Abstract
Background
Heart failure (HF) is a frequent occurrence in chronic kidney disease (CKD) patients and predicts poor survival. Serum bicarbonate is associated with increased rates of HF in CKD; however, the mechanisms leading to this association are incompletely understood. This study aims to assess whether serum bicarbonate is independently associated with structural and functional cardiac abnormalities in CKD.
Methods
The association between serum bicarbonate and left ventricular hypertrophy (LVH), LV mass indexed to height2.7, LV geometry, ejection fraction and diastolic dysfunction were assessed in 3483 participants without NYHA class III/IV HF, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study.
Results
The mean eGFR was 42.5±17ml/min per 1.73m2. The overall prevalence of LVH was 51.2%, with 57.8%, 50.9% and 47.7% for bicarbonate categories <22, 22-26, and >26mmol/L, respectively. Participants with low bicarbonate were more likely to have LVH and abnormal LV geometry (OR 1.32; 95%CI 1.07–1.64, and 1.57; 95%CI 1.14–2.16, respectively). However, the association was not statistically significant after adjustment for demographics, traditional cardiovascular risk factors, medications and kidney function (OR1.07; 95%CI 0.66–1.72, and 1.27; 95%CI 0.64–2.51, respectively). No association was found between bicarbonate and systolic or diastolic dysfunction. During follow-up no significant changes in LV mass or EF were observed in any bicarbonate strata.
Conclusions
In a large CKD study, serum bicarbonate was associated with LV mass and concentric LVH; however, this association was attenuated after adjustment for clinical factors suggesting that the observed cardiac effects are mediated through yet unknown mechanisms.
Keywords: serum bicarbonate, LVH, LV geometry, CKD
Introduction
Acid base disturbances are common in patients with chronic kidney disease.1 The kidneys maintain acid–base equilibrium by excreting acid in amounts that are equal to the extra-renal acid production by reclaiming filtered bicarbonate and regenerating base via the excretion of ammonium and titratable acid.2 Kidney function decline leads to impaired generation of new bicarbonate and abnormal or preserved tubular bicarbonate reabsorption resulting in a low degree chronic metabolic acidosis commonly observed in chronic kidney disease (CKD) patients.3, 4
Heart failure is common, and associated with high morbidity and mortality in patients with CKD.5 Also, left ventricular hypertrophy is common in CKD6-8 and is an important predictor of long-term adverse outcomes.9, 10 The role of acid base abnormalities on cardiac muscle is not completely understood. In animal models, mild renal insufficiency results in early cardiac fibrosis and impaired diastolic function, which progresses to more global left ventricular remodeling and dysfunction.11 Acutely induced myocardial acidosis adversely affects recovery of micro-vascular and left ventricular function and increases indices of apoptosis with potential long term effect on cardiac performance.12 A low pH has been associated with the reduction of Na+–K+-ATPase activity in myocardial cells,13 which could lead to reduced myocardial contractility and congestive heart failure.14 Whether the low grade chronic metabolic acidosis associated with CKD plays a role in left ventricular remodeling is unknown.
Our previous work in the Chronic Renal Insufficiency Cohort (CRIC) study showed a “U-shaped” association between serum bicarbonate and clinical heart failure events, with an increased risk of heart failure at both extremes of serum bicarbonate.15, 16 In another study, the magnitude of change in serum bicarbonate level, regardless of direction, was correlated with increase mortality in a cohort of patients hospitalized for heart failure.17 Whether serum bicarbonate levels are associated with cardiac structural or functional abnormalities that predispose to these clinical outcomes is not known.
The goal of this analysis was to evaluate the association between serum bicarbonate levels and left ventricular structure and function, including left ventricular mass and hypertrophy, ejection fraction, measures of diastolic dysfunction and left ventricular geometry in a cohort of patients with chronic kidney disease.
Methods
Study Design and Population
The CRIC Study enrolled 3,943 individuals aged 21-74 years with estimated glomerular filtration rate (eGFR) 20-70 mL/min/1.73 m2, from June 2003 to December 2008 at seven clinical centers across the US (Ann Arbor, MI; Baltimore, MD; Chicago, IL; Cleveland, OH; New Orleans, LA; Philadelphia, PA; and Oakland, CA). Study design and baseline participant characteristics have been previously published.18-20 Major exclusion criteria included prior dialysis treatment lasting more than one month, NYHA Class III/IV heart failure, polycystic kidney disease, or other primary renal diseases requiring active immunosuppression, human immunodeficiency virus (HIV) infection, pregnancy, and inability to give informed consent or institutionalization. Participants underwent annual study visits and telephone follow-up twice a year. Echocardiogram evaluation was performed at study years 1, 4 and 7. The study population for this analysis included 3483 participants after exclusion of 37 with missing serum bicarbonate measurements at study year one. There was no statistically significant difference between study participants and those excluded from the analyses. (Figure1S Supplemental Material - Consort Diagram) Study participants provided written informed consent and are followed annually under protocols approved by institutional review boards at each of the CRIC Study clinical centers.
