Introduction: Impaired relaxation is the earliest manifestation of ischemic cascade. Risk factors and renal function abnormalities are associated with coronary disease and diastolic dysfunction as well. We aimed to study the association of noninvasive assessment of left ventricular filling pressures and renal function with mortality in high-risk patients undergoing coronary angiography. Patients and Methods: An observational prospective study of 564 consecutive patients undergoing coronary angiography was conducted. The median follow-up was 2,293 days. Patients were categorized into 2 groups according to presence of significant diastolic dysfunction: group 1, 382 patients, with normal and group 2, 182 patients, with elevated filling pressure. Renal insufficiency was determined as calculated glomerular filtration rate <60 mL/min. Patients demographic, clinical, echocardiography, laboratory, and angiographic data were prospectively collected. Results: Fifty-three percent of patients underwent angiography due to acute coronary syndrome (ACS), 85.5% had coronary artery disease, 53.4% had reduced (<50%) left ventricular ejection fraction (LVEF), and 47.4% had abnormal renal function. The mortality during the follow-up period was 30.0%. Patients with elevated filling pressure had significantly higher mortality (50.5% vs. 20.2%, p < 0.0001). Impaired renal failure as well, was associated with higher mortality (48% vs. 15%, p < 0.001). The association remained significant in subgroups of patients with and without ACS and reduced and preserved LVEF. In Cox regression model which combined elevated filling pressure, renal insufficiency, age, diabetes mellitus, hypertension, presence of atrial fibrillation, LVEF, and anemia, elevated filling pressure and renal function impairment were independently associated with higher mortality (HR: 3.717, CI: 1.623–8.475, p < 0.0001 and HR: 0.972, CI: 0.958–0.985, p = 0.0001, respectively). There was an incremental prognostic value of elevated filling pressures and renal function impairment on mortality. Conclusions: Advanced diastolic dysfunction and impaired renal function are signals toward worse outcomes and are associated with mortality in high-risk patients undergoing coronary angiography.

Left ventricular (LV) diastolic dysfunction is associated with risk of congestive heart failure (CHF) and reduced survival similar to systolic dysfunction [1‒3]. Currently, the prevalence of heart failure with preserved LV systolic function is more than that of heart failure with reduced LV function and increases with aging [4, 5]. The rate of mortality in patients with asymptomatic diastolic dysfunction is higher compared with that of general population [5]. New onset of symptomatic heart failure with preserved LV function behaves as a lethal disease with 5-year mortality rate of 30–35% [1, 6].

Diastolic dysfunction is highly prevalent in patients with coronary artery disease (CAD) and it is a powerful predictor of outcomes [7]. Moreover, it is the earliest manifestation of ischemic cascade. CAD may be a cause for CHF or may simply coexist with CHF [8].

Previous studies showed an improvement in diastolic function, after revascularization, however this improvement was for short duration [9]. In long-term follow-up, the improvement in diastolic function occurs in minority of patients [10]. LV diastolic dysfunction parameters, assessed invasively, were shown to be independently associated with increased risk for cardiac death or cardiovascular hospitalization in patients with known or suspected CAD in short- and median-term follow-up (12–44 months) [11, 12]. Other studies, using noninvasive assessment of diastolic function, showed correlation between combined endpoints of heart failure hospitalization and mortality but did not show relation between diastolic dysfunction and all-cause mortality [13, 14].

In patients with CAD, diastolic dysfunction is only partially related to myocardial ischemia and obstructive coronary stenosis. Patients with CAD have usually comorbidities such as hypertension, diabetes mellitus (DM), and other risk factors that affect diastolic function by various mechanisms, including LV remodeling, interstitial fibrosis, microvascular dysfunction, and LV hypertrophy [15]. So, in a high-risk population, the independent prognostic significance of diastolic function may be less clear and significant [16].

Renal function impairment is one of the major risk factors for cardiovascular disease and prognosis [17]. Both diastolic function grade and renal dysfunction are associated with cardiovascular mortality [18]. We aimed to study the association between noninvasively assessed LV filling pressure and renal function with mortality, in high risk patients undergoing coronary angiography.

