Presence of micro- and macroalbuminuria and the association with cardiac mechanics in patients with type 2 diabetes

Presence of micro- and macroalbuminuria and the association with cardiac mechanics in patients... Abstract Aims Albuminuria—a marker of generalized vascular dysfunction—is a strong predictor of heart failure in patients with type 2 diabetes which may be caused by concomitant myocardial dysfunction reflecting the same underlying pathogenesis. Methods and results We included 915 patients with type 2 diabetes from two secondary care centres and stratified according to albuminuria status in normo-, micro-, and macroalbuminuria. We performed comprehensive echocardiography including conventional imaging, tissue Doppler imaging, and 2D speckle tracking. Cardiac remodelling occurred in patients with increasing left ventricular (LV) mass index and LV wall thicknesses with increasing severity of albuminuria. Diastolic measures worsened across groups of albuminuria severity (normo-, micro-, and macroalbuminuria, respectively): septal e′ velocity [mean: 6.9 cm/s (SD 1.9), 6.4 (1.7), and 5.9 (1.7), P < 0.001], septal E/e′ (median: 10.6 [interquartile range: 8.9–13.2], 12.1 [10.3–14.8], and 12.7 [10.4–16.6], P < 0.001), and left atrial volume index (24.3 mL/m2 [19.1–29.9], 25.7 [20.0–31.6], and 29.0 [22.2–34.9], P < 0.001) In contrast, systolic measures were only impaired in patients with macroalbuminuria: global longitudinal strain (GLS): [−14.6% (2.7) in normo- and −13.3 (2.9) in macroalbuminuria, P < 0.001] and GLS rate [mean: −0.79 s−1 (0.17) in normo- and −0.72 (0.16) in macroalbuminuria, P = 0.001]. The findings persisted in subgroup analyses of patients without known coronary heart disease and with normal ejection fraction and in multivariable adjusted analyses. Conclusion In patients with type 2 diabetes, microalbuminuria is associated with decreased diastolic function whereas decreased systolic function was only associated with macroalbuminuria supporting the notion of similar pathogenic mechanisms of albuminuria and impaired myocardial function. type 2 diabetes, albuminuria, heart failure, cardiac remodelling, echocardiography Introduction By 2030, the prevalence of heart failure (HF) in the USA is projected to have increased by 25%, which is expected mainly to be caused by an ageing population.1 However, with the concomitant worldwide, rapid increase in the prevalence of type 2 diabetes (T2D)2—which consistently has been shown to be associated with a 2–4 fold increase in risk of heart failure3–5—the proportion of patients with HF attributable to T2D will also increase substantially in the coming years. Despite much attention, the mechanisms for the development of heart failure in these patients remain not fully understood. The Steno hypothesis suggested, that excretion of albumin in the kidneys reflected not only localized renal disease but was a marker of generalized endothelial dysfunction.6 Accordingly, albuminuria has been shown in a number of studies to be related to other markers of subclinical cardiovascular disease, including ischaemic electrocardiographic changes7 and coronary artery calcium score/carotid intima thickness in non-diabetic populations.8 However, interestingly, in patients with T2D, as well as in patients without T2D, the presence of albuminuria is associated not only with the development of renal impairment and cardiovascular disease in the form of myocardial infarction, stroke, and cardiovascular death, but also to the development of congestive heart failure.9 Consequently, a direct effect on the myocardium of the generalized endothelial dysfunction found in patients with albuminuria may exist. In line with this, previous studies have shown a relationship between albuminuria and increased left ventricular (LV) mass10 in normotensive, and increased LV mass11,12 and diastolic dysfunction12 in patients with hypertension. Also, in patients with T2D, older studies, including The Strong Heart Study have revealed an association between albuminuria and LV mass index and diastolic dysfunction.13,14 In the recent years, development of newer echocardiographic modalities including tissue Doppler Imaging (TDI) and 2D speckle tracking echocardiography (2DSTE) have allowed for detection of subtle changes in both LV systolic and diastolic function. Using these measures, Katz et al.15 found evidence of both systolic and diastolic dysfunction as assessed by TDI and 2DSTE, in a population with a high proportion of hypertensive subjects.15 Also, in patients with type 1 diabetes compared with a control population from the general population, 2DSTE revealed impaired systolic function only in the patients that had developed albuminuria.16 However, this association between albuminuria and cardiac mechanics estimated by TDI and 2DSE—that may reveal associations hitherto undetected—remains to be examined in patients with T2D. In this study, we aimed to describe the association between albuminuria and cardiac mechanics using comprehensive echocardiography in a large contemporary cohort of outpatients with T2D receiving multifactorial treatment. Methods Study population From 2011 to 2013, the Thousand & 2 echocardiographic study recruited patients with type 2 diabetes from two large secondary care centre in the Capital Region of Denmark (Steno Diabetes Center Copenhagen and Center for Diabetes Research, Gentofte Hospital, University of Copenhagen). A total of 2158 patients were invited and 1030 participated. Details on study inclusion and study visit have been described previously.17,18 Before the study visit, the patients were asked to fill out a questionnaire with information on current medication, prior heart disease (myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, congestive heart failure, and atrial fibrillation), prior stroke and peripheral artery disease, family history of coronary heart disease, smoking habits, height, and weight. The questionnaire was reviewed with the patient at the study visit by P.G.J. Blood pressure was measured in the supine position after at least 15 min of rest. Body mass index (BMI) was defined as weight (kg)/height (m)2. Cholesterol levels, creatinine, and haemoglobin A1c were retrieved from the patients’ routine laboratory results. Patients with atrial fibrillation during the echocardiographic examination, more than moderate valve disease and/or previous heart valve surgery were excluded (n = 96). Also, patients without information of urine albumin excretion were excluded (n = 19). The study was conducted in accordance with the Helsinki Declaration, approved by The Danish National Committee on Biomedical Research Ethics, amendment to Protocol No. H-3-2009-139.19 All participants gave written informed consent. Urine albumin excretion measurements Information on urine albumin/creatinine ratio or 24 h urine albumin excretion rate was retrieved from the patient’s standard laboratory measurements. Urine albumin/creatinine ratio or 24 h urine albumin excretion rate was measured at least once a year and repeated in case of elevated levels. Normal albumin excretion rate was defined as <30 mg/g or <30 mg/day. Microalbuminuria was defined as urine albumin/creatinine ratio between 30 and 300 mg/g or urine albumin excretion rate between 30 and 300 mg/day, and macroalbuminuria as urine albumin/creatinine ratio above 300 mg/g or urine albumin excretion rate above 300 mg/day in two consecutive measurements. Albuminuria was considered as present when either micro- or macroalbuminuria was present. Echocardiography The echocardiographic protocol including 2D speckle tracking measurements has been described in detail elsewhere.20 Echocardiography was performed using General Electrics (GE), Vivid 7, and Vivid 9 (GE Vingmed ultrasound, Horten, Norway) and digitally stored. Chamber quantification was done in accordance with the recommendations of the European Association of Echocardiography and the American Society of Echocardiography.21 LV mass was calculated using the formula LV mass = 0.8 × {1.04[(LV internal diameter + posterior wall thickness + septal wall thickness)3 − (LV internal diameter)3]} + 0.6 g and indexed according to height2,7. Left atrial (LA) end-systolic volumes were calculated using the area-length method, where LA volume = 8/3 × π (LA area in 4-chamber view × LA area in 2-chamber view/shortest long axis length in either view) and indexed to body surface area. We considered LA size as a diastolic measurement because of the close relationship between LA size and diastolic function reflected in the current guidelines on diastolic dysfunction.22 Mitral inflow velocities [peak early (E) and peak atrial (A)] and deceleration time of the E wave were measured in the 4-chamber view using pulsed-wave Doppler with the sample volume placed between the tips of the mitral valve leaflets. Early diastolic myocardial velocity (e′) was measured in 4-chamber view with pulsed-wave tissue velocity Doppler with the sample volume placed in the septal and lateral mitral annulus. Left ventricular ejection fraction (LVEF) was calculated using Simpson’s biplane method and was considered normal when >50%. STE was performed off-line on 2D grey scale recordings of 4-, 2-, and 3-chamber apical views and at the level of the papillary muscle in short axis view using dedicated software (GE EchoPac software BT13). A semi-automated function traced the myocardium in the beginning of the systole and allowed for manual modification of the region of interest to ensure only speckles in the myocardium were tracked throughout the cardiac cycle. Visual inspection of the tracking curves ensured accurate tracking of the speckles and segments where the tracking was assessed inadequate were excluded from the analyses. In this study, mid-myocardial global strain provided by the software algorithm was used for both longitudinal and circumferential strain. Global longitudinal strain (GLS) was the mean value of the GLS from all three standard projections. Global circumferential strain (GCS) was measured at the level of the papillary muscle. Overall, GLS was measured in 95.7% [mean frame rate 67.1 s−1 (10.6)] and was thus very feasible in this population and more so than GCS that was obtained in 80.1% [mean frame rate 66.0 s−1 (10.4)]. Strain rate was the rate of these deformations in in either longitudinal or circumferential directions and measured in s−1. Statistics Continuous variables with normal/non-normal distribution are presented as mean (standard deviation)/median (interquartile range) and compared using Welsh’s t-tests or one-way analysis of variance/Mann–Whitney U tests or Kruskall–Wallis tests where appropriate. Categorical values are presented as number (percent) and compared using χ2 tests. Multivariable associations were examined using linear regression with albuminuria status and covariates as independent variables. Statistics were calculated using R for Mac, version 2.15.3 (R Project for Statistical Computing, Vienna University of Economics and Business Administration, Wien, Austria). Results In total, 915 patients with T2D were included. Of these, 703 had no albuminuria and 212 had albuminuria of which 149 had micro- and 63 had macroalbuminuria. Excluding patients with known coronary heart disease and patients with coronary heart disease and/or reduced LVEF yielded population sizes of 755 (171 with albuminuria of which 121 had micro- and 50 had macroalbuminuria) and 673 (151 with albuminuria of which 109 had micro- and 42 had macroalbuminuria), respectively. The population demographics stratified by albuminuria status are shown in Table 1. In summary, diabetes duration, BMI, systolic blood pressure, creatinine level, haemoglobinA1c, insulin, beta-blocker, angiotensin II receptor blocker, calcium antagonist, and diuretics use were positively associated with increasing severity of albuminuria level. On the other hand, use of metformin and glucagon-like peptide 1-receptor agonist use was associated with