Data Collection
Main Predictor
Serum bicarbonate was measured annually using an enzymatic procedure with phosphoenolpyruvate carboxylase on the Ortho Vitros platform at the University of Pennsylvania Core Laboratory. The current analysis examined bicarbonate continuously per 1 mmol/L increase, and categorically using the following groups of serum bicarbonate: <22 mmol/L, 22-26 mmol/L (reference group) and >26 mmol/L. The cut points for categories of serum bicarbonate used are based on the current recommended clinical guidelines in CKD and available literature.15
Outcomes
The study outcomes were 2D mode echocardiography measures of cardiac structure and function. All echocardiograms were read centrally at University of Pennsylvania by one reader who was blinded to the studies. LV mass was calculated using the area–length method and indexed to height2.7.21 Left ventricular hypertrophy (LVH) was defined as LV mass/height2.7 greater or equal to 47g/m2.7 in women and greater or equal to 50g/m2.7 in men.22,23
Relative wall thickness (RTW) was calculated as two times posterior wall thickness/LV internal linear dimension in diastole, and it was considered to be increased if greater or equal to 0.45. LV mass and relative wall thickness were used to categorize LV geometry: normal (normal LV mass and normal RWT), concentric remodeling (normal LV mass and increased RWT), eccentric hypertrophy (increased LV mass and normal RWT), and concentric hypertrophy (increased LV mass and increased RWT).
Left ventricular systolic function was assessed using the ejection fraction (EF) obtained from echocardiograms. LV end-diastolic and end-systolic volumes were calculated using the modified biplane method. EF was calculated as (end-diastolic volume – end-systolic volume)/end-diastolic volume. LV systolic dysfunction was defined as EF less than 45%.24
Left ventricular diastolic function was categorized as normal or mildly, moderately, or severely abnormal (corresponding to normal and grades 1, 2, and 3 diastolic dysfunction) based on mitral inflow E- and A-wave velocities, E-wave deceleration time, and pulmonary venous reverse A-wave duration.25 These parameters were unable to obtain in 564 participants due to equipment limitations of one CRIC center. A small subset (<1%) of participants with atrial fibrillation could not have measurements of diastolic dysfunction.
Covariates
Demographic and clinical information were obtained at the baseline and follow-up study visits by questionnaires, interviews and physical examination. History of any cardiovascular disease included prior myocardial infarction, revascularization, heart failure, stroke, or peripheral arterial disease. Current smoking was defined as self-report of current use of cigarettes and at least 100 cigarettes smoked. At each study visit, participants were queried about any medication usage in the prior 30 days. All anti-hypertensive medications were categorized into drug classes, and the total number of anti-hypertensive drug classes was calculated. All hospitalization records were reviewed and clinical events were adjudicated by two independent reviewers according to CRIC study protocol. eGFR was calculated using the CRIC study equation.26
Diabetes mellitus was defined as a fasting glucose >126 mg/dL, a non-fasting glucose >200 mg/dL, or use of insulin or other antidiabetic medication.27 Hypertension was defined as systolic BP ≥140 mmHg, diastolic BP ≥90 mmHg, or use of antihypertensive medications.28
Statistical Analysis
The characteristics of study participants were depicted using standard descriptive statistics, overall and stratified by categories of serum bicarbonate <22, 22-26 and >26mmol/L. Pearsons χ2 for categorical variables and t-test for continuous variables were used to analyze the covariates of interest and their association with serum bicarbonate.