The Kaplan Medical Center coronary catheterization registry includes all patients who underwent coronary angiography since 2010. Thousands of patients underwent coronary angiography, during regular working hours, between October 2010 and March 2012. Seven hundred eighty-eight patients underwent echocardiography before the catheterization. From this registry, the study group comprised 564 consecutive patients who underwent a comprehensive echocardiography study with assessment of diastolic function. Eighty-four patients with mitral stenosis and patients with severe MR were excluded because of challenging noninvasive assessment of filling pressures in these patients. In 140 patients, diastolic function assessment was undetermined or not completely assessed.

Patients demographic, clinical, laboratory, and angiographic data were prospectively collected. The data included age, sex, coronary risk factors, and detailed history of CAD, atrial fibrillation, heart failure, stroke, and peripheral vascular disease. Laboratory results including hemoglobin, creatinine, and lipid profile were recorded. Indication for coronary angiography, the result, and details of the intervention were collected. The database of the national population registry was used to assess survival. The study was approved by the Local IRB of Kaplan Medical Center and all patients provided written consent.

Echocardiography

Echocardiography examination was performed 1–72 h before coronary catheterization. LV dimension was measured in 2-D parasternal long axis view; LV ejection fraction (LVEF) was estimated using the bi-plane Simpson’s method; diastolic function grade was evaluated according to the published guidelines at the time of the study (ASE 2009 recommendations [19]), based on mitral Doppler inflow and tissue Doppler imaging at the lateral and septal mitral annulus; pulmonary artery pressure was calculated by the maximal tricuspid regurgitation velocity. The patients were divided into 2 groups according to filling pressures. Patients with normal diastolic function or grade 1 diastolic function (impaired relaxation) were in group 1 (normal filling pressure), and patients with grade 2 and 3 diastolic function were in group 2 (elevated filling pressure). Renal function was determined by calculating adjusted glomerular filtration rate (GFR) based on the blood samples obtained before coronary angiography.

Statistical Analysis

Baseline patient clinical characteristics and procedural data were compared between patients in the two groups, according to the absence or presence of the elevated LV filling pressure. Group 1 included patients with normal and group 2 patients with elevated filling pressure. The χ2 test was used for dichotomous variables, and independent t test was used for continuous variables. Data are expressed as mean ± SD or frequency and percentage when appropriate.

Cumulative event proportions were calculated by the Kaplan-Meier method, and outcome differences between the 2 groups were assessed with the log-rank test. Covariates included in the multivariate models were identified using a best subset procedure among candidate variables that were predictive of the endpoint and were unbalanced among the 2 groups, as well as clinically relevant. A p value <0.05 was considered significant. After analysis of the whole patients’ population, Kaplan-Meier survival analysis was used to access survival in the subgroup of patients with and without acute coronary syndrome (ACS), preserved and reduced LVEF, and preserved and reduced renal function. For the subset of patients with ACS, additional Cox regression analysis using the same was performed.

Finally, to evaluate the incremental value of LV filling pressure and renal function over LVEF, the variables were introduced to a baseline Cox regression model in a stepwise manner. Global χ2 values were calculated for all individual models. Data were analyzed using SPSS statistical software version 21.