decreasing albuminuria level. Table 1 Population demographics   No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Clinical   Age (years)  64 [57, 70]  66 [61, 72]  67 [62, 70]  0.010  0.007  0.10   Male sex (%)  433 (62)  116 (78)  45 (71)  <0.001  <0.001  0.16   Diabetes duration (years)  10.0 [4.2, 15.0]  15.0 [10.0, 21.0]  17.0 [13.0, 22.5]  <0.001  <0.001  <0.001   Body mass index (kg/m2)  29.1 [26.3, 33.0]  30.7 [27.1, 33.9]  30.9 [27.2, 35.0]  0.014  0.026  0.034   Systolic blood pressure (mmHg)  135 (16)  138 (19)  146 (20)  <0.001  0.046  <0.001   Diastolic blood pressure (mmHg)  80 (10)  79 (12)  82 (12)  0.23  0.59  0.11   Coronary heart disease (%)  119 (16.9)  28 (18.8)  13 (20.6)  0.68  0.67  0.57   Smoking    Never smoker (%)  308 (43.8)  68 (45.6)  18 (28.6)          Former smoker (%)  290 (41.3)  57 (38.3)  39 (61.9)  <0.001  0.79  0.007    Active smoker (%)  105 (14.9)  24 (16.1)  6 (9.5)         Laboratory values    Total cholesterol (mmol/l)  4.1 [3.5, 4.8]  4.1 [3.4, 4.9]  4.4 [3.7, 5.1]  0.16  0.78  0.05    Creatinine (μmol/l)  75 [64, 89]  91 [70, 108]  97 [83, 141]  <0.001  <0.001  <0.001    Haemoglobin A1c (mmol/l)  54 [46, 64]  58 [50, 70]  63 [54, 76]  <0.001  <0.001  <0.001    Haemoglobin A1c (%)  7.3 (1.4)  7.8 (1.5)  8.3 (1.6)  <0.001  <0.001  <0.001  Medication   Metformin (%)  524 (75)  106 (71)  33 (52)  0.001  0.45  <0.001   DPP4 inhibitors (%)  64 (9)  13 (9)  9 (14)  0.38  1.00  0.26   Sulfonylurea (%)  101 (14)  29 (20)  10 (16)  0.29  0.15  0.89   Glucagon-like peptide 1-receptor agonist (%)  188 (27)  29 (20)  10 (16)  0.041  0.08  0.08   Insulin (%)  288 (41)  94 (63)  46 (73)  <0.001  <0.001  <0.001   Beta blockers (%)  159 (23)  39 (26)  22 (35)  0.07  0.41  0.041   Angiotensin-converting enzyme inhibitors (%)  276 (39)  50 (34)  26 (41)  0.38  0.23  0.86   Angiotensin II receptor blockers (%)  242 (34)  83 (56)  33 (52)  <0.001  <0.001  0.007   Calcium antagonists (%)  209 (30)  54 (36)  31 (49)  0.003  0.14  0.002   Diuretics (%)  310 (44)  96 (64)  46 (73)  <0.001  <0.001  <0.001   Statins (%)  563 (80)  116 (78)  49 (78)  0.78  0.62  0.78    No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Clinical   Age (years)  64 [57, 70]  66 [61, 72]  67 [62, 70]  0.010  0.007  0.10   Male sex (%)  433 (62)  116 (78)  45 (71)  <0.001  <0.001  0.16   Diabetes duration (years)  10.0 [4.2, 15.0]  15.0 [10.0, 21.0]  17.0 [13.0, 22.5]  <0.001  <0.001  <0.001   Body mass index (kg/m2)  29.1 [26.3, 33.0]  30.7 [27.1, 33.9]  30.9 [27.2, 35.0]  0.014  0.026  0.034   Systolic blood pressure (mmHg)  135 (16)  138 (19)  146 (20)  <0.001  0.046  <0.001   Diastolic blood pressure (mmHg)  80 (10)  79 (12)  82 (12)  0.23  0.59  0.11   Coronary heart disease (%)  119 (16.9)  28 (18.8)  13 (20.6)  0.68  0.67  0.57   Smoking    Never smoker (%)  308 (43.8)  68 (45.6)  18 (28.6)          Former smoker (%)  290 (41.3)  57 (38.3)  39 (61.9)  <0.001  0.79  0.007    Active smoker (%)  105 (14.9)  24 (16.1)  6 (9.5)         Laboratory values    Total cholesterol (mmol/l)  4.1 [3.5, 4.8]  4.1 [3.4, 4.9]  4.4 [3.7, 5.1]  0.16  0.78  0.05    Creatinine (μmol/l)  75 [64, 89]  91 [70, 108]  97 [83, 141]  <0.001  <0.001  <0.001    Haemoglobin A1c (mmol/l)  54 [46, 64]  58 [50, 70]  63 [54, 76]  <0.001  <0.001  <0.001    Haemoglobin A1c (%)  7.3 (1.4)  7.8 (1.5)  8.3 (1.6)  <0.001  <0.001  <0.001  Medication   Metformin (%)  524 (75)  106 (71)  33 (52)  0.001  0.45  <0.001   DPP4 inhibitors (%)  64 (9)  13 (9)  9 (14)  0.38  1.00  0.26   Sulfonylurea (%)  101 (14)  29 (20)  10 (16)  0.29  0.15  0.89   Glucagon-like peptide 1-receptor agonist (%)  188 (27)  29 (20)  10 (16)  0.041  0.08  0.08   Insulin (%)  288 (41)  94 (63)  46 (73)  <0.001  <0.001  <0.001   Beta blockers (%)  159 (23)  39 (26)  22 (35)  0.07  0.41  0.041   Angiotensin-converting enzyme inhibitors (%)  276 (39)  50 (34)  26 (41)  0.38  0.23  0.86   Angiotensin II receptor blockers (%)  242 (34)  83 (56)  33 (52)  <0.001  <0.001  0.007   Calcium antagonists (%)  209 (30)  54 (36)  31 (49)  0.003  0.14  0.002   Diuretics (%)  310 (44)  96 (64)  46 (73)  <0.001  <0.001  <0.001   Statins (%)  563 (80)  116 (78)  49 (78)  0.78  0.62  0.78  Continuous traits are reported as mean (standard deviation) or median [interquartile range] in case of non-normal distribution. * P-values are across all groups. † P-values are no albuminuria vs. microalbuminuria. ‡ P-values are no albuminuria vs. macroalbuminuria. Bold text indicates P < 0.05. Table 1 Population demographics   No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Clinical   Age (years)  64 [57, 70]  66 [61, 72]  67 [62, 70]  0.010  0.007  0.10   Male sex (%)  433 (62)  116 (78)  45 (71)  <0.001  <0.001  0.16   Diabetes duration (years)  10.0 [4.2, 15.0]  15.0 [10.0, 21.0]  17.0 [13.0, 22.5]  <0.001  <0.001  <0.001   Body mass index (kg/m2)  29.1 [26.3, 33.0]  30.7 [27.1, 33.9]  30.9 [27.2, 35.0]  0.014  0.026  0.034   Systolic blood pressure (mmHg)  135 (16)  138 (19)  146 (20)  <0.001  0.046  <0.001   Diastolic blood pressure (mmHg)  80 (10)  79 (12)  82 (12)  0.23  0.59  0.11   Coronary heart disease (%)  119 (16.9)  28 (18.8)  13 (20.6)  0.68  0.67  0.57   Smoking    Never smoker (%)  308 (43.8)  68 (45.6)  18 (28.6)          Former smoker (%)  290 (41.3)  57 (38.3)  39 (61.9)  <0.001  0.79  0.007    Active smoker (%)  105 (14.9)  24 (16.1)  6 (9.5)         Laboratory values    Total cholesterol (mmol/l)  4.1 [3.5, 4.8]  4.1 [3.4, 4.9]  4.4 [3.7, 5.1]  0.16  0.78  0.05    Creatinine (μmol/l)  75 [64, 89]  91 [70, 108]  97 [83, 141]  <0.001  <0.001  <0.001    Haemoglobin A1c (mmol/l)  54 [46, 64]  58 [50, 70]  63 [54, 76]  <0.001  <0.001  <0.001    Haemoglobin A1c (%)  7.3 (1.4)  7.8 (1.5)  8.3 (1.6)  <0.001  <0.001  <0.001  Medication   Metformin (%)  524 (75)  106 (71)  33 (52)  0.001  0.45  <0.001   DPP4 inhibitors (%)  64 (9)  13 (9)  9 (14)  0.38  1.00  0.26   Sulfonylurea (%)  101 (14)  29 (20)  10 (16)  0.29  0.15  0.89   Glucagon-like peptide 1-receptor agonist (%)  188 (27)  29 (20)  10 (16)  0.041  0.08  0.08   Insulin (%)  288 (41)  94 (63)  46 (73)  <0.001  <0.001  <0.001   Beta blockers (%)  159 (23)  39 (26)  22 (35)  0.07  0.41  0.041   Angiotensin-converting enzyme inhibitors (%)  276 (39)  50 (34)  26 (41)  0.38  0.23  0.86   Angiotensin II receptor blockers (%)  242 (34)  83 (56)  33 (52)  <0.001  <0.001  0.007   Calcium antagonists (%)  209 (30)  54 (36)  31 (49)  0.003  0.14  0.002   Diuretics (%)  310 (44)  96 (64)  46 (73)  <0.001  <0.001  <0.001   Statins (%)  563 (80)  116 (78)  49 (78)  0.78  0.62  0.78    No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Clinical   Age (years)  64 [57, 70]  66 [61, 72]  67 [62, 70]  0.010  0.007  0.10   Male sex (%)  433 (62)  116 (78)  45 (71)  <0.001  <0.001  0.16   Diabetes duration (years)  10.0 [4.2, 15.0]  15.0 [10.0, 21.0]  17.0 [13.0, 22.5]  <0.001  <0.001  <0.001   Body mass index (kg/m2)  29.1 [26.3, 33.0]  30.7 [27.1, 33.9]  30.9 [27.2, 35.0]  0.014  0.026  0.034   Systolic blood pressure (mmHg)  135 (16)  138 (19)  146 (20)  <0.001  0.046  <0.001   Diastolic blood pressure (mmHg)  80 (10)  79 (12)  82 (12)  0.23  0.59  0.11   Coronary heart disease (%)  119 (16.9)  28 (18.8)  13 (20.6)  0.68  0.67  0.57   Smoking    Never smoker (%)  308 (43.8)  68 (45.6)  18 (28.6)          Former smoker (%)  290 (41.3)  57 (38.3)  39 (61.9)  <0.001  0.79  0.007    Active smoker (%)  105 (14.9)  24 (16.1)  6 (9.5)         Laboratory values    Total cholesterol (mmol/l)  4.1 [3.5, 4.8]  4.1 [3.4, 4.9]  4.4 [3.7, 5.1]  0.16  0.78  0.05    Creatinine (μmol/l)  75 [64, 89]  91 [70, 108]  97 [83, 141]  <0.001  <0.001  <0.001    Haemoglobin A1c (mmol/l)  54 [46, 64]  58 [50, 70]  63 [54, 76]  <0.001  <0.001  <0.001    Haemoglobin A1c (%)  7.3 (1.4)  7.8 (1.5)  8.3 (1.6)  <0.001  <0.001  <0.001  Medication   Metformin (%)  524 (75)  106 (71)  33 (52)  0.001  0.45  <0.001   DPP4 inhibitors (%)  64 (9)  13 (9)  9 (14)  0.38  1.00  0.26   Sulfonylurea (%)  101 (14)  29 (20)  10 (16)  0.29  0.15  0.89   Glucagon-like peptide 1-receptor agonist (%)  188 (27)  29 (20)  10 (16)  0.041  0.08  0.08   Insulin (%)  288 (41)  94 (63)  46 (73)  <0.001  <0.001  <0.001   Beta blockers (%)  159 (23)  39 (26)  22 (35)  0.07  0.41  0.041   Angiotensin-converting enzyme inhibitors (%)  276 (39)  50 (34)  26 (41)  0.38  0.23  0.86   Angiotensin II receptor blockers (%)  242 (34)  83 (56)  33 (52)  <0.001  <0.001  0.007   Calcium antagonists (%)  209 (30)  54 (36)  31 (49)  0.003  0.14  0.002   Diuretics (%)  310 (44)  96 (64)  46 (73)  <0.001  <0.001  <0.001   Statins (%)  563 (80)  116 (78)  49 (78)  0.78  0.62  0.78  Continuous traits are reported as mean (standard deviation) or median [interquartile range] in case of non-normal distribution. * P-values are across all groups. † P-values are no albuminuria vs. microalbuminuria. ‡ P-values are no albuminuria vs. macroalbuminuria. Bold text indicates P < 0.05. Echocardiographic findings The echocardiographic characteristics of patients with T2D stratified by albuminuria status are shown in Table 2. Regarding the structural measures, LV mass index, interventricular septum diameter, and posterior wall diameter were associated with both micro- and macroalbuminuria with increasing values with incremental severity of albuminuria. This was not the case with the LV internal diameter, which was similar in all three groups. The findings regarding diastolic and systolic function of normoalbuminuria compared with albuminuria are shown in Figure 1. We found that with albuminuria both diastolic measures—expressed as e′ velocity, E/e′, and LA volume index—and systolic measures—expressed as GLS and GLS rate—were associated with decreasing function. This was, however, not the case with GCS and GCS rate which were comparable between patients with and without albuminuria. When stratifying within albuminuria status we found that overall, for both patients with micro- and macroalbuminuria, the diastolic parameters were affected with decreased function compared with patients without albuminuria (Table 2 and Figure 2). Regarding the systolic function, we found no significant differences between patients without albuminuria and patients with microalbuminuria in any systolic measurement. However, when comparing with patients having macroalbuminuria, we found indices of decreased longitudinal function expressed as decreased GLS and GLS rate. No difference across the groups was found regarding LVEF or GCS and GCS rate. Also, sensitivity analyses revealed, that the same pattern persisted when excluding patients with coronary heart disease and patients with reduced ejection fraction (Figure 2). Table 2 Echocardiographic findings according to albuminuria status   No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Structural measures   Left ventricular mass index (g/m2.7)  37.9 (11.0)  40.5 (10.5)  45.1 (12.3)  <0.001  0.009  <0.001   Interventricular septum thickness (mm)  10.4 (1.7)  11.3 (1.5)  12.1 (2.0)  <0.001  <0.001  <0.001   End diastolic internal diameter (mm)  46.1 (6.3)  45.7 (6.2)  45.1 (5.9)  0.42  0.49  0.24   Posterior wall thickness (mm)  10.1 (1.51)  10.9 (1.5)  11.6 (1.5)  <0.001  <0.001  <0.001   Relative wall thickness  0.45 (0.10)  0.49 (0.10)  0.52 (0.09)  <0.001  <0.001  <0.001   Left atrial volume index (ml/m2)  24.3 [19.1, 29.9]  25.7 [20.0, 31.6]  29.0 [22.2, 34.9]  <0.001  0.019  <0.001  Diastolic measures   Peak E velocity (m/s)  0.73 [0.62, 0.86]  0.79 [0.66, 0.89]  0.74 [0.62, 0.88]  0.023  0.006  0.69   Peak A velocity (m/s)  0.84 (0.19)  0.85 (0.18)  0.89 (0.18)  0.17  0.72  0.06   E deceleration time (ms)  217 [182, 259]  223 [191, 271]  241 [202, 288]  0.013  0.13  0.008   E/A ratio  0.87 [0.75, 1.05]  0.90 [0.79, 1.12]  0.86 [0.72, 1.00]  0.06  0.08  0.16   Septal e′ (cm/s)  6.9 (1.9)  6.4 (1.7)  5.9 (1.7)  <0.001  0.004  <0.001   Lateral e′ (cm/s)  8.8 (2.5)  8.2 (2.2)  7.6 (2.4)  <0.001  0.004  <0.001   Mean e′ (cm/s)  7.9 (2.0)  7.3 (1.8)  6.8 (1.9)  <0.001  0.002  <0.001   E/e′septal  10.6 [8.9, 