Multivariable linear regression models were used to assess the association between bicarbonate and LV mass, cross-sectional at CRIC study year 1. Secondary longitudinal analyses were performed during follow-up at CRIC study years 4 and 7. To address potential non- linearity, restricted cubic spline models were created. The goodness of curve fit was assessed with the F test. Logistic regression models were built to assess the association between serum bicarbonate and LVH, LV systolic and diastolic dysfunction, cross-sectional at study year 1 and during follow-up at years 4 and 7. Diastolic dysfunction was dichotomized into normal versus abnormal (corresponding to mildly, moderately and severely abnormal) relaxation. Multinomial logistic regression models were built to assess the four categories of LV geometry, using normal geometry as the reference group. The models were adjusted for relevant confounding variables, including demographics (age, sex, race/ethnicity), traditional CVD risk factors (hypertension, diabetes, smoking, LDL cholesterol, prior history of cardiovascular disease), medications (angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, diuretics, anti- acidosis medications) and kidney function (eGFR and urine protein excretion). Sequential multivariable models for each outcome were created based on our assessment of the covariates likelihood of being a confounder in the relationship between serum bicarbonate and heart disease. All models were also adjusted for study clinical center to account for the potential variability across centers. Residual plots were used to confirm model assumptions.
The effect modification by an a priori selected set of baseline characteristics including race/ethnicity, diabetes status, diuretic use, level of kidney function (eGFR<45 and ≥45 mL/min/1.73m2) and proteinuria was also explored. Because the presence of cardiovascular disease is correlated closely with recurrence of cardiovascular events, a secondary set of analyses was performed to evaluate the outcomes of interest in participants without known cardiovascular disease. Additionally, we assessed the subsequent risk of serum bicarbonate to predict LVH in participants without known LVH at study year 1. Similarly we evaluated the risk conferred by serum bicarbonate on the development of abnormal LV geometry during follow-up in participants with normal LV geometry at study year 1. All statistical tests were 2 sided, and P < 0.05 was considered significant. IBM Corp (2013) SPSS Statistics for Windows, Version 22.0, Armonk, NY, and R Development Core Team (2011). R: A language and environment for statistical computing, Vienna, Austria were used for analyses.
Results
The study cohort included 3,483 participants with a mean age of 58.9±10.8 (SD) years, mean eGFR of 42.5mL/min/1.73m2, median 24-hour urine total protein excretion of 0.2g/d and median serum bicarbonate level of 24; interquartile range, 22-26mmol/L. In the study cohort, 1,446 (41.5%) were African Americans, 1,571 (45.1%) were females and 1,726 (49.6%) had diabetes. Compared with participants with serum bicarbonate 22-26mmol/L, participants in the low bicarbonate group (< 22mmol/L) were more likely to be younger, Hispanic, with diabetes and hypertension and not on a diuretic. Additionally, they were more likely to have a lower eGFR, hemoglobin, and albumin and higher proteinuria, parathyroid hormone, phosphorus and FGF23 levels (Table 1).
Table 1.
Characteristics of Chronic Renal Insufficiency Cohort (CRIC) study participants by groups of serum bicarbonate
| Strata of serum bicarbonate |
|||||
|---|---|---|---|---|---|