Patient’s Characteristics according to Filling Pressure

Five hundred sixty-four patients were included in the study. The indication for coronary angiography was ACS in 298 (53%), chest pain evaluation in 208 (37%) patients, and coronary evaluation before aortic valve intervention (mainly aortic stenosis) in 58 (10%) patients. The patients were divided into two groups, according to the LV filling pressure: group 1 (382 patients) with normal and group 2 (182 patients) with elevated filling pressures. As can be seen in Table 1, there was a very high incidence of risk factors in study population: hypertension in 77% of patients, hyperlipidemia in 70% of patients, and DM in 45% of patients. In addition, the frequency of patients with history of coronary artery bypass surgery was also relatively high (21.6%) in the study population. The detailed differences between the groups are outlined in Table 1. Patients in group 2 were older (72.3 ± 10.6 years vs. 67.9 ± 11.4 years, p < 0.0001), more frequently women (35.2% vs. 26.2%, p = 0.028) with higher percent of hypertension (84.5% vs. 73.5%, p = 0.004) and diabetes (54.4 vs. 41.1%, p = 0.007). The LVEF was lower (44.5 ± 11.4% vs. 51.0 ± 8.7%, p < 0.0001) in patients in group 2 as was history of heart failure (31.3% vs. 6.1%, p ≤ 0.0001) and atrial fibrillation (35.2% vs. 11.5%, p < 0.001). There was no difference between the groups with regard to ACS (50.5% vs. 53.8%, p = 0.45) as an indication for coronary angiography or presence of CAD (85.2% vs. 85.6%, p = 0.89), as well as history of previous myocardial infarction (22.5% vs. 26.4%, p = 0.320). There was a higher rate of peripheral vascular disease (12.3% vs. 4%, p < 0.0001) and history of cerebrovascular accident (14% vs. 7.8%, p = 0.021) with a trend toward higher frequency of multivessel disease (43% vs. 33.2%, p = 0.066) in patients in group 2. The hemoglobin level was lower (12.5 ± 1.6 g/dL vs. 13.4 ± 1.5 g/dL, p < 0.0001) and the renal function was more impaired (GFR: 55.2 ± 31.6 mL/min vs. 71.5 ± 28.0 mL/min, p < 0.0001) in patients in group 2.

Table 1.

Baseline patient’s characteristics according to the LV filling pressure

VariableTotal patients; 564 (%)Patients with normal LVFP; 382 (67.7%)Patients with elevated LVFP; 182 (32.3%)p value
Age 69.3±11.3 67.9±11.4 72.3±10.6 <0.0001 
Female 164 (29.1) 100 (26.2) 64 (35.2) 0.028 
BMI 28.4±4.9 28.3±4.7 28.5±5.3 0.694 
