolic dysfunction based on transthoracic echocardiography the following criteria should be met[5].

Average E/e’ > 14; Septal e’ < 7 cm/second or lateral e’ < 10 cm/second; TR velocity > 2.8 m/second; LA volume index > 34 mL/m².

These variables will change during trans-oesophageal echocardiography due to effect of anaesthesia drugs, different posture of patient and positive pressure ventilation. Brain natriuretic peptide (BNP) and its inactive N-terminal fragment pro-BNP (NT-proBNP) are used to screen heart failure. NT-proBNP levels are higher in CKD patients. This could be due to decreased renal clearance or increased incidence of heart failure in these patients. Patients with heart failure and CKD have higher risk of adverse outcomes as compared to patients with heart failure but no CKD having same NT-proBNP levels[10]. Therefore raised levels of NT-proBNP in CKD patients should be investigated further.

Uraemic cardiomyopathy is well known in CKD patients and is reported to affect 80% of patients on haemodialysis[11]. Cardiac remodelling has been described in CKD patients and is associated with hypertrophy, fibrosis and destruction of capillaries[12]. Decreasing glomerular filtration rate (GFR) has been associated with left ventricular hypertrophy (LVH) due to enlarged myocytes and cardiomyocytes[13]. These myocytes and cardiomyocytes are embedded in the extracellular matrix (ECM) which is rich in collagen[14]. Collagen precursors are secreted by fibroblasts which can remodel the ECM. Increased collagen production can lead to destruction of function myocytes leading to myocardial fibrosis and increased stiffness of left ventricle[15]. This leads to left ventricular diastolic dysfunction. Microangiopathy due to CKD is known to lead to tissue hypoxia, loss of elastic fibres, vascular calcification and dysfunctional angiogenesis[15]. Impaired functioning of antioxidants and increase in reactive oxygen species also contributes to myocardial hypertrophy and fibrosis. Uraemic toxins like asymmetric dimethylarginine, advanced glycation end products indoxyl sulphate, p-cresyl sulphate and trimethylamine N-oxide cause direct cardiotoxicity[16,17].

STUDIES

Diastolic dysfunction is one of the most common echocardiographic findings in asymptomatic CKD patients. The CRIC study which enrolled patients with stage 2-4 CKD reported diastolic dysfunction in 71% of the patients[1]. Another study which enrolled patients with CKD stage 4-5 (eGFR < 30 mL/minute/1.73 m²) reported diastolic dysfunction in 85% of the patients of which 35% had grade 2 or higher diastolic dysfunction. Diastolic dysfunction is probably due to increased levels of plasma phosphate and calcium phosphate in these patients[18]. Also higher levels of collagen content has been reported in the myocardial tissue of these patients[19]. Porras et al[20] in their study have reported an inverse relation between estimated glomerular filtration rate (eGFR) and echocardiographic parameters prognostic of diastolic dysfunction. They further reported that various stages of worsening kidney dysfunction were associated with gradual increase in abnormal echocardiographic diastolic dysfunction parameters after accounting for age, gender and comorbidities like hypertension. Patients with eGFR < 45 mL/minute/1.73 m² have been reported to have a mortality of 50% over a period of 5 years[21,22].

Diastolic dysfunction associated with elevated Troponin T levels and left ventricular hypertrophy or systolic dysfunction in CKD patients both diabetic and non-diabetic is an early marker of myocardial disease and a predictor of adverse outcomes[23-25]. Cardio-renal syndrome (CRS) has a complex bidirectional relation where the kidneys and heart can either be the initiator or the target of the dysfunction. In patients with CKD, progression of diastolic dysfunction is likely to worsen the stage of CKD[4]. In their study Kang et al[4] stated that for every 1 unit increase in E/e’ there was a 2.1% increase in risk of development of a renal event. They further put forward a hypothesis that the systolic hyperfunction seen in CKD patients is a subclinical adaption of the heart to worsening diastolic dysfunction. In patients with CRS, with progressive dysfunction of each organ there are increased chances of hospitalization and mortality[26,27].

MANAGEMENT OF DIASTOLIC DYSFUNCTION FROM ANAESTHESIA PERSPECTIVE

Long term dialysis may cause irreversible damage to myocardial structure[28]. Hypervolemia and hyperparathyroidism are known factors leading to diastolic dysfunction[29,30]. Studies have reported a significant improvement in diastolic dysfunction 1 to 5 years after renal transplant[31,32]. However this improvement in diastolic dysfunction has not been seen in all studies[26,33]. Calcineurin inhibitors and steroids started after renal transplant are known to increase the vascular and cellular fibrosis in the myocardium and this might worsen the cardiac structural changes and prevent the diastolic dysfunction from returning to normal[26]. Calcium channel blockers and spironolactone are known to decrease morbidity in these patients. The CHARM-preserved study has shown a significant reduction in hospitalization rate in patients taking candesartan a specific angiotensin-receptor blocker[34]. Sodium-glucose cotransporters-2 (SGLT-2) inhibitors and glucagon–like peptide 1 (GLP-1) receptor agonists are the newer therapeutic modalities which have cardio-protective benefits[20]. Significant reduction in hospitalisation and cardiovascular death in patients with diastolic dysfunction with preserved ejection fraction who are on SGLT2 inhibitors has been reported in the EMPEROR-Preserved and DELIVER trials[35,36]. Cardiovascular protective action of GLP-1 receptor agonists in heart failure in nondiabetic patients has not been clearly established[37].

Symptomatic pulmonary congestion in heart failure patients who have systolic ejection fraction more than 50% is known as heart failure with preserved ejection fraction[38]. Diastolic dysfunction has been reported in at least 70% of these patients[39]. In the preoperative evaluation of these patients, echocardiographic assessment of LV diastolic function should be included in cardiovascular assessment[5]. Some of these patients who are asymptomatic for diastolic dysfunction can decompensate intra or post operatively despite adequate preoperative assessment. This decompensation usually occurs on weaning from mechanical ventilation. Emergence from anaesthesia can cause adrenergic surge leading to tachycardia and hypertension. Anaesthetic agents and haemodynamic changes such as arrhythmias, uncontrolled hypertension and myocardial ischaemia can adversely affect left ventricular diastolic function. Intraoperative fluid management is critical in these patients as the amount of intraoperative fluid administered is an independent risk factor for deterioration of diastolic dysfunction[2].

Intraoperatively the extent of invasive cardiac monitoring depends on the type of surgical procedure and the grade of diastolic dysfunction. Intraoperative fluid management is the mainstay of anaesthesia management in these patients. Intraoperatively the systolic blood pressure should not increase more than 10%-20% of baseline[5]. The beta independent phosphodeiesterase inhibitor milrinone as bolus of 50 μg/kg over 10 minutes followed by infusion of 0.375-0.75 μg/kg/minute and calcium sensitizer levosimendan are known to improve diastolic dysfunction[6,40]. Intraoperatively a combination of low dose nitroglycerine 0.5-4 μg/kg/min and phenylephrine titration from 0.25 μg/kg/minute onwards has been found to maintain haemodynamic stability[41,42].

CONCLUSION

In CKD, ventricular hypertrophy and stiffness leads to decrease in ventricular compliance. This diastolic dysfunction is manifested as decrease in e’ velocity on mitral annular tissue Doppler imaging. At the same time the sodium and water retention in these patients manifests as increase in E velocity. Higher E/e’ ratios are associated with diastolic dysfunction and increasing values are indicative of development of heart failure independent from stage of CKD.