| Characteristic | All Participants (n=3483) | < 22 (n=614) | (mmol/L) [22-26] (n=2001) | > 26 (n=868) | p-value* |
| Serum bicarbonate (mmol/L) | 24.4 (3.3) | 19.5 (1.8) | 24.1 (1.4) | 28.4 (1.7) | <.0001 |
| Death | 556 (16.3) | 166 (29.9) | 207 (37.2) | 183 (32.9) | 0.09 |
| Demographic data: | |||||
| Age (years) | 58.9 (10.8) | 57.5 (11.7) | 58.8 (10.7) | 59.9 (10.1) | <.0001 |
| Women | 1571 (45.1) | 258 (42.0) | 901 (45.0) | 412 (47.5) | 0.12 |
| Race | |||||
| Non-Hispanic White | 1499 (43.0) | 237 (38.6) | 883 (44.1) | 379 (43.7) | <.0001 |
| Non-Hispanic Black | 1446 (41.5) | 250 (40.7) | 813 (40.6) | 383 (44.1) | <.0001 |
| Hispanic | 401 (11.5) | 105 (17.1) | 237 (11.8) | 59 (6.8) | <.0001 |
| Other | 137 (3.9) | 22 (3.6) | 68 (3.4) | 47 (5.4) | <.0001 |
| Hypertension | 3103 (89.2) | 563 (91.7) | 1779 (89.0) | 761 (87.8) | 0.05 |
| Diabetes | 1726 (49.6) | 331 (53.9) | 987 (49.3) | 408 (47.0) | 0.03 |
| Any cardiovascular disease | 1251 (35.9) | 216 (35.2) | 707 (35.3) | 328 (37.8) | 0.41 |
| Current smoking | 424 (12.2) | 119 (19.4) | 235 (11.7) | 70 (8.1) | <.0001 |
| Chronic Obstructive Pulmonary Disease | 166 (4.8) | 23 (3.8) | 93 (4.7) | 50 (5.8) | 0.19 |
| Body Mass Index (kg/m2) | 32.1 (7.7) | 31.6 (7.5) | 32.3 (7.7) | 31.8 (8.0) | 0.08 |
| Systolic blood pressure (mmHg) | 127.1 (21.7) | 129.1 (23.7) | 126.5 (21.1) | 127.1 (21.6) | 0.03 |
| Diastolic blood pressure (mmHg) | 69.9 (12.9) | 69.8 (13.1) | 69.7 (12.7) | 70.5 (13.2) | 0.36 |
| LDL Cholesterol (mg/dL) | 99.4 (34.7) | 97.7 (37.6) | 99.3 (34.2) | 101.1 (33.9) | 0.17 |
| HDL Cholesterol (mg/dL) | 48.5 (15.7) | 45.3 (15.8) | 48.5 (15.7) | 50.9 (15.3) | <.0001 |
| Medications: | |||||
| Aspirin | 1619 (46.7) | 281 (46.3) | 932 (46.7) | 406 (46.8) | 0.98 |
| Beta-Blockers | 1775 (51.2) | 312 (51.4) | 1011 (50.7) | 452 (52.1) | 0.78 |
| Statins | 2053 (59.2) | 360 (59.3) | 1185 (59.4) | 508 (58.6) | 0.92 |
| ACE inhibitor / ARB | 2400 (69.2) | 444 (73.1) | 1385 (69.5) | 571 (65.9) | 0.01 |
| Anti-acidosis medications^ | 99 (2.9) | 25 (4.1) | 53 (2.7) | 21 (2.4) | 0.11 |
| Any diuretic | 2071 (59.7) | 358 (59.0) | 1142 (57.3) | 571 (65.9) | <.0001 |
| Laboratory data: | |||||
| eGFR (ml/min/1.73m2)$ | 42.5 (16.0) | 32.8 (14.4) | 43.3 (16.0) | 47.6 (14.0) | <.0001 |
| Creatinine (mg/dL) | 2.0 (1.1) | 2.6 (1.3) | 2.0 (1.0) | 1.8 (1.1) | <.0001 |
| 24Hours Urine protein (g/24H)# | 0.16 (0.07 - 0.87) | 0.38 (0.11 - 1.53) | 0.16 (0.07 - 0.81) | 0.12 (0.06 - 0.47) | <.0001 |
| Calcium (mg/dL) | 9.3 (0.5) | 9.2 (0.6) | 9.3 (0.5) | 9.3 (0.5) | <.0001 |
| Phosphorus (mg/dL) | 3.8 (0.7) | 4.4 (0.9) | 3.8 (0.6) | 3.5 (0.6) | 0.04 |
| Parathyroid Hormone (pg/ml) | 61.0 (42.0 - 92.0) | 83.0 (50.0 - 140.0) | 60.0 (42.0 - 92.5) | 56.0 (39.8 - 82.0) | <.0001 |
| Albumin (g/dL) | 4.0 (0.4) | 4.0 (0.5) | 4.0 (0.4) | 4.1 (0.4) | <.0001 |
| Hemoglobin (g/dL) | 12.8 (1.8) | 12.2 (1.8) | 12.8 (1.8) | 13.1 (1.8) | <.0001 |
| Fibroblast Growth Factor 23 (RU/ml)# | 131.4 (85.7 - 224.4) | 171.8 (105.4 - 326.9) | 130.5 (86.4 - 218.4) | 115.5 (72.6 - 188.5) | <.0001 |
| High sensitivity C Reactive Protein# | 2.2 (1.2 - 4.1) | 2.9 (2.2 - 3.8) | 1.9 (1.1 - 4.1) | 2.2 (1.2 - 5.5) | 0.40 |
| Dietary protein (g/kg/day) | 0.9 (0.5) | 0.9 (0.6) | 0.9 (0.4) | 0.9 (0.4) | 0.93 |
Unless otherwise noted, values are n (%) or means ± SDs. ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker.
p-value obtained from one way ANOVA or Chi square as appropriate
Median (interquartile range)
Anti-acidosis medications are represented by: calcium citrate, magnesium citrate, potassium citrate, sodium bicarbonate, sodium lactate, sodium citrate, sodium acetate, tromethamine, and lactated potassium saline.