DM 255 (45.4) 156 (41.1) 99 (54.4) 0.007 
HTN 431 (77.1) 278 (73.5) 153 (84.5) 0.004 
Dyslipidemia 392 (70.6) 261 (69.6) 131 (72.8) 0.442 
Previous MI 139 (25.1) 99 (26.4) 40 (22.5) 0.320 
Previous PCI 201 (36.2) 142 (37.7) 59 (33.0) 0.281 
Previous CABG 120 (21.6) 74 (19.6) 46 (25.7) 0.104 
History of CHF 75 (14.1) 23 (6.1) 55 (31.3) <0.0001 
Previous CVA 54 (9.8) 29 (7.8) 25 (14.0) 0.021 
History of PVD 37 (6.7) 15 (4.0) 22 (12.3) <0.0001 
ACS 298 (53) 206 (54) 92 (50.5) 0.450 
Abnormal CA 482 (85.5) 327 (85.6) 155 (85.2) 0.890 
Obstructive CAD 354 (62.8) 242 (63.4) 112 (61.5) 0.677 
3V CAD 189 (36.3) 118 (33.2) 71 (43.0) 0.066 
Calcified CA 115 (23.2) 72 (21.3) 43 (27.2) 0.189 
Ectatic CA 32 (6.4) 27 (7.9) 5 (3.2) 0.028 
EF, % 48.9±10.1 51.0±8.7 44.5±11.4 <0.0001 
Aortic stenosis 106 (18.9) 58 (15.3) 48 (26.4) 0.002 
Atrial fibrillation 108 (19.1) 44 (11.5) 64 (35.2) <0.001 
Creatinine, mg/dL 1.19±1.12 1.06±0.89 1.45±1.44 0.001 
GFR, mL/min 66.2±30.2 71.5±28.0 55.2±31.6 <0.0001 
HB, g/dL 13.1±1.6 13.4±1.5 12.5±1.6 <0.0001 
Mortality 169 (30.0) 77 (20.2) 92 (50.5) <0.0001 
VariableTotal patients; 564 (%)Patients with normal LVFP; 382 (67.7%)Patients with elevated LVFP; 182 (32.3%)p value
Age 69.3±11.3 67.9±11.4 72.3±10.6 <0.0001 
Female 164 (29.1) 100 (26.2) 64 (35.2) 0.028 
BMI 28.4±4.9 28.3±4.7 28.5±5.3 0.694 
DM 255 (45.4) 156 (41.1) 99 (54.4) 0.007 
HTN 431 (77.1) 278 (73.5) 153 (84.5) 0.004 
Dyslipidemia 392 (70.6) 261 (69.6) 131 (72.8) 0.442 
Previous MI 139 (25.1) 99 (26.4) 40 (22.5) 0.320 
Previous PCI 201 (36.2) 142 (37.7) 59 (33.0) 0.281 
Previous CABG 120 (21.6) 74 (19.6) 46 (25.7) 0.104 
History of CHF 75 (14.1) 23 (6.1) 55 (31.3) <0.0001 
Previous CVA 54 (9.8) 29 (7.8) 25 (14.0) 0.021 
History of PVD 37 (6.7) 15 (4.0) 22 (12.3) <0.0001 
ACS 298 (53) 206 (54) 92 (50.5) 0.450 
Abnormal CA 482 (85.5) 327 (85.6) 155 (85.2) 0.890 
Obstructive CAD 354 (62.8) 242 (63.4) 112 (61.5) 0.677 
3V CAD 189 (36.3) 118 (33.2) 71 (43.0) 0.066 
Calcified CA 115 (23.2) 72 (21.3) 43 (27.2) 0.189 
Ectatic CA 32 (6.4) 27 (7.9) 5 (3.2) 0.028 
EF, % 48.9±10.1 51.0±8.7 44.5±11.4 <0.0001 
Aortic stenosis 106 (18.9) 58 (15.3) 48 (26.4) 0.002 
Atrial fibrillation 108 (19.1) 44 (11.5) 64 (35.2) <0.001 
Creatinine, mg/dL 1.19±1.12 1.06±0.89 1.45±1.44 0.001 
GFR, mL/min 66.2±30.2 71.5±28.0 55.2±31.6 <0.0001 
HB, g/dL 13.1±1.6 13.4±1.5 12.5±1.6 <0.0001 
Mortality 169 (30.0) 77 (20.2) 92 (50.5) <0.0001 