13.2]  12.1 [10.3, 14.8]  12.7 [10.4, 16.6]  <0.001  <0.001  <0.001   E/e′lateral  8.3 [6.8, 10.5]  9.6 [7.7, 11.4]  10.7 [7.4, 13.8]  <0.001  <0.001  <0.001   E/e′mean  9.3 [7.8, 11.4]  10.5 [8.8, 12.5]  11.9 [8.9, 15.3]  <0.001  <0.001  <0.001  Systolic measures   Ejection fraction (%)  60.7 [55.7, 65.2]  59.9 [55.7, 64.4]  58.5 [53.1, 62.7]  0.21  0.39  0.10   Reduced ejection fraction (<50%) (%)  70 (10.3)  18 (12.2)  11 (18.0)  0.17  0.60  0.10   Global longitudinal strain (%)  −14.6 (2.7)  −14.1 (3.0)  −13.3 (2.9)  0.001  0.07  <0.001   Global longitudinal strain rate (s−1)  −0.79 (0.17)  −0.77 (0.18)  −0.72 (0.16)  0.005  0.25  0.001   Global circumferential strain (%)  −18.0 (5.3)  −18.0 (5.2)  −16.9 (5.6)  0.41  1.00  0.19   Global circumferential strain rate (s−1)  −1.05 (0.35)  −1.04 (0.33)  −0.98 (0.33)  0.37  0.67  0.17    No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Structural measures   Left ventricular mass index (g/m2.7)  37.9 (11.0)  40.5 (10.5)  45.1 (12.3)  <0.001  0.009  <0.001   Interventricular septum thickness (mm)  10.4 (1.7)  11.3 (1.5)  12.1 (2.0)  <0.001  <0.001  <0.001   End diastolic internal diameter (mm)  46.1 (6.3)  45.7 (6.2)  45.1 (5.9)  0.42  0.49  0.24   Posterior wall thickness (mm)  10.1 (1.51)  10.9 (1.5)  11.6 (1.5)  <0.001  <0.001  <0.001   Relative wall thickness  0.45 (0.10)  0.49 (0.10)  0.52 (0.09)  <0.001  <0.001  <0.001   Left atrial volume index (ml/m2)  24.3 [19.1, 29.9]  25.7 [20.0, 31.6]  29.0 [22.2, 34.9]  <0.001  0.019  <0.001  Diastolic measures   Peak E velocity (m/s)  0.73 [0.62, 0.86]  0.79 [0.66, 0.89]  0.74 [0.62, 0.88]  0.023  0.006  0.69   Peak A velocity (m/s)  0.84 (0.19)  0.85 (0.18)  0.89 (0.18)  0.17  0.72  0.06   E deceleration time (ms)  217 [182, 259]  223 [191, 271]  241 [202, 288]  0.013  0.13  0.008   E/A ratio  0.87 [0.75, 1.05]  0.90 [0.79, 1.12]  0.86 [0.72, 1.00]  0.06  0.08  0.16   Septal e′ (cm/s)  6.9 (1.9)  6.4 (1.7)  5.9 (1.7)  <0.001  0.004  <0.001   Lateral e′ (cm/s)  8.8 (2.5)  8.2 (2.2)  7.6 (2.4)  <0.001  0.004  <0.001   Mean e′ (cm/s)  7.9 (2.0)  7.3 (1.8)  6.8 (1.9)  <0.001  0.002  <0.001   E/e′septal  10.6 [8.9, 13.2]  12.1 [10.3, 14.8]  12.7 [10.4, 16.6]  <0.001  <0.001  <0.001   E/e′lateral  8.3 [6.8, 10.5]  9.6 [7.7, 11.4]  10.7 [7.4, 13.8]  <0.001  <0.001  <0.001   E/e′mean  9.3 [7.8, 11.4]  10.5 [8.8, 12.5]  11.9 [8.9, 15.3]  <0.001  <0.001  <0.001  Systolic measures   Ejection fraction (%)  60.7 [55.7, 65.2]  59.9 [55.7, 64.4]  58.5 [53.1, 62.7]  0.21  0.39  0.10   Reduced ejection fraction (<50%) (%)  70 (10.3)  18 (12.2)  11 (18.0)  0.17  0.60  0.10   Global longitudinal strain (%)  −14.6 (2.7)  −14.1 (3.0)  −13.3 (2.9)  0.001  0.07  <0.001   Global longitudinal strain rate (s−1)  −0.79 (0.17)  −0.77 (0.18)  −0.72 (0.16)  0.005  0.25  0.001   Global circumferential strain (%)  −18.0 (5.3)  −18.0 (5.2)  −16.9 (5.6)  0.41  1.00  0.19   Global circumferential strain rate (s−1)  −1.05 (0.35)  −1.04 (0.33)  −0.98 (0.33)  0.37  0.67  0.17  Continuous traits are reported as mean (standard deviation) or median [interquartile range] in case of non-normal distribution. * P-values are across all groups. † P-values are no albuminuria vs. microalbuminuria. ‡ P-values are no albuminuria vs. macroalbuminuria. Bold text indicates P < 0.05. Table 2 Echocardiographic findings according to albuminuria status   No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Structural measures   Left ventricular mass index (g/m2.7)  37.9 (11.0)  40.5 (10.5)  45.1 (12.3)  <0.001  0.009  <0.001   Interventricular septum thickness (mm)  10.4 (1.7)  11.3 (1.5)  12.1 (2.0)  <0.001  <0.001  <0.001   End diastolic internal diameter (mm)  46.1 (6.3)  45.7 (6.2)  45.1 (5.9)  0.42  0.49  0.24   Posterior wall thickness (mm)  10.1 (1.51)  10.9 (1.5)  11.6 (1.5)  <0.001  <0.001  <0.001   Relative wall thickness  0.45 (0.10)  0.49 (0.10)  0.52 (0.09)  <0.001  <0.001  <0.001   Left atrial volume index (ml/m2)  24.3 [19.1, 29.9]  25.7 [20.0, 31.6]  29.0 [22.2, 34.9]  <0.001  0.019  <0.001  Diastolic measures   Peak E velocity (m/s)  0.73 [0.62, 0.86]  0.79 [0.66, 0.89]  0.74 [0.62, 0.88]  0.023  0.006  0.69   Peak A velocity (m/s)  0.84 (0.19)  0.85 (0.18)  0.89 (0.18)  0.17  0.72  0.06   E deceleration time (ms)  217 [182, 259]  223 [191, 271]  241 [202, 288]  0.013  0.13  0.008   E/A ratio  0.87 [0.75, 1.05]  0.90 [0.79, 1.12]  0.86 [0.72, 1.00]  0.06  0.08  0.16   Septal e′ (cm/s)  6.9 (1.9)  6.4 (1.7)  5.9 (1.7)  <0.001  0.004  <0.001   Lateral e′ (cm/s)  8.8 (2.5)  8.2 (2.2)  7.6 (2.4)  <0.001  0.004  <0.001   Mean e′ (cm/s)  7.9 (2.0)  7.3 (1.8)  6.8 (1.9)  <0.001  0.002  <0.001   E/e′septal  10.6 [8.9, 13.2]  12.1 [10.3, 14.8]  12.7 [10.4, 16.6]  <0.001  <0.001  <0.001   E/e′lateral  8.3 [6.8, 10.5]  9.6 [7.7, 11.4]  10.7 [7.4, 13.8]  <0.001  <0.001  <0.001   E/e′mean  9.3 [7.8, 11.4]  10.5 [8.8, 12.5]  11.9 [8.9, 15.3]  <0.001  <0.001  <0.001  Systolic measures   Ejection fraction (%)  60.7 [55.7, 65.2]  59.9 [55.7, 64.4]  58.5 [53.1, 62.7]  0.21  0.39  0.10   Reduced ejection fraction (<50%) (%)  70 (10.3)  18 (12.2)  11 (18.0)  0.17  0.60  0.10   Global longitudinal strain (%)  −14.6 (2.7)  −14.1 (3.0)  −13.3 (2.9)  0.001  0.07  <0.001   Global longitudinal strain rate (s−1)  −0.79 (0.17)  −0.77 (0.18)  −0.72 (0.16)  0.005  0.25  0.001   Global circumferential strain (%)  −18.0 (5.3)  −18.0 (5.2)  −16.9 (5.6)  0.41  1.00  0.19   Global circumferential strain rate (s−1)  −1.05 (0.35)  −1.04 (0.33)  −0.98 (0.33)  0.37  0.67  0.17    No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Structural measures   Left ventricular mass index (g/m2.7)  37.9 (11.0)  40.5 (10.5)  45.1 (12.3)  <0.001  0.009  <0.001   Interventricular septum thickness (mm)  10.4 (1.7)  11.3 (1.5)  12.1 (2.0)  <0.001  <0.001  <0.001   End diastolic internal diameter (mm)  46.1 (6.3)  45.7 (6.2)  45.1 (5.9)  0.42  0.49  0.24   Posterior wall thickness (mm)  10.1 (1.51)  10.9 (1.5)  11.6 (1.5)  <0.001  <0.001  <0.001   Relative wall thickness  0.45 (0.10)  0.49 (0.10)  0.52 (0.09)  <0.001  <0.001  <0.001   Left atrial volume index (ml/m2)  24.3 [19.1, 29.9]  25.7 [20.0, 31.6]  29.0 [22.2, 34.9]  <0.001  0.019  <0.001  Diastolic measures   Peak E velocity (m/s)  0.73 [0.62, 0.86]  0.79 [0.66, 0.89]  0.74 [0.62, 0.88]  0.023  0.006  0.69   Peak A velocity (m/s)  0.84 (0.19)  0.85 (0.18)  0.89 (0.18)  0.17  0.72  0.06   E deceleration time (ms)  217 [182, 259]  223 [191, 271]  241 [202, 288]  0.013  0.13  0.008   E/A ratio  0.87 [0.75, 1.05]  0.90 [0.79, 1.12]  0.86 [0.72, 1.00]  0.06  0.08  0.16   Septal e′ (cm/s)  6.9 (1.9)  6.4 (1.7)  5.9 (1.7)  <0.001  0.004  <0.001   Lateral e′ (cm/s)  8.8 (2.5)  8.2 (2.2)  7.6 (2.4)  <0.001  0.004  <0.001   Mean e′ (cm/s)  7.9 (2.0)  7.3 (1.8)  6.8 (1.9)  <0.001  0.002  <0.001   E/e′septal  10.6 [8.9, 13.2]  12.1 [10.3, 14.8]  12.7 [10.4, 16.6]  <0.001  <0.001  <0.001   E/e′lateral  8.3 [6.8, 10.5]  9.6 [7.7, 11.4]  10.7 [7.4, 13.8]  <0.001  <0.001  <0.001   E/e′mean  9.3 [7.8, 11.4]  10.5 [8.8, 12.5]  11.9 [8.9, 15.3]  <0.001  <0.001  <0.001  Systolic measures   Ejection fraction (%)  60.7 [55.7, 65.2]  59.9 [55.7, 64.4]  58.5 [53.1, 62.7]  0.21  0.39  0.10   Reduced ejection fraction (<50%) (%)  70 (10.3)  18 (12.2)  11 (18.0)  0.17  0.60  0.10   Global longitudinal strain (%)  −14.6 (2.7)  −14.1 (3.0)  −13.3 (2.9)  0.001  0.07  <0.001   Global longitudinal strain rate (s−1)  −0.79 (0.17)  −0.77 (0.18)  −0.72 (0.16)  0.005  0.25  0.001   Global circumferential strain (%)  −18.0 (5.3)  −18.0 (5.2)  −16.9 (5.6)  0.41  1.00  0.19   Global circumferential strain rate (s−1)  −1.05 (0.35)  −1.04 (0.33)  −0.98 (0.33)  0.37  0.67  0.17  Continuous traits are reported as mean (standard deviation) or median [interquartile range] in case of non-normal distribution. * P-values are across all groups. † P-values are no albuminuria vs. microalbuminuria. ‡ P-values are no albuminuria vs. macroalbuminuria. Bold text indicates P < 0.05. Figure 1 View largeDownload slide Box-plots of diastolic function, longitudinal, and circumferential strain and strain rate according to albuminuria status. Figure 1 View largeDownload slide Box-plots of diastolic function, longitudinal, and circumferential strain and strain rate according to albuminuria status. Figure 2 View largeDownload slide Mean and median values of diastolic and systolic findings according to albuminuria status. Values are means unless otherwise stated. Levels of significance: P < 0.10, *P < 0.05, **P < 0.01, ***P < 0.001. CHD, coronary heart disease; LVEF, left ventricular ejection fraction. Figure 2 View largeDownload slide Mean and median values of diastolic and systolic findings according to albuminuria status. Values are means unless otherwise stated. Levels of significance: P < 0.10, *P < 0.05, **P < 0.01, ***P < 0.001. CHD, coronary heart disease; LVEF, left ventricular ejection fraction. Multivariable findings The effect of albuminuria status on measures of diastolic and systolic function after adjusting for age, sex, BMI, systolic blood pressure, and smoking status is found in Table 3. In general, the pattern of decreased diastolic measures in both patients with micro- and macroalbuminuria and only decreased systolic measures in patients with macroalbuminuria persisted after adjusting for possible confounding factors although the association between albuminuria status and GLS rate was attenuated in the group without known heart disease and normal LVEF. Table 3 Multivariable adjusted analyses of association between diastolic and systolic measures and albuminuria status   All patients  No CHD  No CHD and normal LVEF      n = 915   n = 755   n = 673       β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  Diastolic measures   e′ septal (cm/s)   Albuminuria  −0.4 (0.1)  0.004  −0.5 (0.2)  <0.001  −0.5 (0.2)  <0.001    Microalbuminuria  −0.3 (0.2)  0.07  −0.4 (0.2)  0.036  −0.4 (0.8)  0.020    Macroalbuminuria  −0.7 (0.2)  0.002  −0.9 (0.3)  <0.001  −0.8 (0.3)  0.002  E/e′septal   Albuminuria  1.3 (0.4)  <0.001  1.6 (0.4)  <0.001  1.4 (0.4)  <0.001    Microalbuminuria  1.3 (0.4)  0.002  1.7 (0.5)  <0.001  1.6 (0.5)  <0.001    Macroalbuminuria  1.3 (0.6)  0.031  1.5 (0.7)  0.030  1.1 (0.7)  0.11  LA size (ml/m2)   Albuminuria  2.2 (0.7)  0.001  3.0 (0.7)  <0.001  2.8 (0.8)  0.001    Microalbuminuria  1.8 (0.8)  0.013  2.9 (0.8)  <0.001  2.6 (0.9)  0.003    Macroalbuminuria  2.9 (1.1)  0.008  3.1 (1.2)  0.011  3.5 (1.3)  0.008  Systolic measures   GLS (%)   Albuminuria  0.42 (0.23)  0.07  0.48 (0.25)  0.05  0.37 (0.24)  0.12    Microalbuminuria  0.20 (0.26)  0.44  0.24 (0.28)  0.39  0.17 (0.27)  0.53    Macroalbuminuria  0.96 (0.38)  0.013  1.06 (0.41)  0.010  0.89 (0.41)  0.029  GLS rate (s−1)   Albuminuria  0.03 (0.01)  0.08  0.03 (0.02)  0.035  0.02 (0.02)  0.15    Microalbuminuria  0.01 (0.02)  0.42  0.02 (0.01)  0.20  0.02 (0.02)  0.35    Macroalbuminuria  0.06 (0.02)  0.021  0.06 (0.03)  0.025  0.04 (0.03)  0.14    All patients  No CHD  No CHD and normal LVEF      n = 915   n = 755   n = 673       β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  Diastolic measures   e′ septal (cm/s)   Albuminuria  −0.4 (0.1)  0.004  −0.5 (0.2)  <0.001  −0.5 (0.2)  <0.001    Microalbuminuria  −0.3 (0.2)  0.07  −0.4 (0.2)  0.036  −0.4 (0.8)  0.020    Macroalbuminuria  −0.7 (0.2)  0.002  −0.9 (0.3)  <0.001  −0.8 (0.3)  0.002  E/e′septal   Albuminuria  1.3 (0.4)  <0.001  1.6 (0.4)  <0.001  1.4 (0.4)  <0.001    Microalbuminuria  1.3 (0.4)  0.002  1.7 (0.5)  <0.001  1.6 (0.5)  <0.001    Macroalbuminuria  1.3 (0.6)  0.031  1.5 (0.7)  0.030  1.1 (0.7)  0.11  LA size (ml/m2)   Albuminuria  2.2 (0.7)  0.001  3.0 (0.7)  <0.001  2.8 (0.8)  0.001    Microalbuminuria  1.8 (0.8)  0.013  2.9 (0.8)  <0.001  2.6 (0.9)  0.003    Macroalbuminuria  2.9 (1.1)  0.008  3.1 (1.2)  0.011  3.5 (1.3)  0.008  Systolic measures   GLS (%)   Albuminuria  0.42 (0.23)  0.07  0.48 (0.25)  0.05  0.37 (0.24)  0.12    Microalbuminuria  0.20 (0.26)  0.44  0.24 (0.28)  0.39  0.17 (0.27)  0.53    Macroalbuminuria  0.96 (0.38)  0.013  1.06 (0.41)  0.010  0.89 (0.41)  0.029  GLS rate (s−1)   Albuminuria  0.03 (0.01)  0.08  0.03 (0.02)  0.035  0.02 (0.02)  0.15    Microalbuminuria  0.01 (0.02)  0.42  0.02 (0.01)  0.20  0.02 (0.02)  0.35    Macroalbuminuria  0.06 (0.02)  0.021  0.06 (0.03)  0.025  0.04 (0.03)  0.14  Adjusted for age and sex, body mass index, systolic blood pressure, smoking status, use of either renin-angiotensin-aldosterone system blocking or beta-blocking agents and use of diuretics. β-Coefficients are compared to ‘no albuminuria’. CHD, coronary heart disease; LVEF, left ventricular ejection fraction; LA, left atrial; GLS, global longitudinal strain. Bold text indicates P < 0.05. Table 3 Multivariable adjusted analyses of association between diastolic and systolic measures and albuminuria status   All patients  No CHD  No CHD and normal LVEF      n = 915   n = 755   n = 673       β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  Diastolic measures   e′ septal (cm/s)   Albuminuria  −0.4 (0.1)  0.004  −0.5 (0.2)  <0.001  −0.5 (0.2)  <0.001    Microalbuminuria  −0.3 (0.2)  0.07  −0.4 (0.2)  0.036  −0.4 (0.8)  0.020    Macroalbuminuria  −0.7 (0.2)  0.002  −0.9 (0.3)  <0.001  −0.8 (0.3)  0.002  E/e′septal   Albuminuria  1.3 (0.4)  <0.001  1.6 (0.4)  <0.001  1.4 (0.4)  <0.001    Microalbuminuria  1.3 (0.4)  0.002  1.7 (0.5)  <0.001  1.6 (0.5)  <0.001    Macroalbuminuria  1.3 (0.6)  0.031  1.5 (0.7)  0.030  1.1 (0.7)  0.11  LA size (ml/m2)   Albuminuria  2.2 (0.7)  0.001  3.0 (0.7)  <0.001  2.8 (0.8)  0.001    Microalbuminuria  1.8 (0.8)  0.013  2.9 (0.8)  <0.001  2.6 (0.9)  0.003    Macroalbuminuria  2.9 (1.1)  0.008  3.1 (1.2)  0.011  3.5 (1.3)  0.008  Systolic measures   GLS (%)   Albuminuria  0.42 (0.23)  0.07  0.48 (0.25)  0.05  0.37 (0.24)  0.12    Microalbuminuria  0.20 (0.26)  0.44  0.24 (0.28)  0.39  0.17 (0.27)  0.53    Macroalbuminuria  0.96 (0.38)  0.013  1.06 (0.41)  0.010  0.89 (0.41)  0.029  GLS rate (s−1)   Albuminuria  0.03 (0.01)  0.08  0.03 (0.02)  0.035  0.02 (0.02)  0.15    Microalbuminuria  0.01 (0.02)  0.42  0.02 (0.01)  0.20  0.02 (0.02)  0.35    Macroalbuminuria  0.06 (0.02)  0.021  0.06 (0.03)  0.025  0.04 (0.03)  0.14    All patients  No CHD  No CHD and normal LVEF      n = 915   n = 755   n = 673       β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  Diastolic measures   e′ septal (cm/s)   Albuminuria  −0.4 (0.1)  0.004  −0.5 (0.2)  <0.001  −0.5 (0.2)  <0.001    Microalbuminuria  −0.3 (0.2)  0.07  −0.4 (0.2)  0.036  −0.4 (0.8)  0.020    Macroalbuminuria  −0.7 (0.2)  0.002  −0.9 (0.3)  <0.001  −0.8 (0.3)  0.002  E/e′septal   Albuminuria  1.3 (0.4)  <0.001  1.6 (0.4)  <0.001  1.4 (0.4)  <0.001    Microalbuminuria  1.3 (0.4)  0.002  1.7 (0.5)  <0.001  1.6 (0.5)  <0.001    Macroalbuminuria  1.3 (0.6)  0.031  1.5 (0.7)  0.030  1.1 (0.7)  0.11  LA size (ml/m2)   Albuminuria  2.2 (0.7)  0.001  3.0 (0.7)  <0.001  2.8 (0.8)  0.001    Microalbuminuria  1.8 (0.8)  0.013  2.9 (0.8)  <0.001  2.6 (0.9)  0.003    Macroalbuminuria  2.9 (1.1)  0.008  3.1 (1.2)  0.011  3.5 (1.3)  0.008  Systolic measures   GLS (%)   Albuminuria  0.42 (0.23)  0.07  0.48 (0.25)  0.05  0.37 (0.24)  0.12    Microalbuminuria  0.20 (0.26)  0.44  0.24 (0.28)  0.39  0.17 (0.27)  0.53    Macroalbuminuria  0.96 (0.38)  0.013  1.06 (0.41)  0.010  0.89 (0.41)  0.029  GLS rate (s−1)   Albuminuria  0.03 (0.01)  0.08  0.03 (0.02)  0.035  0.02 (0.02)  0.15    Microalbuminuria  0.01 (0.02)  0.42  0.02 (0.01)  0.20  0.02 (0.02)  0.35    Macroalbuminuria  0.06 (0.02)  0.021  0.06 (0.03)  0.025  0.04 (0.03)  0.14  Adjusted for age and sex, body mass index, systolic blood pressure, smoking status, use of either renin-angiotensin-aldosterone system blocking or beta-blocking agents and use of diuretics. β-Coefficients are compared to ‘no albuminuria’. CHD, coronary heart disease; LVEF, left ventricular ejection fraction; LA, left atrial; GLS, global longitudinal strain. Bold text indicates P < 0.05. Discussion The main findings in this study were, that, in patients with T2D, impaired diastolic function was present in both patients with micro- and macroalbuminuria, but impaired systolic function was only present in patients with macroalbuminuria. This pattern was in general also present when excluding patients with known coronary heart disease and patients with decreased LVEF and persisted even in multivariable analyses. Also, we found that LV remodelling, expressed as LV mass index and wall thicknesses, was accentuated as albuminuria status progressed. These findings indicate that both the development of albuminuria and cardiac damage share a common background: as minor degrees of general vascular damage develop, the result is microalbuminuria and LV diastolic function and when the general vascular damage is aggravated, both macroalbuminuria and systolic impairment occurs. Thus, our study, supports the notion of vascular damage in association with albuminuria as a cause of heart failure in patients with T2D and suggests that renal protection strategies are important in the management of patients with T2D. Albuminuria and myocardial impairment in patients with type 2 diabetes In this study, diastolic measures including e′, E/e′, and LA size were affected in patients with both micro- and macroalbuminuria. Measures of systolic longitudinal function, GLS and GLS rate, were only affected in patients with macroalbuminuria, whereas systolic circumferential deformation, GCS and GCS rate, was similar regardless of albuminuria status. The Strong Heart Study investigated the relation between albuminuria status and systolic and diastolic function in a population of American Indians using 2D and spectral Doppler echocardiography. In accordance to our results, they found increased LV mass index with albuminuria and cardiac changes primarily related to diastolic impairment in patients with microalbuminuria and to diastolic and systolic impairment in patients with macroalbuminuria. However, they did also describe decreased LVEF in patients with macroalbuminuria compared with patients with normo- and microalbuminuria whereas we were only able to demonstrate decreased systolic function measured by 2DSTE. Also, in a smaller study including 123 patients with T2D, myocardial performance estimated with the Tei index was found to be strongly correlated with degree of albuminuria,23 and recently, the association between albuminuria and GLS was confirmed in 144 asymptomatic patients with T2D without coronary heart disease.24 Also, we have previously shown that among a number of clinical values, albuminuria was associated with the presence of any echocardiographic abnormality including hypertrophy, LVEF, LV diastolic dysfunction, right ventricular dysfunction, LA enlargement, and valve disorder.17 Microvascular dysfunction is thought to play a role in the pathogenesis of LV diastolic and systolic dysfunction in patients with T2D,25 and previous studies using contrast echocardiography and Doppler derived coronary flow reserve have demonstrated decreased microvascular function in patients with T2D26,27 and especially when combined with other cardiovascular risk factors such as hypertension and obesity.28 Though one previous study in patients with diabetes failed to find association between microvascular function and perfusion,29 in a rather recent study, microvascular function very accurately measured with 82Rb PET/CT was decreased both in patients with T2D but especially in patients with T2D and microalbuminuria indicating common microvascular impairment in multiple vascular beds thus supporting our findings.30 Hence, our study extends and verifies these findings by confirming impaired diastolic and systolic function using comprehensive, recent echocardiographic modalities and by demonstrating that these changes are present even in a contemporary population of patients with T2D receiving multifactorial treatment including a high proportion of patients receiving renin–angiotensin–aldosterone-system blocking agents. As outlined, albuminuria is thought to be a marker of generalized vascular damage and impaired endothelial function.6,31 In the myocardium, the subendocardial layer, which is thought to be most sensitive myocardial layer due to the distance to the epicardial coronary arteries and because it undergoes high pressure variations throughout the cardiac cycle, is where the myocardial fibres mainly responsible for the longitudinal cardiac motion are found.32 Thus, pathogenic mechanisms affecting the myocardium are thought to give rise to primarily longitudinal dysfunction in the early stages of the disease process. In accordance, our findings suggest that the effect of the generalized vascular damage associated with albuminuria takes place mainly in the subendocardium affecting longitudinal function. Thus, the systolic impairment that was found in patients with macroalbuminuria was in our study characterized by decreased longitudinal and not circumferential function.33 Strengths and limitations The strengths of the present study include the large, well-characterized, contemporary multicentre cohort of patients with T2D receiving multifactorial treatment including patients with all stages of the disease that makes our results applicable to the clinical populations. Also, the echocardiograms and analyses were performed almost exclusively by one investigator limiting interobserver variations to a minimum. There are, however, limitations to this study as well: The study population was recruited from secondary care centres and the results should be interpreted with cautions in patients in early stages of the disease followed in the primary sector. Also, though it was a large cohort of patients with T2D, only 63 patients had macroalbuminuria, which, however, underlines the beneficial effects of multifactorial treatment decreasing microvascular dysfunction in these patients. Finally, as GCS and strain rate was only obtainable in 80.1% of the study population the results regarding these parameters should be interpreted with care. Conclusion In patients with type 2 diabetes, microalbuminuria is associated with decreased diastolic function whereas decreased systolic function was only associated with macroalbuminuria supporting the notion of similar pathogenic mechanisms of albuminuria and impaired myocardial function. Funding The study was carried out as part of PGJ’s employment at Gentofte Hospital, University of Copenhagen, Denmark. References 1 Heidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, Fonarow GC et al.   Forecasting the impact of heart failure in the United States. Circ Heart Fail  2013; 6: 606– 19. Google Scholar CrossRef Search ADS PubMed  2 Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract  2014; 103: 137– 49. Google Scholar CrossRef Search ADS PubMed  3 Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol  1974; 34: 29– 34. Google Scholar CrossRef Search ADS PubMed  4 He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med  2001; 161: 996– 1002. Google Scholar CrossRef Search ADS PubMed  5 Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care  2004; 27: 699– 703. 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Google Scholar CrossRef Search ADS PubMed  31 Jensen JS, Borch-Johnsen K, Jensen G, Feldt-Rasmussen B. Microalbuminuria reflects a generalized transvascular albumin leakiness in clinically healthy subjects. Clin Sci  1995; 88: 629– 33. Google Scholar CrossRef Search ADS PubMed  32 Sabbah HN, Marzilli M, Stein PD. The relative role of subendocardium and subepicardium in left ventricular mechanics. Am J Physiol  1981; 240: H920– 6. Google Scholar PubMed  33 Stanton T, Marwick TH. Assessment of subendocardial structure and function. JACC Cardiovasc Imaging  2010; 3: 867– 75. Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Presence of micro- and macroalbuminuria and the association with cardiac mechanics in patients with type 2 diabetes

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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.