Estimated GFR was calculated from serum creatinine and cystatin C using a CRIC Study equation.47
Serum bicarbonate and structural cardiac abnormalities
LV mass was higher in participants in the stratum of bicarbonate < 22mmol/L (53.3 ± 14.6 g/m2) compared to stratum of bicarbonate > 26mmol/L (50.5 ± 14.5 g/m2, p=0.002) (Figure 1). In demographically adjusted models, there was an inverse association between bicarbonate and LV mass, with 0.29 g/m2 lower LV mass with each 1 mmol/L increase in serum bicarbonate (OR -0.29; 95%CI (−0.45 to −0.13) (Table 2). After adjustments for traditional cardiovascular risk factors, the association lost its statistical significance (1.47; 95%CI −1.19 to 4.14). Additional adjustments for renal function and proteinuria did not further influence the association. Exploratory non-linear modeling revealed a lack of statistical significance for a nonlinear relationship between bicarbonate and LV mass (p= 0.13) (Figure 2).
Figure 1.
Mean LV mass (g/m2.7) by serum bicarbonate categories
Table 2.
Association of serum bicarbonate and LV structure among CRIC participants
| Model 1 | Model 2 | Model 3 | Model 4 | |||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | p | HR (95% CI) | p | HR (95% CI) | p | |
| LV mass (g/m2.7) (n=2650) | ||||||||
| Serum Bicarbonate (per 1 mmol/L increase) | −0.23(−0.40 – −0.07) | 0.005 | −0.29(−0.45 – −0.13) | <0.001 | 1.47 ( −1.19 – 4.14) | 0.25 | 1.35 (−1.15 – 3.86) | 0.26 |
| LV Hypertrophy (n = 2650) | ||||||||
| Serum Bicarbonate < 22 mmol/L | 1.32 (1.07 – 1.64) | 0.01 | 1.38 (1.10 – 1.72) | 0.005 | 1.26 (0.82 – 1.96) | 0.29 | 1.07 (0.66 – 1.72) | 0.79 |
| Serum Bicarbonate > 26 mmol/L | 0.88 (0.74 – 1.05) | 0.17 | 0.82 (0.68 – 0.99) | 0.04 | 0.78 (0.55 – 1.10) | 0.15 | 0.85 (0.58 – 1.23) | 0.38 |
| LV geometry (n=2542) | ||||||||
| Concentric Remodeling (n=733) | ||||||||
| Serum Bicarbonate < 22 mmol/L | 1.21 (0.86 – 1.70) | 0.27 | 1.22 (0.85 – 1.73) | 0.28 | 1.32 (0.68 – 2.55) | 0.41 | 1.24 (0.63 – 2.46) | 0.53 |
| Serum Bicarbonate > 26 mmol/L | 0.86 (0.67 – 1.12) | 0.27 | 0.85 (0.65 – 1.11) | 0.24 | (0.89 (0.56 – 1.44) | 0.63 | 0.65 (0.39 – 1.09) | 0.10 |
| Eccentric Hypertrophy (n=379) | ||||||||
| Serum Bicarbonate < 22 mmol/L | 1.50 (1.03 – 2.18) | 0.04 | 1.48 (1.00 – 2.19) | 0.05 | 1.99 (0.94 – 4.24) | 0.07 | 2.09 (0.94 – 4.63) | 0.07 |
| Serum Bicarbonate > 26 mmol/L | 0.71 (0.52 – 0.98) | 0.04 | 0.69 (0.49 – 0.96) | 0.03 | 0.86 (0.47 – 1.58) | 0.62 | 0.65 (0.33 – 1.28) | 0.21 |
| Concentric Hypertrophy (n=913) | ||||||||
| Serum Bicarbonate < 22 mmol/L | 1.57 (1.14 – 2.16) | 0.005 | 1.58 (1.12 – 2.24) | 0.009 | 1.39 (0.72 – 2.67) | 0.33 | 1.27 (0.64 – 2.51) | 0.49 |
| Serum Bicarbonate > 26 mmol/L | 0.89 (0.69 – 1.14) | 0.34 | 0.86 (0.65 – 1.12) | 0.26 | 0.66 (0.402 – 1.07) | 0.09 | 0.59 (0.35 – 1.00) | 0.05 |
Model 1 - unadjusted
Model 2 – adjusted for demographics (age, sex, race) and clinical center
Model 3 – adjusted for variables in model 2 plus diabetes, hypertension, current tobacco use, cardiovascular disease, diuretics, ACEi/ARB, anti-acidosis medication. LDL, FGF23
Model 4- adjusted for variables in model 3 plus proteinuria and eGFR
Figure 2.