BMI, body mass index; DM, diabetes mellitus; HTN, hypertension; MI, myocardial infarction; PCI, percutaneous coronary angiography; CABG, coronary artery bypass grafting; CHF, congestive heart failure; CVA, cerebrovascular accident; PVD, peripheral vascular disease; ACS, acute coronary syndrome; CA, coronary artery; CAD, coronary artery disease; EF, ejection fraction; GFR, glomerular filtration rate; HB, hemoglobin; LVFP, left ventricular filling pressures.

Patients Survival

The median follow-up was 2,293 (769–2,485) days. Hundred sixty-nine (30%) patients died during follow-up. The patients in group 2 had more than 2.5-fold higher mortality than patients in group 2 (50.5 vs. 20.2, p < 0.0001, Fig. 1).

Fig. 1.

Kaplan-Meyer survival analysis according to LV filling pressures in patients undergoing coronary angiography.

Fig. 1.

Kaplan-Meyer survival analysis according to LV filling pressures in patients undergoing coronary angiography.

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We performed univariate analysis to study the association of demographic, clinical, laboratory, and angiographic variables with mortality. The variables that reached statistical significance and other clinically important variables are shown in Table 2.

Table 2.

Univariate and multivariate analysis of predictors on mortality

VariableTotal patients; 564 (%)Alive; 395 (70%)Deceased; 169 (30%)p valueMultivariate
HR (95% CI)p value
Age 69.3±11.3 67.0±11.7 74.9±9.6 <0.0001 1.069 (1.031–1.108) 0.0001 
Female 29.1 26.8 34.3 0.073   
BMI 28.4±4.9 28.4±4.7 28.2±5.4 0.738   
DM 45.4 40.6 56.5 0.001  0.534 
HTN 77.1 73.1 86.3 0.001  0.442 
Dyslipidemia 70.6 70.2 71.7 0.721   
Previous MI 25.1 26.5 21.8 0.241   
Previous PCI 36.2 35.7 37.1 0.754   
Previous CABG 21.6 20.6 24.0 0.374   
Previous CVA 9.8 8.3 13.2 0.076   
History of CHF 14.1 8.6 26.9 <0.0001  0.250 
History of PVD 6.7 2.8 15.6 <0.0001  0.123 
ACS 55.7 56.3 54.3 0.679  0.319 
Abnormal CA 85.5 84.6 87.6 0.352   
Obstructive CAD 62.8 62.8 62.7 0.989   
3V CAD 36.3 33.0 44.2 0.086   
EF 48.9±10.1 50.2±9.2 45.7±11.5 <0.0001 0.960 (0.934–0.987) 0.004 
Elevated LVFP 32.3 22.8 54.4 <0.0001 3.717 (1.623–8.475) 0.002 
Aortic stenosis 18.9 14.1 30.2 <0.0001  0.446 
Atrial fibrillation 19.1 13.7 32.0 <0.0001  0.157 
Creatinine, mg/dL 1.19±1.12 1.05±0.90 1.50±1.45 <0.0001   
GFR, mL/min 66.2±30.2 72.5±28.3 51.4±29.3 <0.0001 0.972 (0.958–0.985) 0.0001 
HB, g/dL 13.1±1.6 13.4±1.5 12.3±1.6 <0.0001 0.753 (0.592–0.959) 0.021 
VariableTotal patients; 564 (%)Alive; 395 (70%)Deceased; 169 (30%)p valueMultivariate
HR (95% CI)p value
Age 69.3±11.3 67.0±11.7 74.9±9.6 <0.0001 1.069 (1.031–1.108) 0.0001 
Female 29.1 26.8 34.3 0.073   
BMI 28.4±4.9 28.4±4.7 28.2±5.4 0.738   
DM 45.4 40.6 56.5 0.001  0.534 
HTN 77.1 73.1 86.3 0.001  0.442 
Dyslipidemia 70.6 70.2 71.7 0.721   
Previous MI 25.1 26.5 21.8 0.241   
Previous PCI 36.2 35.7 37.1 0.754   
Previous CABG 21.6 20.6 24.0 0.374   
Previous CVA 9.8 8.3 13.2 0.076   
History of CHF 14.1 8.6 26.9 <0.0001  0.250 
History of PVD 6.7 2.8 15.6 <0.0001  0.123 
ACS 55.7 56.3 54.3 0.679  0.319 
Abnormal CA 85.5 84.6 87.6 0.352   
Obstructive CAD 62.8 62.8 62.7 0.989   
3V CAD 36.3 33.0 44.2 0.086   
EF 48.9±10.1 50.2±9.2 45.7±11.5 <0.0001 0.960 (0.934–0.987) 0.004 
Elevated LVFP 32.3 22.8 54.4 <0.0001 3.717 (1.623–8.475) 0.002 
Aortic stenosis 18.9 14.1 30.2 <0.0001  0.446 
Atrial fibrillation 19.1 13.7 32.0 <0.0001  0.157 
Creatinine, mg/dL 1.19±1.12 1.05±0.90 1.50±1.45 <0.0001   
GFR, mL/min 66.2±30.2 72.5±28.3 51.4±29.3 <0.0001 0.972 (0.958–0.985) 0.0001 
HB, g/dL 13.1±1.6 13.4±1.5 12.3±1.6 <0.0001 0.753 (0.592–0.959) 0.021 

HR for age: for 1 year increase.

HR for LVEF: for 1% increase.

HR for GFR: for 1 mL/min increase.

HR for HB: for 1 mg/dL increase.

BMI, body mass index; DM, diabetes mellitus; HTN, hypertension; MI, myocardial infarction; PCI, percutaneous coronary angiography; CABG, coronary artery bypass grafting; CHF, congestive heart failure; CVA, cerebrovascular accident; PVD, peripheral vascular disease; ACS, acute coronary syndrome; CA, coronary artery; CAD, coronary artery disease; EF, ejection fraction; GFR, glomerular filtration rate; HB, hemoglobin; LVFP, left ventricular filling pressures.

Elevated LV filling pressure remained independently associated with all-cause mortality after adjusting for age, history of heart failure and peripheral vascular disease, CAD and presence of ACS, reduced LVEF, risk factors, renal insufficiency, and paroxysmal atrial fibrillation (HR: 3.171, CI: 1.623–8.475, p = 0.002). Other factors that were significant in multivariate analysis, were age (HR: 1.069, CI: 1.031–1.108, p = 0.0001), LVEF (HR: 0.960, CI: 0.934–0.987, p = 0.004), GFR (HR: 0.972, CI: 0.958–0.985, p = 0.0001), and hemoglobin level (HR: 0.753, CI: 0.592–0.959, p = 0.021). These findings show the importance of systolic and diastolic function for predicting prognosis in patients referred to coronary angiography.