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Abstract

Abstract Aims Albuminuria—a marker of generalized vascular dysfunction—is a strong predictor of heart failure in patients with type 2 diabetes which may be caused by concomitant myocardial dysfunction reflecting the same underlying pathogenesis. Methods and results We included 915 patients with type 2 diabetes from two secondary care centres and stratified according to albuminuria status in normo-, micro-, and macroalbuminuria. We performed comprehensive echocardiography including conventional imaging, tissue Doppler imaging, and 2D speckle tracking. Cardiac remodelling occurred in patients with increasing left ventricular (LV) mass index and LV wall thicknesses with increasing severity of albuminuria. Diastolic measures worsened across groups of albuminuria severity (normo-, micro-, and macroalbuminuria, respectively): septal e′ velocity [mean: 6.9 cm/s (SD 1.9), 6.4 (1.7), and 5.9 (1.7), P < 0.001], septal E/e′ (median: 10.6 [interquartile range: 8.9–13.2], 12.1 [10.3–14.8], and 12.7 [10.4–16.6], P < 0.001), and left atrial volume index (24.3 mL/m2 [19.1–29.9], 25.7 [20.0–31.6], and 29.0 [22.2–34.9], P < 0.001) In contrast, systolic measures were only impaired in patients with macroalbuminuria: global longitudinal strain (GLS): [−14.6% (2.7) in normo- and −13.3 (2.9) in macroalbuminuria, P < 0.001] and GLS rate [mean: −0.79 s−1 (0.17) in normo- and −0.72 (0.16) in macroalbuminuria, P = 0.001]. The findings persisted in subgroup analyses of patients without known coronary heart disease and with normal ejection fraction and in multivariable adjusted analyses. Conclusion In patients with type 2 diabetes, microalbuminuria is associated with decreased diastolic function whereas decreased systolic function was only associated with macroalbuminuria supporting the notion of similar pathogenic mechanisms of albuminuria and impaired myocardial function. type 2 diabetes, albuminuria, heart failure, cardiac remodelling, echocardiography Introduction By 2030, the prevalence of heart failure (HF) in the USA is projected to have increased by 25%, which is expected mainly to be caused by an ageing population.1 However, with the concomitant worldwide, rapid increase in the prevalence of type 2 diabetes (T2D)2—which consistently has been shown to be associated with a 2–4 fold increase in risk of heart failure3–5—the proportion of patients with HF attributable to T2D will also increase substantially in the coming years. Despite much attention, the mechanisms for the development of heart failure in these patients remain not fully understood. The Steno hypothesis suggested, that excretion of albumin in the kidneys reflected not only localized renal disease but was a marker of generalized endothelial dysfunction.6 Accordingly, albuminuria has been shown in a number of studies to be related to other markers of subclinical cardiovascular disease, including ischaemic electrocardiographic changes7 and coronary artery calcium score/carotid intima thickness in non-diabetic populations.8 However, interestingly, in patients with T2D, as well as in patients without T2D, the presence of albuminuria is associated not only with the development of renal impairment and cardiovascular disease in the form of myocardial infarction, stroke, and cardiovascular death, but also to the development of congestive heart failure.9 Consequently, a direct effect on the myocardium of the generalized endothelial dysfunction found in patients with albuminuria may exist. In line with this, previous studies have shown a relationship between albuminuria and increased left ventricular (LV) mass10 in normotensive, and increased LV mass11,12 and diastolic dysfunction12 in patients with hypertension. Also, in patients with T2D, older studies, including The Strong Heart Study have revealed an association between albuminuria and LV mass index and diastolic dysfunction.13,14 In the recent years, development of newer echocardiographic modalities including tissue Doppler Imaging (TDI) and 2D speckle tracking echocardiography (2DSTE) have allowed for detection of subtle changes in both LV systolic and diastolic function. Using these measures, Katz et al.15 found evidence of both systolic and diastolic dysfunction as assessed by TDI and 2DSTE, in a population with a high proportion of hypertensive subjects.15 Also, in patients with type 1 diabetes compared with a control population from the general population, 2DSTE revealed impaired systolic function only in the patients that had developed albuminuria.16 However, this association between albuminuria and cardiac mechanics estimated by TDI and 2DSE—that may reveal associations hitherto undetected—remains to be examined in patients with T2D. In this study, we aimed to describe the association between albuminuria and cardiac mechanics using comprehensive echocardiography in a large contemporary cohort of outpatients with T2D receiving multifactorial treatment. Methods Study population From 2011 to 2013, the Thousand & 2 echocardiographic study recruited patients with type 2 diabetes from two large secondary care centre in the Capital Region of Denmark (Steno Diabetes Center Copenhagen and Center for Diabetes Research, Gentofte Hospital, University of Copenhagen). A total of 2158 patients were invited and 1030 participated. Details on study inclusion and study visit have been described previously.17,18 Before the study visit, the patients were asked to fill out a questionnaire with information on current medication, prior heart disease (myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, congestive heart failure, and atrial fibrillation), prior stroke and peripheral artery disease, family history of coronary heart disease, smoking habits, height, and weight. The questionnaire was reviewed with the patient at the study visit by P.G.J. Blood pressure was measured in the supine position after at least 15 min of rest. Body mass index (BMI) was defined as weight (kg)/height (m)2. Cholesterol levels, creatinine, and haemoglobin A1c were retrieved from the patients’ routine laboratory results. Patients with atrial fibrillation during the echocardiographic examination, more than moderate valve disease and/or previous heart valve surgery were excluded (n = 96). Also, patients without information of urine albumin excretion were excluded (n = 19). The study was conducted in accordance with the Helsinki Declaration, approved by The Danish National Committee on Biomedical Research Ethics, amendment to Protocol No. H-3-2009-139.19 All participants gave written informed consent. Urine albumin excretion measurements Information on urine albumin/creatinine ratio or 24 h urine albumin excretion rate was retrieved from the patient’s standard laboratory measurements. Urine albumin/creatinine ratio or 24 h urine albumin excretion rate was measured at least once a year and repeated in case of elevated levels. Normal albumin excretion rate was defined as <30 mg/g or <30 mg/day. Microalbuminuria was defined as urine albumin/creatinine ratio between 30 and 300 mg/g or urine albumin excretion rate between 30 and 300 mg/day, and macroalbuminuria as urine albumin/creatinine ratio above 300 mg/g or urine albumin excretion rate above 300 mg/day in two consecutive measurements. Albuminuria was considered as present when either micro- or macroalbuminuria was present. Echocardiography The echocardiographic protocol including 2D speckle tracking measurements has been described in detail elsewhere.20 Echocardiography was performed using General Electrics (GE), Vivid 7, and Vivid 9 (GE Vingmed ultrasound, Horten, Norway) and digitally stored. Chamber quantification was done in accordance with the recommendations of the European Association of Echocardiography and the American Society of Echocardiography.21 LV mass was calculated using the formula LV mass = 0.8 × {1.04[(LV internal diameter + posterior wall thickness + septal wall thickness)3 − (LV internal diameter)3]} + 0.6 g and indexed according to height2,7. Left atrial (LA) end-systolic volumes were calculated using the area-length method, where LA volume = 8/3 × π (LA area in 4-chamber view × LA area in 2-chamber view/shortest long axis length in either view) and indexed to body surface area. We considered LA size as a diastolic measurement because of the close relationship between LA size and diastolic function reflected in the current guidelines on diastolic dysfunction.22 Mitral inflow velocities [peak early (E) and peak atrial (A)] and deceleration time of the E wave were measured in the 4-chamber view using pulsed-wave Doppler with the sample volume placed between the tips of the mitral valve leaflets. Early diastolic myocardial velocity (e′) was measured in 4-chamber view with pulsed-wave tissue velocity Doppler with the sample volume placed in the septal and lateral mitral annulus. Left ventricular ejection fraction (LVEF) was calculated using Simpson’s biplane method and was considered normal when >50%. STE was performed off-line on 2D grey scale recordings of 4-, 2-, and 3-chamber apical views and at the level of the papillary muscle in short axis view using dedicated software (GE EchoPac software BT13). A semi-automated function traced the myocardium in the beginning of the systole and allowed for manual modification of the region of interest to ensure only speckles in the myocardium were tracked throughout the cardiac cycle. Visual inspection of the tracking curves ensured accurate tracking of the speckles and segments where the tracking was assessed inadequate were excluded from the analyses. In this study, mid-myocardial global strain provided by the software algorithm was used for both longitudinal and circumferential strain. Global longitudinal strain (GLS) was the mean value of the GLS from all three standard projections. Global circumferential strain (GCS) was measured at the level of the papillary muscle. Overall, GLS was measured in 95.7% [mean frame rate 67.1 s−1 (10.6)] and was thus very feasible in this population and more so than GCS that was obtained in 80.1% [mean frame rate 66.0 s−1 (10.4)]. Strain rate was the rate of these deformations in in either longitudinal or circumferential directions and measured in s−1. Statistics Continuous variables with normal/non-normal distribution are presented as mean (standard deviation)/median (interquartile range) and compared using Welsh’s t-tests or one-way analysis of variance/Mann–Whitney U tests or Kruskall–Wallis tests where appropriate. Categorical values are presented as number (percent) and compared using χ2 tests. Multivariable associations were examined using linear regression with albuminuria status and covariates as independent variables. Statistics were calculated using R for Mac, version 2.15.3 (R Project for Statistical Computing, Vienna University of Economics and Business Administration, Wien, Austria). Results In total, 915 patients with T2D were included. Of these, 703 had no albuminuria and 212 had albuminuria of which 149 had micro- and 63 had macroalbuminuria. Excluding patients with known coronary heart disease and patients with coronary heart disease and/or reduced LVEF yielded population sizes of 755 (171 with albuminuria of which 121 had micro- and 50 had macroalbuminuria) and 673 (151 with albuminuria of which 109 had micro- and 42 had macroalbuminuria), respectively. The population demographics stratified by albuminuria status are shown in Table 1. In summary, diabetes duration, BMI, systolic blood pressure, creatinine level, haemoglobinA1c, insulin, beta-blocker, angiotensin II receptor blocker, calcium antagonist, and diuretics use were