Association between serum bicarbonate level (mmol/L) and left ventricular mass indexed to height at 2.7 (g/m2.7). Adjusted restricted cubic spline model with knots at 20, 24 and 28. The solid line represents the effect. (p=0.13)
The prevalence of LVH was 51.2% for the entire cohort, with 57.8%, 50.5% and 47.7% for the low, normal and high serum bicarbonate groups respectively. In unadjusted and demographically adjusted models, associations of serum bicarbonate with LVH were significant, with nearly 40% higher risk of LVH for the low serum bicarbonate (<22 mmol/L) group (1.38; 95%CI 1.10-1.72), and almost 20% lower risk of LVH for the high serum bicarbonate (>26 mmol/L) group (0.82; 95%CI 0.68-0.99) when compared with the normal group (22-26 mmol/L) (Table 2). After multivariable adjustments, there was no statistically significant association between serum bicarbonate strata and LVH (Table 2).
Approximately 80% of study participants had abnormal LV geometry: 28.9% (729) concentric remodeling, 14.9% (377) eccentric hypertrophy and 35.8% (905) concentric hypertrophy. The participants in the lowest bicarbonate stratum were more likely to have concentric hypertrophy (40.8 %, N=173) compared to those in the normal (34.7%, N=501) and high bicarbonate strata (35.1%, N=231), χ = 17.06, p=0.009. After adjustments for demographics, participants in the low bicarbonate stratum (< 22mmol/L) were 58% more likely to have concentric hypertrophy, when compared to the group of bicarbonate 22-26mmol/L (1.58; 95%CI 1.12–2.24, p=0.009) (Table 2). Participants in the high bicarbonate group were less likely to have abnormal LV geometry, and eccentric hypertrophy, in particular (0.69; 95%CI 0.49 – 0.96, p=0.03). However, after multivariable adjustments, there was no statistically significant association between strata of serum bicarbonate and LV geometry (Figure 3).
Figure 3.
Left ventricular geometry by the levels of serum bicarbonate
Serum bicarbonate and functional cardiac abnormalities
The majority of participants (88.6%) had preserved ejection fraction (≥ 45%). The odds of having systolic dysfunction (ejection fraction < 45%) was similar across serum bicarbonate strata in univariate and multivariable adjusted models. There was no statistically significant association between bicarbonate levels and measures of diastolic dysfunction in multivariable logistic regression models, adjusted for demographics, traditional cardiovascular risk factors and kidney function (Table 3).
Table 3.
Association of serum bicarbonate and LV function among CRIC participants
| Model 1 | Model 2 | |||
|---|---|---|---|---|
| HR (95% CI) | p-value | HR (95% CI) | p-value | |
| Systolic Dysfunction | ||||
| Serum Bicarbonate < 22 mmol/L | 1.04 (0.78 – 1.38) | 0.86 | 0.76 (0.41 – 1.42) | 0.37 |
| Serum Bicarbonate > 26 mmol/L | 1.06 (0.82 – 1.38) | 0.64 | 0.77 (0.44 – 1.37) | 0.40 |
| Diastolic Dysfunction | ||||
| Mildly Abnormal Relaxation | ||||
| Serum Bicarbonate < 22 mmol/L | 1.02 (0.83 – 1.27) | 0.83 | 1.09 (0.84 – 1.41) | 0.51 |
| Serum Bicarbonate > 26 mmol/L | 0.99 (0.81 – 1.20) | 0.88 | 1.03 (0.83 – 1.28) | 0.80 |
| Moderately Abnormal Relaxation | ||||
| Serum Bicarbonate < 22 mmol/L | 0.70 (0.47 – 1.03) | 0.07 | 0.68 (0.44 – 1.04) | 0.09 |
| Serum Bicarbonate > 26 mmol/L | 0.93 (0.67 – 1.29) | 0.68 | 0.94 (0.66 – 1.34) | 0.72 |
| Severely Abnormal Relaxation | ||||
| Serum Bicarbonate < 22 mmol/L | 0.70 (0.26 – 1.89) | 0.48 | 0.53 (0.14- 1.91) | 0.33 |
| Serum Bicarbonate > 26 mmol/L | 1.46 (0.69 – 3.09) | 0.32 | 1.64 (0.67 – 3.99) | 0.28 |
Model 1 – unadjusted
Model 2 – adjusted for demographics (age, sex, race) and clinical center, diabetes, hypertension, current tobacco use, cardiovascular disease, diuretics, ACEi/ARB, anti-acidosis medication. LDL, FGF23, proteinuria and eGFR
Longitudinal changes in structural and functional cardiac abnormalities
Echocardiography measurements performed at study year 1 were repeated at subsequent study years 4 and 7 (Table 4). Over time, no statistically significant changes were observed in LV mass or EF, in any of the bicarbonate strata. We examined the strength of association between serum bicarbonate at year 1 and progression to LVH in subsequent years, in the subgroup of participants without LVH at year 1. Serum bicarbonate was not an independent predictor of development of LVH in this subgroup. (Table 1S Supplemental material).