Survival of Patients according to Subgroups

Patients with ACS

In 298 patients with ACS, 206 had normal filling pressure and 92 had elevated LV filling pressure (p = 0.45). Hundred and eleven patients had ST-elevation myocardial infarction (STEMI). In ACS patients, the mortality rate was 51/92 (55.4%) in group 2 versus 37/206 (17.9%) in group 1 during the follow-up period (p < 0.0001); the overall mortality was 88/298 (29.5%) in this group. Kaplan-Meier analysis demonstrated significant association of the elevated LV filling pressure and mortality (Fig. 2a, b). The impact of elevated LV filling pressure on mortality was seen in STEMI and non-STEMI patients (57.6% vs. 21.3% and 51.6% vs. 14.5%, respectively, p < 0.0001 for both groups). Moreover, the presence of ACS did not affect mortality in patients with normal filling pressure as well is in patients with elevated filling pressure (p = 0.22 and p = 0.243, respectively, Fig. 2c, d).

Fig. 2.

a Kaplan-Meyer survival analysis according to normal versus elevated LV filling pressure in patients with ACS undergoing coronary angiography. b Kaplan-Meyer survival analysis according to normal versus elevated LV filling pressure in patients without ACS undergoing coronary angiography. c Kaplan-Meyer survival analysis according to presence of ACS in patients with normal filling pressure undergoing coronary angiography. d Kaplan-Meyer survival analysis according to presence of ACS in patients with elevated filling pressure undergoing coronary angiography.

Fig. 2.

a Kaplan-Meyer survival analysis according to normal versus elevated LV filling pressure in patients with ACS undergoing coronary angiography. b Kaplan-Meyer survival analysis according to normal versus elevated LV filling pressure in patients without ACS undergoing coronary angiography. c Kaplan-Meyer survival analysis according to presence of ACS in patients with normal filling pressure undergoing coronary angiography. d Kaplan-Meyer survival analysis according to presence of ACS in patients with elevated filling pressure undergoing coronary angiography.

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We also performed similar Cox regression model in this group (excluding presence of ACS). Elevated filling pressure was independently associated with higher mortality (HR: 6.803, CI: 2.347–19.608, p < 0.0001; Table 3). Other significant predictors of mortality were age, LVEF, DM, and renal function.

Table 3.

Cox regression multivariate analysis of effect on mortality (patients with ACS)

VariableHazard ratioCIp value
Age 1.063 1.014–1.113 0.011 
DM 1.680 1.075–2.632 0.023 
HTN   0.198 
History of CHF   0.286 
PVD   0.163 
EF 0.953 0.919–0.989 0.012 
Elevated LVFP 6.803 2.347–19.608 <0.0001 
Aortic stenosis   0.306 
Atrial fibrillation   0.187 
GFR 0.973 0.951–0.996 0.023 
HB   0.089 
VariableHazard ratioCIp value
Age 1.063 1.014–1.113 0.011 
DM 1.680 1.075–2.632 0.023 
HTN   0.198 
History of CHF   0.286 
PVD   0.163 
EF 0.953 0.919–0.989 0.012 
Elevated LVFP 6.803 2.347–19.608 <0.0001 
Aortic stenosis   0.306 
Atrial fibrillation   0.187 
GFR 0.973 0.951–0.996 0.023 
HB   0.089 

HR for age: for 1 year increase.

HR for LVEF: for 1% increase.

HR for GFR: for 1 mL/min increase.

HR for HB: for 1 mg/dL increase.

Patients Who Underwent Coronary Intervention

As seen in Table 2, CAD was present in the majority of patients (85.5%). Percutaneous coronary intervention (PCI) was performed in 53% of patients. As seen in Figure 3a–c, elevated filling pressure was a prognostic factor in patients who underwent PCI with drug-eluting stents and bare-metal stents, as well as in patients who did not undergo PCI (p < 0.01 for all).

Fig. 3.

a Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressures in patients undergoing coronary angioplasty with bare-metal stent. b Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressure in patients undergoing coronary angioplasty with drug-eluting stent. c Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressure in patients undergoing coronary angioplasty without coronary intervention.