positively associated with increasing severity of albuminuria level. On the other hand, use of metformin and glucagon-like peptide 1-receptor agonist use was associated with decreasing albuminuria level. Table 1 Population demographics   No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Clinical   Age (years)  64 [57, 70]  66 [61, 72]  67 [62, 70]  0.010  0.007  0.10   Male sex (%)  433 (62)  116 (78)  45 (71)  <0.001  <0.001  0.16   Diabetes duration (years)  10.0 [4.2, 15.0]  15.0 [10.0, 21.0]  17.0 [13.0, 22.5]  <0.001  <0.001  <0.001   Body mass index (kg/m2)  29.1 [26.3, 33.0]  30.7 [27.1, 33.9]  30.9 [27.2, 35.0]  0.014  0.026  0.034   Systolic blood pressure (mmHg)  135 (16)  138 (19)  146 (20)  <0.001  0.046  <0.001   Diastolic blood pressure (mmHg)  80 (10)  79 (12)  82 (12)  0.23  0.59  0.11   Coronary heart disease (%)  119 (16.9)  28 (18.8)  13 (20.6)  0.68  0.67  0.57   Smoking    Never smoker (%)  308 (43.8)  68 (45.6)  18 (28.6)          Former smoker (%)  290 (41.3)  57 (38.3)  39 (61.9)  <0.001  0.79  0.007    Active smoker (%)  105 (14.9)  24 (16.1)  6 (9.5)         Laboratory values    Total cholesterol (mmol/l)  4.1 [3.5, 4.8]  4.1 [3.4, 4.9]  4.4 [3.7, 5.1]  0.16  0.78  0.05    Creatinine (μmol/l)  75 [64, 89]  91 [70, 108]  97 [83, 141]  <0.001  <0.001  <0.001    Haemoglobin A1c (mmol/l)  54 [46, 64]  58 [50, 70]  63 [54, 76]  <0.001  <0.001  <0.001    Haemoglobin A1c (%)  7.3 (1.4)  7.8 (1.5)  8.3 (1.6)  <0.001  <0.001  <0.001  Medication   Metformin (%)  524 (75)  106 (71)  33 (52)  0.001  0.45  <0.001   DPP4 inhibitors (%)  64 (9)  13 (9)  9 (14)  0.38  1.00  0.26   Sulfonylurea (%)  101 (14)  29 (20)  10 (16)  0.29  0.15  0.89   Glucagon-like peptide 1-receptor agonist (%)  188 (27)  29 (20)  10 (16)  0.041  0.08  0.08   Insulin (%)  288 (41)  94 (63)  46 (73)  <0.001  <0.001  <0.001   Beta blockers (%)  159 (23)  39 (26)  22 (35)  0.07  0.41  0.041   Angiotensin-converting enzyme inhibitors (%)  276 (39)  50 (34)  26 (41)  0.38  0.23  0.86   Angiotensin II receptor blockers (%)  242 (34)  83 (56)  33 (52)  <0.001  <0.001  0.007   Calcium antagonists (%)  209 (30)  54 (36)  31 (49)  0.003  0.14  0.002   Diuretics (%)  310 (44)  96 (64)  46 (73)  <0.001  <0.001  <0.001   Statins (%)  563 (80)  116 (78)  49 (78)  0.78  0.62  0.78    No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Clinical   Age (years)  64 [57, 70]  66 [61, 72]  67 [62, 70]  0.010  0.007  0.10   Male sex (%)  433 (62)  116 (78)  45 (71)  <0.001  <0.001  0.16   Diabetes duration (years)  10.0 [4.2, 15.0]  15.0 [10.0, 21.0]  17.0 [13.0, 22.5]  <0.001  <0.001  <0.001   Body mass index (kg/m2)  29.1 [26.3, 33.0]  30.7 [27.1, 33.9]  30.9 [27.2, 35.0]  0.014  0.026  0.034   Systolic blood pressure (mmHg)  135 (16)  138 (19)  146 (20)  <0.001  0.046  <0.001   Diastolic blood pressure (mmHg)  80 (10)  79 (12)  82 (12)  0.23  0.59  0.11   Coronary heart disease (%)  119 (16.9)  28 (18.8)  13 (20.6)  0.68  0.67  0.57   Smoking    Never smoker (%)  308 (43.8)  68 (45.6)  18 (28.6)          Former smoker (%)  290 (41.3)  57 (38.3)  39 (61.9)  <0.001  0.79  0.007    Active smoker (%)  105 (14.9)  24 (16.1)  6 (9.5)         Laboratory values    Total cholesterol (mmol/l)  4.1 [3.5, 4.8]  4.1 [3.4, 4.9]  4.4 [3.7, 5.1]  0.16  0.78  0.05    Creatinine (μmol/l)  75 [64, 89]  91 [70, 108]  97 [83, 141]  <0.001  <0.001  <0.001    Haemoglobin A1c (mmol/l)  54 [46, 64]  58 [50, 70]  63 [54, 76]  <0.001  <0.001  <0.001    Haemoglobin A1c (%)  7.3 (1.4)  7.8 (1.5)  8.3 (1.6)  <0.001  <0.001  <0.001  Medication   Metformin (%)  524 (75)  106 (71)  33 (52)  0.001  0.45  <0.001   DPP4 inhibitors (%)  64 (9)  13 (9)  9 (14)  0.38  1.00  0.26   Sulfonylurea (%)  101 (14)  29 (20)  10 (16)  0.29  0.15  0.89   Glucagon-like peptide 1-receptor agonist (%)  188 (27)  29 (20)  10 (16)  0.041  0.08  0.08   Insulin (%)  288 (41)  94 (63)  46 (73)  <0.001  <0.001  <0.001   Beta blockers (%)  159 (23)  39 (26)  22 (35)  0.07  0.41  0.041   Angiotensin-converting enzyme inhibitors (%)  276 (39)  50 (34)  26 (41)  0.38  0.23  0.86   Angiotensin II receptor blockers (%)  242 (34)  83 (56)  33 (52)  <0.001  <0.001  0.007   Calcium antagonists (%)  209 (30)  54 (36)  31 (49)  0.003  0.14  0.002   Diuretics (%)  310 (44)  96 (64)  46 (73)  <0.001  <0.001  <0.001   Statins (%)  563 (80)  116 (78)  49 (78)  0.78  0.62  0.78  Continuous traits are reported as mean (standard deviation) or median [interquartile range] in case of non-normal distribution. * P-values are across all groups. † P-values are no albuminuria vs. microalbuminuria. ‡ P-values are no albuminuria vs. macroalbuminuria. Bold text indicates P < 0.05. Table 1 Population demographics   No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Clinical   Age (years)  64 [57, 70]  66 [61, 72]  67 [62, 70]  0.010  0.007  0.10   Male sex (%)  433 (62)  116 (78)  45 (71)  <0.001  <0.001  0.16   Diabetes duration (years)  10.0 [4.2, 15.0]  15.0 [10.0, 21.0]  17.0 [13.0, 22.5]  <0.001  <0.001  <0.001   Body mass index (kg/m2)  29.1 [26.3, 33.0]  30.7 [27.1, 33.9]  30.9 [27.2, 35.0]  0.014  0.026  0.034   Systolic blood pressure (mmHg)  135 (16)  138 (19)  146 (20)  <0.001  0.046  <0.001   Diastolic blood pressure (mmHg)  80 (10)  79 (12)  82 (12)  0.23  0.59  0.11   Coronary heart disease (%)  119 (16.9)  28 (18.8)  13 (20.6)  0.68  0.67  0.57   Smoking    Never smoker (%)  308 (43.8)  68 (45.6)  18 (28.6)          Former smoker (%)  290 (41.3)  57 (38.3)  39 (61.9)  <0.001  0.79  0.007    Active smoker (%)  105 (14.9)  24 (16.1)  6 (9.5)         Laboratory values    Total cholesterol (mmol/l)  4.1 [3.5, 4.8]  4.1 [3.4, 4.9]  4.4 [3.7, 5.1]  0.16  0.78  0.05    Creatinine (μmol/l)  75 [64, 89]  91 [70, 108]  97 [83, 141]  <0.001  <0.001  <0.001    Haemoglobin A1c (mmol/l)  54 [46, 64]  58 [50, 70]  63 [54, 76]  <0.001  <0.001  <0.001    Haemoglobin A1c (%)  7.3 (1.4)  7.8 (1.5)  8.3 (1.6)  <0.001  <0.001  <0.001  Medication   Metformin (%)  524 (75)  106 (71)  33 (52)  0.001  0.45  <0.001   DPP4 inhibitors (%)  64 (9)  13 (9)  9 (14)  0.38  1.00  0.26   Sulfonylurea (%)  101 (14)  29 (20)  10 (16)  0.29  0.15  0.89   Glucagon-like peptide 1-receptor agonist (%)  188 (27)  29 (20)  10 (16)  0.041  0.08  0.08   Insulin (%)  288 (41)  94 (63)  46 (73)  <0.001  <0.001  <0.001   Beta blockers (%)  159 (23)  39 (26)  22 (35)  0.07  0.41  0.041   Angiotensin-converting enzyme inhibitors (%)  276 (39)  50 (34)  26 (41)  0.38  0.23  0.86   Angiotensin II receptor blockers (%)  242 (34)  83 (56)  33 (52)  <0.001  <0.001  0.007   Calcium antagonists (%)  209 (30)  54 (36)  31 (49)  0.003  0.14  0.002   Diuretics (%)  310 (44)  96 (64)  46 (73)  <0.001  <0.001  <0.001   Statins (%)  563 (80)  116 (78)  49 (78)  0.78  0.62  0.78    No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Clinical   Age (years)  64 [57, 70]  66 [61, 72]  67 [62, 70]  0.010  0.007  0.10   Male sex (%)  433 (62)  116 (78)  45 (71)  <0.001  <0.001  0.16   Diabetes duration (years)  10.0 [4.2, 15.0]  15.0 [10.0, 21.0]  17.0 [13.0, 22.5]  <0.001  <0.001  <0.001   Body mass index (kg/m2)  29.1 [26.3, 33.0]  30.7 [27.1, 33.9]  30.9 [27.2, 35.0]  0.014  0.026  0.034   Systolic blood pressure (mmHg)  135 (16)  138 (19)  146 (20)  <0.001  0.046  <0.001   Diastolic blood pressure (mmHg)  80 (10)  79 (12)  82 (12)  0.23  0.59  0.11   Coronary heart disease (%)  119 (16.9)  28 (18.8)  13 (20.6)  0.68  0.67  0.57   Smoking    Never smoker (%)  308 (43.8)  68 (45.6)  18 (28.6)          Former smoker (%)  290 (41.3)  57 (38.3)  39 (61.9)  <0.001  0.79  0.007    Active smoker (%)  105 (14.9)  24 (16.1)  6 (9.5)         Laboratory values    Total cholesterol (mmol/l)  4.1 [3.5, 4.8]  4.1 [3.4, 4.9]  4.4 [3.7, 5.1]  0.16  0.78  0.05    Creatinine (μmol/l)  75 [64, 89]  91 [70, 108]  97 [83, 141]  <0.001  <0.001  <0.001    Haemoglobin A1c (mmol/l)  54 [46, 64]  58 [50, 70]  63 [54, 76]  <0.001  <0.001  <0.001    Haemoglobin A1c (%)  7.3 (1.4)  7.8 (1.5)  8.3 (1.6)  <0.001  <0.001  <0.001  Medication   Metformin (%)  524 (75)  106 (71)  33 (52)  0.001  0.45  <0.001   DPP4 inhibitors (%)  64 (9)  13 (9)  9 (14)  0.38  1.00  0.26   Sulfonylurea (%)  101 (14)  29 (20)  10 (16)  0.29  0.15  0.89   Glucagon-like peptide 1-receptor agonist (%)  188 (27)  29 (20)  10 (16)  0.041  0.08  0.08   Insulin (%)  288 (41)  94 (63)  46 (73)  <0.001  <0.001  <0.001   Beta blockers (%)  159 (23)  39 (26)  22 (35)  0.07  0.41  0.041   Angiotensin-converting enzyme inhibitors (%)  276 (39)  50 (34)  26 (41)  0.38  0.23  0.86   Angiotensin II receptor blockers (%)  242 (34)  83 (56)  33 (52)  <0.001  <0.001  0.007   Calcium antagonists (%)  209 (30)  54 (36)  31 (49)  0.003  0.14  0.002   Diuretics (%)  310 (44)  96 (64)  46 (73)  <0.001  <0.001  <0.001   Statins (%)  563 (80)  116 (78)  49 (78)  0.78  0.62  0.78  Continuous traits are reported as mean (standard deviation) or median [interquartile range] in case of non-normal distribution. * P-values are across all groups. † P-values are no albuminuria vs. microalbuminuria. ‡ P-values are no albuminuria vs. macroalbuminuria. Bold text indicates P < 0.05. Echocardiographic findings The echocardiographic characteristics of patients with T2D stratified by albuminuria status are shown in Table 2. Regarding the structural measures, LV mass index, interventricular septum diameter, and posterior wall diameter were associated with both micro- and macroalbuminuria with increasing values with incremental severity of albuminuria. This was not the case with the LV internal diameter, which was similar in all three groups. The findings regarding diastolic and systolic function of normoalbuminuria compared with albuminuria are shown in Figure 1. We found that with albuminuria both diastolic measures—expressed as e′ velocity, E/e′, and LA volume index—and systolic measures—expressed as GLS and GLS rate—were associated with decreasing function. This was, however, not the case with GCS and GCS rate which were comparable between patients with and without albuminuria. When stratifying within albuminuria status we found that overall, for both patients with micro- and macroalbuminuria, the diastolic parameters were affected with decreased function compared with patients without albuminuria (Table 2 and Figure 2). Regarding the systolic function, we found no significant differences between patients without albuminuria and patients with microalbuminuria in any systolic measurement. However, when comparing with patients having macroalbuminuria, we found indices of decreased longitudinal function expressed as decreased GLS and GLS rate. No difference across the groups was found regarding LVEF or GCS and GCS rate. Also, sensitivity analyses revealed, that the same pattern persisted when excluding patients with coronary heart disease and patients with reduced ejection fraction (Figure 2). Table 2 Echocardiographic findings according to albuminuria status   No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Structural measures   Left ventricular mass index (g/m2.7)  37.9 (11.0)  40.5 (10.5)  45.1 (12.3)  <0.001  0.009  <0.001   Interventricular septum thickness (mm)  10.4 (1.7)  11.3 (1.5)  12.1 (2.0)  <0.001  <0.001  <0.001   End diastolic internal diameter (mm)  46.1 (6.3)  45.7 (6.2)  45.1 (5.9)  0.42  0.49  0.24   Posterior wall thickness (mm)  10.1 (1.51)  10.9 (1.5)  11.6 (1.5)  <0.001  <0.001  <0.001   Relative wall thickness  0.45 (0.10)  0.49 (0.10)  0.52 (0.09)  <0.001  <0.001  <0.001   Left atrial volume index (ml/m2)  24.3 [19.1, 29.9]  25.7 [20.0, 31.6]  29.0 [22.2, 34.9]  <0.001  0.019  <0.001  Diastolic measures   Peak E velocity (m/s)  0.73 [0.62, 0.86]  0.79 [0.66, 0.89]  0.74 [0.62, 0.88]  0.023  0.006  0.69   Peak A velocity (m/s)  0.84 (0.19)  0.85 (0.18)  0.89 (0.18)  0.17  0.72  0.06   E deceleration time (ms)  217 [182, 259]  223 [191, 271]  241 [202, 288]  0.013  0.13  0.008   E/A ratio  0.87 [0.75, 1.05]  0.90 [0.79, 1.12]  0.86 [0.72, 1.00]  0.06  0.08  0.16   Septal e′ (cm/s)  6.9 (1.9)  6.4 (1.7)  5.9 (1.7)  <0.001  0.004  <0.001   Lateral e′ (cm/s)  8.8 (2.5)  8.2 (2.2)  7.6 (2.4)  <0.001  0.004  <0.001   Mean e′ (cm/s)  7.9 (2.0)  7.3 (1.8)  6.8 (1.9)  <0.001  0.002  <0.001   E/e′septal  10.6 [8.9, 13.2]  12.1 [10.3, 14.8]  12.7 [10.4, 16.6]  <0.001  <0.001  <0.001   E/e′lateral  8.3 [6.8, 10.5]  9.6 [7.7, 11.4]  10.7 [7.4, 13.8]  <0.001  <0.001  <0.001   E/e′mean  9.3 [7.8, 11.4]  10.5 [8.8, 12.5]  11.9 [8.9, 15.3]  <0.001  <0.001  <0.001  Systolic measures   Ejection fraction (%)  60.7 [55.7, 65.2]  59.9 [55.7, 64.4]  58.5 [53.1, 62.7]  0.21  0.39  0.10   Reduced ejection fraction (<50%) (%)  70 (10.3)  18 (12.2)  11 (18.0)  0.17  0.60  0.10   Global longitudinal strain (%)  −14.6 (2.7)  −14.1 (3.0)  −13.3 (2.9)  0.001  0.07  <0.001   Global longitudinal strain rate (s−1)  −0.79 (0.17)  −0.77 (0.18)  −0.72 (0.16)  0.005  0.25  0.001   Global circumferential strain (%)  −18.0 (5.3)  −18.0 (5.2)  −16.9 (5.6)  0.41  1.00  0.19   Global circumferential strain rate (s−1)  −1.05 (0.35)  −1.04 (0.33)  −0.98 (0.33)  0.37  0.67  0.17    No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Structural measures   Left ventricular mass index (g/m2.7)  37.9 (11.0)  40.5 (10.5)  45.1 (12.3)  <0.001  0.009  <0.001   Interventricular septum thickness (mm)  10.4 (1.7)  11.3 (1.5)  12.1 (2.0)  <0.001  <0.001  <0.001   End diastolic internal diameter (mm)  46.1 (6.3)  45.7 (6.2)  45.1 (5.9)  0.42  0.49  0.24   Posterior wall thickness (mm)  10.1 (1.51)  10.9 (1.5)  11.6 (1.5)  <0.001  <0.001  <0.001   Relative wall thickness  0.45 (0.10)  0.49 (0.10)  0.52 (0.09)  <0.001  <0.001  <0.001   Left atrial volume index (ml/m2)  24.3 [19.1, 29.9]  25.7 [20.0, 31.6]  29.0 [22.2, 34.9]  <0.001  0.019  <0.001  Diastolic measures   Peak E velocity (m/s)  0.73 [0.62, 0.86]  0.79 [0.66, 0.89]  0.74 [0.62, 0.88]  0.023  0.006  0.69   Peak A velocity (m/s)  0.84 (0.19)  0.85 (0.18)  0.89 (0.18)  0.17  0.72  0.06   E deceleration time (ms)  217 [182, 259]  223 [191, 271]  241 [202, 288]  0.013  0.13  0.008   E/A ratio  0.87 [0.75, 1.05]  0.90 [0.79, 1.12]  0.86 [0.72, 1.00]  0.06  0.08  0.16   Septal e′ (cm/s)  6.9 (1.9)  6.4 (1.7)  5.9 (1.7)  <0.001  0.004  <0.001   Lateral e′ (cm/s)  8.8 (2.5)  8.2 (2.2)  7.6 (2.4)  <0.001  0.004  <0.001   Mean e′ (cm/s)  7.9 (2.0)  7.3 (1.8)  6.8 (1.9)  <0.001  0.002  <0.001   E/e′septal  10.6 [8.9, 13.2]  12.1 [10.3, 14.8]  12.7 [10.4, 16.6]  <0.001  <0.001  <0.001   E/e′lateral  8.3 [6.8, 10.5]  9.6 [7.7, 11.4]  10.7 [7.4, 13.8]  <0.001  <0.001  <0.001   E/e′mean  9.3 [7.8, 11.4]  10.5 [8.8, 12.5]  11.9 [8.9, 15.3]  <0.001  <0.001  <0.001  Systolic measures   Ejection fraction (%)  60.7 [55.7, 65.2]  59.9 [55.7, 64.4]  58.5 [53.1, 62.7]  0.21  0.39  0.10   Reduced ejection fraction (<50%) (%)  70 (10.3)  18 (12.2)  11 (18.0)  0.17  0.60  0.10   Global longitudinal strain (%)  −14.6 (2.7)  −14.1 (3.0)  −13.3 (2.9)  0.001  0.07  <0.001   Global longitudinal strain rate (s−1)  −0.79 (0.17)  −0.77 (0.18)  −0.72 (0.16)  0.005  0.25  0.001   Global circumferential strain (%)  −18.0 (5.3)  −18.0 (5.2)  −16.9 (5.6)  0.41  1.00  0.19   Global circumferential strain rate (s−1)  −1.05 (0.35)  −1.04 (0.33)  −0.98 (0.33)  0.37  0.67  0.17  Continuous traits are reported as mean (standard deviation) or median [interquartile range] in case of non-normal distribution. * P-values are across all groups. † P-values are no albuminuria vs. microalbuminuria. ‡ P-values are no albuminuria vs. macroalbuminuria. Bold text indicates P < 0.05. Table 2 Echocardiographic findings according to albuminuria status   No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Structural measures   Left ventricular mass index (g/m2.7)  37.9 (11.0)  40.5 (10.5)  45.1 (12.3)  <0.001  0.009  <0.001   Interventricular septum thickness (mm)  10.4 (1.7)  11.3 (1.5)  12.1 (2.0)  <0.001  <0.001  <0.001   End diastolic internal diameter (mm)  46.1 (6.3)  45.7 (6.2)  45.1 (5.9)  0.42  0.49  0.24   Posterior wall thickness (mm)  10.1 (1.51)  10.9 (1.5)  11.6 (1.5)  <0.001  <0.001  <0.001   Relative wall thickness  0.45 (0.10)  0.49 (0.10)  0.52 (0.09)  <0.001  <0.001  <0.001   Left atrial volume index (ml/m2)  24.3 [19.1, 29.9]  25.7 [20.0, 31.6]  29.0 [22.2, 34.9]  <0.001  0.019  <0.001  Diastolic measures   Peak E velocity (m/s)  0.73 [0.62, 0.86]  0.79 [0.66, 0.89]  0.74 [0.62, 0.88]  0.023  0.006  0.69   Peak A velocity (m/s)  0.84 (0.19)  0.85 (0.18)  0.89 (0.18)  0.17  0.72  0.06   E deceleration time (ms)  217 [182, 259]  223 [191, 271]  241 [202, 288]  0.013  0.13  0.008   E/A ratio  0.87 [0.75, 1.05]  0.90 [0.79, 1.12]  0.86 [0.72, 1.00]  0.06  0.08  0.16   Septal e′ (cm/s)  6.9 (1.9)  6.4 (1.7)  5.9 (1.7)  <0.001  0.004  <0.001   Lateral e′ (cm/s)  8.8 (2.5)  8.2 (2.2)  7.6 (2.4)  <0.001  0.004  <0.001   Mean e′ (cm/s)  7.9 (2.0)  7.3 (1.8)  6.8 (1.9)  <0.001  0.002  <0.001   E/e′septal  10.6 [8.9, 13.2]  12.1 [10.3, 14.8]  12.7 [10.4, 16.6]  <0.001  <0.001  <0.001   E/e′lateral  8.3 [6.8, 10.5]  9.6 [7.7, 11.4]  10.7 [7.4, 13.8]  <0.001  <0.001  <0.001   E/e′mean  9.3 [7.8, 11.4]  10.5 [8.8, 12.5]  11.9 [8.9, 15.3]  <0.001  <0.001  <0.001  Systolic measures   Ejection fraction (%)  60.7 [55.7, 65.2]  59.9 [55.7, 64.4]  58.5 [53.1, 62.7]  0.21  0.39  0.10   Reduced ejection fraction (<50%) (%)  70 (10.3)  18 (12.2)  11 (18.0)  0.17  0.60  0.10   Global longitudinal strain (%)  −14.6 (2.7)  −14.1 (3.0)  −13.3 (2.9)  0.001  0.07  <0.001   Global longitudinal strain rate (s−1)  −0.79 (0.17)  −0.77 (0.18)  −0.72 (0.16)  0.005  0.25  0.001   Global circumferential strain (%)  −18.0 (5.3)  −18.0 (5.2)  −16.9 (5.6)  0.41  1.00  0.19   Global circumferential strain rate (s−1)  −1.05 (0.35)  −1.04 (0.33)  −0.98 (0.33)  0.37  0.67  0.17    No albuminuria  Microalbuminuria  Macroalbuminuria  P-value*  P-value†  P-value‡    n = 703  n = 149  n = 63  Structural measures   Left ventricular mass index (g/m2.7)  37.9 (11.0)  40.5 (10.5)  45.1 (12.3)  <0.001  0.009  <0.001   Interventricular septum thickness (mm)  10.4 (1.7)  11.3 (1.5)  12.1 (2.0)  <0.001  <0.001  <0.001   End diastolic internal diameter (mm)  46.1 (6.3)  45.7 (6.2)  45.1 (5.9)  0.42  0.49  0.24   Posterior wall thickness (mm)  10.1 (1.51)  10.9 (1.5)  11.6 (1.5)  <0.001  <0.001  <0.001   Relative wall thickness  0.45 (0.10)  0.49 (0.10)  0.52 (0.09)  <0.001  <0.001  <0.001   Left atrial volume index (ml/m2)  24.3 [19.1, 29.9]  25.7 [20.0, 31.6]  29.0 [22.2, 34.9]  <0.001  0.019  <0.001  Diastolic measures   Peak E velocity (m/s)  0.73 [0.62, 0.86]  0.79 [0.66, 0.89]  0.74 [0.62, 0.88]  0.023  0.006  0.69   Peak A velocity (m/s)  0.84 (0.19)  0.85 (0.18)  0.89 (0.18)  0.17  0.72  0.06   E deceleration time (ms)  217 [182, 259]  223 [191, 271]  241 [202, 288]  0.013  0.13  0.008   E/A ratio  0.87 [0.75, 1.05]  0.90 [0.79, 1.12]  0.86 [0.72, 1.00]  0.06  0.08  0.16   Septal e′ (cm/s)  6.9 (1.9)  6.4 (1.7)  5.9 (1.7)  <0.001  0.004  <0.001   Lateral e′ (cm/s)  8.8 (2.5)  8.2 (2.2)  7.6 (2.4)  <0.001  0.004  <0.001   Mean e′ (cm/s)  7.9 (2.0)  7.3 (1.8)  6.8 (1.9)  <0.001  0.002  <0.001   E/e′septal  10.6 [8.9, 13.2]  12.1 [10.3, 14.8]  12.7 [10.4, 16.6]  <0.001  <0.001  <0.001   E/e′lateral  8.3 [6.8, 10.5]  9.6 [7.7, 11.4]  10.7 [7.4, 13.8]  <0.001  <0.001  <0.001   E/e′mean  9.3 [7.8, 11.4]  10.5 [8.8, 12.5]  11.9 [8.9, 15.3]  <0.001  <0.001  <0.001  Systolic measures   Ejection fraction (%)  60.7 [55.7, 65.2]  59.9 [55.7, 64.4]  58.5 [53.1, 62.7]  0.21  0.39  0.10   Reduced ejection fraction (<50%) (%)  70 (10.3)  18 (12.2)  11 (18.0)  0.17  0.60  0.10   Global longitudinal strain (%)  −14.6 (2.7)  −14.1 (3.0)  −13.3 (2.9)  0.001  0.07  <0.001   Global longitudinal strain rate (s−1)  −0.79 (0.17)  −0.77 (0.18)  −0.72 (0.16)  0.005  0.25  0.001   Global circumferential strain (%)  −18.0 (5.3)  −18.0 (5.2)  −16.9 (5.6)  0.41  1.00  0.19   Global circumferential strain rate (s−1)  −1.05 (0.35)  −1.04 (0.33)  −0.98 (0.33)  0.37  0.67  0.17  Continuous traits are reported as mean (standard deviation) or median [interquartile range] in case of non-normal distribution. * P-values are across all groups. † P-values are no albuminuria vs. microalbuminuria. ‡ P-values are no albuminuria vs. macroalbuminuria. Bold text indicates P < 0.05. Figure 1 View largeDownload slide Box-plots of diastolic function, longitudinal, and circumferential strain and strain rate according to albuminuria status. Figure 1 View largeDownload slide Box-plots of diastolic function, longitudinal, and circumferential strain and strain rate according to albuminuria status. Figure 2 View largeDownload slide Mean and median values of diastolic and systolic findings according to albuminuria status. Values are means unless otherwise stated. Levels of significance: P < 0.10, *P < 0.05, **P < 0.01, ***P < 0.001. CHD, coronary heart disease; LVEF, left ventricular ejection fraction. Figure 2 View largeDownload slide Mean and median values of diastolic and systolic findings according to albuminuria status. Values are means unless otherwise stated. Levels of significance: P < 0.10, *P < 0.05, **P < 0.01, ***P < 0.001. CHD, coronary heart disease; LVEF, left ventricular ejection fraction. Multivariable findings The effect of albuminuria status on measures of diastolic and systolic function after adjusting for age, sex, BMI, systolic blood pressure, and smoking status is found in Table 3. In general, the pattern of decreased diastolic measures in both patients with micro- and macroalbuminuria and only decreased systolic measures in patients with macroalbuminuria persisted after adjusting for possible confounding factors although the association between albuminuria status and GLS rate was attenuated in the group without known heart disease and normal LVEF. Table 3 Multivariable adjusted analyses of association between diastolic and systolic measures and albuminuria status   All patients  No CHD  No CHD and normal LVEF      n = 915   n = 755   n = 673       β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  Diastolic measures   e′ septal (cm/s)   Albuminuria  −0.4 (0.1)  0.004  −0.5 (0.2)  <0.001  −0.5 (0.2)  <0.001    Microalbuminuria  −0.3 (0.2)  0.07  −0.4 (0.2)  0.036  −0.4 (0.8)  0.020    Macroalbuminuria  −0.7 (0.2)  0.002  −0.9 (0.3)  <0.001  −0.8 (0.3)  0.002  E/e′septal   Albuminuria  1.3 (0.4)  <0.001  1.6 (0.4)  <0.001  1.4 (0.4)  <0.001    Microalbuminuria  1.3 (0.4)  0.002  1.7 (0.5)  <0.001  1.6 (0.5)  <0.001    Macroalbuminuria  1.3 (0.6)  0.031  1.5 (0.7)  0.030  1.1 (0.7)  0.11  LA size (ml/m2)   Albuminuria  2.2 (0.7)  0.001  3.0 (0.7)  <0.001  2.8 (0.8)  0.001    Microalbuminuria  1.8 (0.8)  0.013  2.9 (0.8)  <0.001  2.6 (0.9)  0.003    Macroalbuminuria  2.9 (1.1)  0.008  3.1 (1.2)  0.011  3.5 (1.3)  0.008  Systolic measures   GLS (%)   Albuminuria  0.42 (0.23)  0.07  0.48 (0.25)  0.05  0.37 (0.24)  0.12    Microalbuminuria  0.20 (0.26)  0.44  0.24 (0.28)  0.39  0.17 (0.27)  0.53    Macroalbuminuria  0.96 (0.38)  0.013  1.06 (0.41)  0.010  0.89 (0.41)  0.029  GLS rate (s−1)   Albuminuria  0.03 (0.01)  0.08  0.03 (0.02)  0.035  0.02 (0.02)  0.15    Microalbuminuria  0.01 (0.02)  0.42  0.02 (0.01)  0.20  0.02 (0.02)  0.35    Macroalbuminuria  0.06 (0.02)  0.021  0.06 (0.03)  0.025  0.04 (0.03)  0.14    All patients  No CHD  No CHD and normal LVEF      n = 915   n = 755   n = 673       β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  Diastolic measures   e′ septal (cm/s)   Albuminuria  −0.4 (0.1)  0.004  −0.5 (0.2)  <0.001  −0.5 (0.2)  <0.001    Microalbuminuria  −0.3 (0.2)  0.07  −0.4 (0.2)  0.036  −0.4 (0.8)  0.020    Macroalbuminuria  −0.7 (0.2)  0.002  −0.9 (0.3)  <0.001  −0.8 (0.3)  0.002  E/e′septal   Albuminuria  1.3 (0.4)  <0.001  1.6 (0.4)  <0.001  1.4 (0.4)  <0.001    Microalbuminuria  1.3 (0.4)  0.002  1.7 (0.5)  <0.001  1.6 (0.5)  <0.001    Macroalbuminuria  1.3 (0.6)  0.031  1.5 (0.7)  0.030  1.1 (0.7)  0.11  LA size (ml/m2)   Albuminuria  2.2 (0.7)  0.001  3.0 (0.7)  <0.001  2.8 (0.8)  0.001    Microalbuminuria  1.8 (0.8)  0.013  2.9 (0.8)  <0.001  2.6 (0.9)  0.003    Macroalbuminuria  2.9 (1.1)  0.008  3.1 (1.2)  0.011  3.5 (1.3)  0.008  Systolic measures   GLS (%)   Albuminuria  0.42 (0.23)  0.07  0.48 (0.25)  0.05  0.37 (0.24)  0.12    Microalbuminuria  0.20 (0.26)  0.44  0.24 (0.28)  0.39  0.17 (0.27)  0.53    Macroalbuminuria  0.96 (0.38)  0.013  1.06 (0.41)  0.010  0.89 (0.41)  0.029  GLS rate (s−1)   Albuminuria  0.03 (0.01)  0.08  0.03 (0.02)  0.035  0.02 (0.02)  0.15    Microalbuminuria  0.01 (0.02)  0.42  0.02 (0.01)  0.20  0.02 (0.02)  0.35    Macroalbuminuria  0.06 (0.02)  0.021  0.06 (0.03)  0.025  0.04 (0.03)  0.14  Adjusted for age and sex, body mass index, systolic blood pressure, smoking status, use of either renin-angiotensin-aldosterone system blocking or beta-blocking agents and use of diuretics. β-Coefficients are compared to ‘no albuminuria’. CHD, coronary heart disease; LVEF, left ventricular ejection fraction; LA, left atrial; GLS, global longitudinal strain. Bold text indicates P < 0.05. Table 3 Multivariable adjusted analyses of association between diastolic and systolic measures and albuminuria status   All patients  No CHD  No CHD and normal LVEF      n = 915   n = 755   n = 673       β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  Diastolic measures   e′ septal (cm/s)   Albuminuria  −0.4 (0.1)  0.004  −0.5 (0.2)  <0.001  −0.5 (0.2)  <0.001    Microalbuminuria  −0.3 (0.2)  0.07  −0.4 (0.2)  0.036  −0.4 (0.8)  0.020    Macroalbuminuria  −0.7 (0.2)  0.002  −0.9 (0.3)  <0.001  −0.8 (0.3)  0.002  E/e′septal   Albuminuria  1.3 (0.4)  <0.001  1.6 (0.4)  <0.001  1.4 (0.4)  <0.001    Microalbuminuria  1.3 (0.4)  0.002  1.7 (0.5)  <0.001  1.6 (0.5)  <0.001    Macroalbuminuria  1.3 (0.6)  0.031  1.5 (0.7)  0.030  1.1 (0.7)  0.11  LA size (ml/m2)   Albuminuria  2.2 (0.7)  0.001  3.0 (0.7)  <0.001  2.8 (0.8)  0.001    Microalbuminuria  1.8 (0.8)  0.013  2.9 (0.8)  <0.001  2.6 (0.9)  0.003    Macroalbuminuria  2.9 (1.1)  0.008  3.1 (1.2)  0.011  3.5 (1.3)  0.008  Systolic measures   GLS (%)   Albuminuria  0.42 (0.23)  0.07  0.48 (0.25)  0.05  0.37 (0.24)  0.12    Microalbuminuria  0.20 (0.26)  0.44  0.24 (0.28)  0.39  0.17 (0.27)  0.53    Macroalbuminuria  0.96 (0.38)  0.013  1.06 (0.41)  0.010  0.89 (0.41)  0.029  GLS rate (s−1)   Albuminuria  0.03 (0.01)  0.08  0.03 (0.02)  0.035  0.02 (0.02)  0.15    Microalbuminuria  0.01 (0.02)  0.42  0.02 (0.01)  0.20  0.02 (0.02)  0.35    Macroalbuminuria  0.06 (0.02)  0.021  0.06 (0.03)  0.025  0.04 (0.03)  0.14    All patients  No CHD  No CHD and normal LVEF      n = 915   n = 755   n = 673       β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  β-coefficient (standard error)  P-value  Diastolic measures   e′ septal (cm/s)   Albuminuria  −0.4 (0.1)  0.004  −0.5 (0.2)  <0.001  −0.5 (0.2)  <0.001    Microalbuminuria  −0.3 (0.2)  0.07  −0.4 (0.2)  0.036  −0.4 (0.8)  0.020    Macroalbuminuria  −0.7 (0.2)  0.002  −0.9 (0.3)  <0.001  −0.8 (0.3)  0.002  E/e′septal   Albuminuria  1.3 (0.4)  <0.001  1.6 (0.4)  <0.001  1.4 (0.4)  <0.001    Microalbuminuria  1.3 (0.4)  0.002  1.7 (0.5)  <0.001  1.6 (0.5)  <0.001    Macroalbuminuria  1.3 (0.6)  0.031  1.5 (0.7)  0.030  1.1 (0.7)  0.11  LA size (ml/m2)   Albuminuria  2.2 (0.7)  0.001  3.0 (0.7)  <0.001  2.8 (0.8)  0.001    Microalbuminuria  1.8 (0.8)  0.013  2.9 (0.8)  <0.001  2.6 (0.9)  0.003    Macroalbuminuria  2.9 (1.1)  0.008  3.1 (1.2)  0.011  3.5 (1.3)  0.008  Systolic measures   GLS (%)   Albuminuria  0.42 (0.23)  0.07  0.48 (0.25)  0.05  0.37 (0.24)  0.12    Microalbuminuria  0.20 (0.26)  0.44  0.24 (0.28)  0.39  0.17 (0.27)  0.53    Macroalbuminuria  0.96 (0.38)  0.013  1.06 (0.41)  0.010  0.89 (0.41)  0.029  GLS rate (s−1)   Albuminuria  0.03 (0.01)  0.08  0.03 (0.02)  0.035  0.02 (0.02)  0.15    Microalbuminuria  0.01 (0.02)  0.42  0.02 (0.01)  0.20  0.02 (0.02)  0.35    Macroalbuminuria  0.06 (0.02)  0.021  0.06 (0.03)  0.025  0.04 (0.03)  0.14  Adjusted for age and sex, body mass index, systolic blood pressure, smoking status, use of either renin-angiotensin-aldosterone system blocking or beta-blocking agents and use of diuretics. β-Coefficients are compared to ‘no albuminuria’. CHD, coronary heart disease; LVEF, left ventricular ejection fraction; LA, left atrial; GLS, global longitudinal strain. Bold text indicates P < 0.05. Discussion The main findings in this study were, that, in patients with T2D, impaired diastolic function was present in both patients with micro- and macroalbuminuria, but impaired systolic function was only present in patients with macroalbuminuria. This pattern was in general also present when excluding patients with known coronary heart disease and patients with decreased LVEF and persisted even in multivariable analyses. Also, we found that LV remodelling, expressed as LV mass index and wall thicknesses, was accentuated as albuminuria status progressed. These findings indicate that both the development of albuminuria and cardiac damage share a common background: as minor degrees of general vascular damage develop, the result is microalbuminuria and LV diastolic function and when the general vascular damage is aggravated, both macroalbuminuria and systolic impairment occurs. Thus, our study, supports the notion of vascular damage in association with albuminuria as a cause of heart failure in patients with T2D and suggests that renal protection strategies are important in the management of patients with T2D. Albuminuria and myocardial impairment in patients with type 2 diabetes In this study, diastolic measures including e′, E/e′, and LA size were affected in patients with both micro- and macroalbuminuria. Measures of systolic longitudinal function, GLS and GLS rate, were only affected in patients with macroalbuminuria, whereas systolic circumferential deformation, GCS and GCS rate, was similar regardless of albuminuria status. The Strong Heart Study investigated the relation between albuminuria status and systolic and diastolic function in a population of American Indians using 2D and spectral Doppler echocardiography. In accordance to our results, they found increased LV mass index with albuminuria and cardiac changes primarily related to diastolic impairment in patients with microalbuminuria and to diastolic and systolic impairment in patients with macroalbuminuria. However, they did also describe decreased LVEF in patients with macroalbuminuria compared with patients with normo- and microalbuminuria whereas we were only able to demonstrate decreased systolic function measured by 2DSTE. Also, in a smaller study including 123 patients with T2D, myocardial performance estimated with the Tei index was found to be strongly correlated with degree of albuminuria,23 and recently, the association between albuminuria and GLS was confirmed in 144 asymptomatic patients with T2D without coronary heart disease.24 Also, we have previously shown that among a number of clinical values, albuminuria was associated with the presence of any echocardiographic abnormality including hypertrophy, LVEF, LV diastolic dysfunction, right ventricular dysfunction, LA enlargement, and valve disorder.17 Microvascular dysfunction is thought to play a role in the pathogenesis of LV diastolic and systolic dysfunction in patients with T2D,25 and previous studies using contrast echocardiography and Doppler derived coronary flow reserve have demonstrated decreased microvascular function in patients with T2D26,27 and especially when combined with other cardiovascular risk factors such as hypertension and obesity.28 Though one previous study in patients with diabetes failed to find association between microvascular function and perfusion,29 in a rather recent study, microvascular function very accurately measured with 82Rb PET/CT was decreased both in patients with T2D but especially in patients with T2D and microalbuminuria indicating common microvascular impairment in multiple vascular beds thus supporting our findings.30 Hence, our study extends and verifies these findings by confirming impaired diastolic and systolic function using comprehensive, recent echocardiographic modalities and by demonstrating that these changes are present even in a contemporary population of patients with T2D receiving multifactorial treatment including a high proportion of patients receiving renin–angiotensin–aldosterone-system blocking agents. As outlined, albuminuria is thought to be a marker of generalized vascular damage and impaired endothelial function.6,31 In the myocardium, the subendocardial layer, which is thought to be most sensitive myocardial layer due to the distance to the epicardial coronary arteries and because it undergoes high pressure variations throughout the cardiac cycle, is where the myocardial fibres mainly responsible for the longitudinal cardiac motion are found.32 Thus, pathogenic mechanisms affecting the myocardium are thought to give rise to primarily longitudinal dysfunction in the early stages of the disease process. In accordance, our findings suggest that the effect of the generalized vascular damage associated with albuminuria takes place mainly in the subendocardium affecting longitudinal function. Thus, the systolic impairment that was found in patients with macroalbuminuria was in our study characterized by decreased longitudinal and not circumferential function.33 Strengths and limitations The strengths of the present study include the large, well-characterized, contemporary multicentre cohort of patients with T2D receiving multifactorial treatment including patients with all stages of the disease that makes our results applicable to the clinical populations. Also, the echocardiograms and analyses were performed almost exclusively by one investigator limiting interobserver variations to a minimum. There are, however, limitations to this study as well: The study population was recruited from secondary care centres and the results should be interpreted with cautions in patients in early stages of the disease followed in the primary sector. Also, though it was a large cohort of patients with T2D, only 63 patients had macroalbuminuria, which, however, underlines the beneficial effects of multifactorial treatment decreasing microvascular dysfunction in these patients. Finally, as GCS and strain rate was only obtainable in 80.1% of the study population the results regarding these parameters should be interpreted with care. Conclusion In patients with type 2 diabetes, microalbuminuria is associated with decreased diastolic function whereas decreased systolic function was only associated with macroalbuminuria supporting the notion of similar pathogenic mechanisms of albuminuria and impaired myocardial function. Funding The study was carried out as part of PGJ’s employment at Gentofte Hospital, University of Copenhagen, Denmark. References 1 Heidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, Fonarow GC et al.   Forecasting the impact of heart failure in the United States. Circ Heart Fail  2013; 6: 606– 19. 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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Oct 3, 2017

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