Table 4.
Longitudinal changes in left ventricular structure and function by serum bicarbonate groups
| Serum Bicarbonate Groups at study year 1 | |||
|---|---|---|---|
| < 22 mmol/L | [22-26] mmol/L | > 26 mmol/L | |
| Mean LV mass indexed to height27, g/m2.7(SD)* | |||
| Year 1 | 48.1 (12.0) | 46.6 (12.1) | 48.1 (13.8) |
| Year 4 | 49.4 (11.9) | 47.0 (10.6) | 47.9 (11.6) |
| Year 7 | 48.8 (12.0) | 47.1 (11.1) | 46.3 (12.5) |
| Mean LV ejection fraction, % (SD)** | |||
| Year 1 | 55.2 (6.9) | 54.3 (7.5) | 54.9 (7.9) |
| Year 4 | 51.9 (8.4) | 51.7 (8.2) | 51.6 (8.5) |
| Year 7 | 48.3 (8.7) | 48.7 (8.5) | 49.0 (8.8) |
Analyses based on the same 448 CRIC participants with available measures of LV mass at study years 1, 4 and 7
Analyses based on the same 597 CRIC participants with available measurements of LV ejection fraction at study years 1, 4 and 7
Similarly, we explored the association between serum bicarbonate and LV geometry at study years 4 and 7, after exclusion of participants with abnormal geometry, with similar findings (Table 2S Supplemental material).
Subgroup Analyses
We performed a series of a priori defined subgroup analyses; the association between serum bicarbonate level and structural and functional cardiac abnormalities was consistent when stratified by race/ethnicity, diabetes status, proteinuria and eGFR levels (Table 3S Supplemental material). In other sensitivity analyses, we excluded participants with cardiovascular disease at study baseline and/or in the first year, prior to first echocardiography evaluation; results were consistent (Table 4S Supplemental material).
Discussion
CKD is frequently associated with heart failure and confers the highest risk of mortality and hospitalizations for heart failure.29 Mechanisms underlying this association are incompletely understood. In this large cohort of individuals with mild to moderate CKD and without NYHA class III/IV heart failure, we hypothesized that low serum bicarbonate, a feature of chronic metabolic acidosis observed in CKD, is associated with heart structural and functional abnormalities. We found that LV mass is higher, and LVH and abnormal LV geometry are more common in CKD patients with low serum bicarbonate. However, these associations were attenuated and not statistically significant after adjustment for traditional cardiovascular risk factors and kidney function.
To our knowledge, this is the first study to comprehensively evaluate the association between serum bicarbonate and echocardiographic measures of cardiac structure and function in CKD patients. Left ventricular mass was higher, and LVH was more prevalent in participants in the lower serum bicarbonate stratum. Humoral regulatory mechanisms aimed to increase urinary acidification in CKD, including activation of Angiotensin II, aldosterone and endothelin can cause direct cardiac damage.30-32 The potential link between chronic acidosis in CKD and heart structure abnormalities could be mediated through inflammatory and neurohumoral mechanisms activation. Acidosis and inflammation are strongly linked in CKD.33, 34, 35 It is reasonable to speculate that the chronic metabolic acidosis results in neuro-hormonal stimulation and increased inflammatory markers, which could contribute to changes in left ventricular mass and geometry. However, in our study, adjustment for traditional risk factors for heart disease attenuated the association. This suggests that the association between serum bicarbonate and cardiac structure is confounded by the presence of common clinical conditions such as diabetes and hypertension which may share similar inflammatory and neurohumoral milieu. It is also possible that the association between serum bicarbonate levels and clinical heart failure episodes is mediated by other factors such as changes in endothelial function and peripheral vascular resistance as discussed below but which are not captured by cardiac imaging.