Fig. 3.

a Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressures in patients undergoing coronary angioplasty with bare-metal stent. b Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressure in patients undergoing coronary angioplasty with drug-eluting stent. c Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressure in patients undergoing coronary angioplasty without coronary intervention.

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Patients with Aortic Stenosis

Aortic valve stenosis of any degree was present in 106 patients. In patients with aortic stenosis, elevated filling pressure was associated with mortality (p = 0.0001).

Subgroup Analysis by LVEF and Renal Function

Since LVEF and renal function were strong predictors of survival; we performed subgroup analysis, to assess the significance of LV filling pressures in patients with preserved and reduced LVEF and in preserved and impaired renal function. Elevated filling pressure affected survival in patients with preserved LVEF and in patients with reduced LVEF (Fig. 4, p < 0.001 for both).

Fig. 4.

a Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressures in patients undergoing coronary angiography with reduced LV systolic function. b Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressure in patients undergoing coronary angiography with preserved LV systolic function.

Fig. 4.

a Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressures in patients undergoing coronary angiography with reduced LV systolic function. b Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressure in patients undergoing coronary angiography with preserved LV systolic function.

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There was an additive effect of LV filling pressures and renal function in the studied population (Fig. 5a, b). Increased severity of renal dysfunction corresponded to increased mortality (Fig. 5c). In patients with elevated filling pressure and impaired renal function, the prognosis was very poor (Fig. 5d, p = 0.001). The addition of LV filling pressure and renal function to LVEF resulted in a significant increase in χ2 values (Fig. 6).

Fig. 5.

a Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressure in patients undergoing coronary angiography with preserved renal function. b Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressure in patients undergoing coronary angiography with impaired renal function. c Kaplan-Meyer survival analysis according to the severity of GFR impairment. d Kaplan-Meyer survival analysis according to the combination of normal versus elevated LV filling pressure and normal and impaired renal function in patients undergoing coronary angiography.

Fig. 5.

a Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressure in patients undergoing coronary angiography with preserved renal function. b Kaplan-Meyer survival analysis according to the normal versus elevated LV filling pressure in patients undergoing coronary angiography with impaired renal function. c Kaplan-Meyer survival analysis according to the severity of GFR impairment. d Kaplan-Meyer survival analysis according to the combination of normal versus elevated LV filling pressure and normal and impaired renal function in patients undergoing coronary angiography.

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Fig. 6.

Incremental prognostic value of LV filling pressures and renal function in patients undergoing coronary angiography.

Fig. 6.

Incremental prognostic value of LV filling pressures and renal function in patients undergoing coronary angiography.

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The main findings of the study are as follows: (a) elevated LV filling pressure is associated with long-term all-cause mortality in high-risk patients that undergo coronary angiography; (b) the prognostic significance of elevated filling pressure was seen in various subgroups of patients, in patients with ACS as well as stable coronary disease, in patients who underwent coronary intervention as well as patients with conservative treatment; (c) advanced diastolic dysfunction and impaired renal failure showed additive effect on survival in these patients.

The prognostic significance of impaired diastolic function is shown in various clinical settings. In the NEDA study, that assessed the prognosis of diastolic dysfunction in a very large unselected population, diastolic dysfunction was associated with increased mortality. They also reported prognostic significance of various isolated echocardiographic parameters. There was no risk factor adjustment in this study [20]. However, some community studies showed that when adjusting to risk factors, the prognostic significance of diastolic function is modest [16].

In patients with coronary disease, the prognostic significance of diastolic function was also studied. Restrictive filling pattern in patients with STEMI was related to worse outcome [21]. In a recent study, Leistner et al. [12] assessed invasively left ventricular end-diastolic pressure (LVEDP) in patients undergoing percutaneous coronary intervention for ACS. They found that LVEDP was independently related to mortality, beyond the traditional risk factors, in a mean follow-up of 246 days. The other significant factors were prior myocardial infarction, LVEF, and renal function. Fukuta et al. assessed the association of LV diastolic dysfunction assessed by cardiac catheterization as well as Doppler echocardiography, with subsequent cardiovascular events in patients undergoing cardiac catheterization for CAD assessment. In this population, LVEDP was not found to be related to outcome, whereas impaired LV relaxation assessed by both cardiac catheterization and Doppler echocardiography, was independently associated with increased risk for cardiac death or cardiovascular hospitalization. The population was different and did not include patients with ACS, heart failure, or cardiomyopathy. The incidence of hypertension was significantly lower in this study compared to patients in our study.

Diastolic function and filling pressures are dynamic. Usually, they do not improve with time [6]. In patients who undergo revascularization, there is an improvement in diastolic function in a small percent of patients, and in some patients, the diastolic function worsens [10]. The prognosis and MACE of patients with more advanced impairment in diastolic function were less favorable. Patients with worsened diastolic function had a higher SYNTAX score, larger number of treated coronary artery lesions, and higher frequencies of hypertension, chronic kidney disease, and multivessel disease than did patients with improved diastolic function.

Our study included patients referred for coronary angiography, mean age of 69 years, with high incidence of hypertension and DM, and high prevalence of CAD. DM and hypertension were related to mortality in univariate model only. Age, systolic function, advanced diastolic function, hemoglobin level, and renal function were related to mortality. The prognostic significance of the noninvasive assessment of LV filling pressures in our study is in line with prognostic significance of invasively assessed LVEDP in the study of Leistner et al., with LVEF and renal function also being independently related to outcome.

Diastolic dysfunction in patients with CAD is only partially related to myocardial ischemia and obstructive coronary stenosis. As can be seen from the work by Kim et al. [15], multivessel revascularization was actually associated with worsening in diastolic function. CAD and risk factors affect diastolic function by various mechanisms, including LV remodeling, interstitial fibrosis, microvascular dysfunction, and LV hypertrophy.

Renal function is an important prognostic function in patients with cardiovascular disease, and vice versa, cardiovascular disease is an important prognostic function in patients with kidney disease [18, 22‒24]. We show the additive effect of even mild impairment in renal function to systolic and diastolic function, on long-term survival.

The treatment of patients with various cardiovascular diseases includes pharmacological treatments and interventions. The patients included in the study underwent appropriate intervention, with prevention strategies of contrast nephropathy when needed, but the prognosis was related to the LV systolic and diastolic function and renal function. We hypothesize, that in a high-risk population similar to our cohort, with high prevalence of risk factors and coronary disease, the assessment of diastolic function and renal function is important along with intervention.

Recently, new therapies, including novel antidiabetic drugs, showed improved survival in patients with heart failure and renal failure [25‒27]. High-risk patients that undergo coronary angiography should have risk assessment that include LV function, including LVEF and diastolic function, risk factor assessment, and renal function assessment. Patients with advanced diastolic dysfunction and especially those with even mild renal function impairment need intense follow-up and treatment, possibly including SGLT2 inhibitors and GLP-1 receptor agonists.

First, this is a single-center observational study with inherent selection bias. Second, only limited number of patients was involved in this registry. The study population is heterogeneous; however, this may be strength as well, since the filling pressures prognostic significance was a significant independent predictor in the whole heterogeneous population. Additionally, the population registry database used to access survival does not state the diagnosis or whether the death was from cardiac or noncardiac cause. Diastolic function assessment was done according to 2009 recommendations that were valid at the time when the echocardiography studies were performed. We assessed diastolic function noninvasively only. Invasive assessment of LVEDP is not routinely performed in patients with suspected and known coronary disease in our institution.

LV systolic function and filling pressures, along with renal function are signals toward longer term worse outcomes and associated with mortality in high-risk patients undergoing coronary angiography. This is valid in the whole patient cohort and in patients with ACS. Risk assessment and treatment based on it should be done in addition to intervention.

The study was approved by the Local IRB of Kaplan Medical Center, approval number 0109-10-KMC. All patients provided written consent.

The authors have no conflicts of interest to declare.

No funding was received for this study.

Nicholay Teodorovich – data collection and analysis and manuscript preparation. Yakov Fabrikant – data collection. Gera Gandelman and Michael Jonas – protocol design and patients recruitment. Moshe Swissa – data analysis. Jacob George – supervision. Sara Shimoni – protocol design and manuscript writing.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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