Animal models described an association between acidosis and myocardial dysfunction. Acute acidemia causes depression of left ventricular function in a dog model14 and contributes to reduced myocardial contractility in rats with heart failure.36 This can be physiologically explained. In order for crossbridges between actin and myosin to be created and contraction to occur, the inhibitory action of troponin on actin-myosin interaction must be overcome. In the setting of high intracellular H+, a smaller percentage of the available calcium is able to react with troponin, fewer actin-myosin interactions occur, and the strength of contraction is reduced. Similarly, sarcoplasmic reticulum isolated from heart tissue releases less Ca when the pH of the medium is low. If the results are extrapolated to the intact animal, acute acidosis may cause a lower amount of calcium released during each beat and a subsequent diminished force of contraction.37
Few studies have been done in humans to assess the effect of acidosis or alkalosis on the heart. Our previous study in CRIC15 showed an increased risk of heart failure episodes both with high and low serum bicarbonate. Some of the symptoms of heart failure including weakness and shortness of breath can be caused by poor oxygen delivery to the peripheral tissues, an action affected by the blood pH. It is reasonable to conceive that at any given increase in blood pH, one would encounter reduced oxygen delivery that would clinically manifest as weakness, shortness of breath, fatigue, without any significant effect on heart structural or functional abnormalities. In human end-stage failing myocardium, mild acute acidosis impaired contractility and the b- adrenergic response.38 However, other studies failed to show a link between acidosis and impaired cardiac function39 and that debate was solved with the discovery that the direct effect of acute acidosis on the myocardium could be masked by the effect of catecholamines.40, 41 This might be indeed the rationale behind our previous found link between serum bicarbonate and heart failure events, but negative association with systolic or diastolic dysfunction. Neurohumoral activation of sympathetic and renin-angiotensin-aldosterone systems induced by chronic acidosis potentially leads to endothelial dysfunction, increase in peripheral venous and arterial resistance, with subsequent increase in preload and afterload, progressive retention of salt and water and edema. However, this hypothesis cannot be directly tested in our current analyses. In addition, the lack of association of serum bicarbonate with systolic dysfunction might not be unexpected given that patients with NYHA III/IV were excluded from study enrollment and only about 11% had a low ejection fraction at study year 1.
This study has some key strengths: it represents the largest and most comprehensive analyses of the association between serum bicarbonate and cardiac structure and function in CKD. The large and racially diverse patient population, long duration of follow-up, comprehensive covariate measurements, and large subgroup sizes to allow robust subgroup analyses are also important strengths. However, there are important limitations. Cardiac structure and function measurements were done using 2D mode echocardiography and not cardiac magnetic resonance. Left ventricular mass evaluated by cardiac magnetic resonance imaging is more precise and reliable compared to that provided by the 2D mode echocardiography.42,43 Furthermore, the ability of 2D mode echocardiography technique to detect serial changes in LV mass measurements may be limited.44, 45 Therefore it is possible that the lack of statistical significance in our models may be due to echocardiograms measurement bias. Second, serum bicarbonate alone is not a true estimation of the acid base status, but blood gas analyses were not available in CRIC. We did however adjust the analyses for the presence of lung disease, since some participants might have high bicarbonate as a compensatory mechanism for respiratory acidosis. Third, serum bicarbonate measurements occurred 1-2 days after the original blood draw, and there is a reduction up to 4 mmol/L in serum bicarbonate concentration for all determinations done 24-48 hours from collection; however, this time gap in measurement is common in large epidemiologic studies that use a central laboratory.46 Lastly, data on valve replacement or cardiac resynchronization therapies that could potentially influence cardiac structure and function were not available; this limit the interpretation of the longitudinal changes in cardiac structure, but not the detailed cross-sectional analyses reported in this paper.
In summary, in this large cohort of patients with CKD, serum bicarbonate was not independently associated with cardiac structural and functional abnormalities. These findings suggest that the association between serum bicarbonate and heart disease are either confounded or mediated by other more traditional cardiovascular risk factors. Other perhaps neurohumoral mechanisms, activated by changes in acid base balance may mediate the association between serum bicarbonate and heart failure events and merit further studies.
Supplementary Material
Acknowledgments
Sources of Funding
Funding for the CRIC Study was obtained under a cooperative agreement from NIDDK (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by: University of Pennsylvania Clinical and Translational Science Award NIH/NCATS UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) UL1TR000433, University of Illinois at Chicago CTSA UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, Kaiser Permanente NIH/NCRR UCSF-CTSI UL1 RR-024131. MD is supported by 13FTF15920005. KS is supported by DK094352-01.
Footnotes
Disclosures: The authors have no conflict of interest to disclose.
Appendix
Alan S. Go, MD, Jiang He, MD, John W. Kusek, PhD, Akinlolu Ojo, MD, James P. Lash, MD, Raymond R. Townsend, MD
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