Study Population

This is a multicenter study designed by the Italian Society of Cardiovascular Echography, the Disfunzione Asintomatica del Ventricolo Sinistro study, which included 1097 consecutive asymptomatic subjects (stage A) aged more than 18 years who were admitted to 19 echocardiographic laboratories for transthoracic examination as a screening evaluation in the presence of one or more cardiovascular risk factors. All laboratories were selected according to the operator’s competence, level 3, in agreement with the American Society of Echocardiography (ASE) requirements. The American College of Cardiology/American Heart Association guideline 2005 for HF identifies four stages of HF: stage A, at high risk for HF but without structural heart diseases or symptoms of HF; stage B, structural heart disease but without signs or symptoms of HF; stage C, structural heart disease with prior or current symptoms of HF; and stage D, refractory HF requiring specialized interventions.

The study was approved by the local research ethic committees. The study enrolled subjects without a clinical history of HF or other cardiovascular diseases, according to inclusion criteria, with normal electrocardiography (ECG) tracings, and with normal clinical examination results in the presence of one or more cardiovascular risk factors. The definition of a normal ECG scan was according to Marriott’s Practical Electrocardiography normality criteria. All selected subjects underwent a complete two-dimensional echocardiographic study to evaluate LV functional and structural findings. Exclusion criteria were symptoms or clinical and instrumental signs of coronary artery disease (CAD), valvular heart disease (except mild forms not hemodynamically relevant), previous cardiac surgery or percutaneous coronary intervention, history of paroxysmal or persistent atrial fibrillation, anemia (hemoglobin < 12 mg/dL in women and < 13 mg/dL in men), renal failure (serum creatinine > 1.3 mg/dL), endocrinologic diseases (in particular, hypo- and hyperthyroidism, hyperaldosteronism). Pericardial disease, pulmonary hypertension, aortopathy, and cardiomyopathy were excluded on the basis of echocardiography.

All subjects provided written informed consent and detailed medical history, particularly on cardiovascular risk factors, comorbidities, and drug therapies. For study purposes, six cardiovascular risk factors were considered: hypertension (systolic blood pressure ≥ 140 mm Hg, diastolic blood pressure ≥ 90 mm Hg, or in drug treatment), diabetes mellitus (fasting glycemia ≥ 7.0 mmol/L ⁻¹ or in drug treatment), hypercholesterolemia (>200 mg/dL or in drug treatment), family history of cardiovascular disease (including CAD, cardiomyopathy, and other hereditary forms of cardiopathy), smoking (≥1 cigarette/day, cessation of smoking < 10 years previously was still considered as smoking), and obesity (body mass index ≥ 30 kg/m ² ). We enrolled only prehypertensive (54%) or mild hypertensive (46%) asymptomatic subjects with normal ECG findings; on these terms, these patients were classified in class A.

Diagnostic Criteria

All patients enrolled in the study underwent a physical examination, 12-lead electrocardiogram, and complete transthoracic echocardiographic examination, according to the standard protocol based on the ASE recommendations. Anthropometric measurements (weight, height) were obtained, and body mass index was calculated (body weight in kilograms divided by height in meters squared). Blood pressure was measured twice at the right arm after a 10-minute rest in the supine position using a calibrated sphygmomanometer and then averaged. Echocardiograms were acceptable when at least 80% of the endocardium was visible. Quantitative analysis was done, for each laboratory, by the same expert operator. Measurements of LV ejection fraction (EF) were performed using the modified biplane Simpson’s rule as a mean of three cardiac cycles. EF less than 50% was used as a cutoff for abnormal LVEF (LV dysfunction). LV diastolic function was evaluated according to the standard criteria. The mitral flow was recorded in basal condition and during Valsalva maneuver. The following diastolic parameters were assessed from the Doppler mitral flow and tissue velocities tracings: E-wave velocity, A-wave velocity, E/A, Δ E/A (changes from basal to Valsalva maneuvers), E-wave deceleration time, A-wave duration, E/e’, and pulmonary venous flow (systolic velocity, diastolic velocity, a reverse wave duration). Diastolic function was classified according to recent recommendations of ASE on diastolic functional evaluation. The grading scheme was mild or grade I (impaired relaxation pattern), moderate or grade II (pseudonormalized filling), and severe (restrictive pattern) or grade III ( Table 1 ). The majority of patients showed a normal diastolic filling pattern (58%), 32% of patients presented grade I diastolic dysfunction, and 10% of patients presented grade II diastolic dysfunction. LV mass was calculated according to the Penn convention and indexed for height (g/m ^2.7 ). LV hypertrophy was defined as LV mass index > 49.2 g/m ^2.7 in men and > 46.2 g/m ^2.7 in women. A random sample of 5% was centrally reanalyzed by two independent observers. The mean and standard deviation of variability between the two readings and by the same observer for the echocardiographic parameters were as follows: The intraobserver variability mean ± standard deviation values for EF were 64% ± 4% versus 66% ± 5% ( P < . 06), and the interobserver values were 62% ± 6% versus 67% ± 7% ( P < . 07). If the interobserver and intraobserver variability were considered in the identification of LV systolic or diastolic dysfunction, interobserver variability was 8.2% and intraobserver variability was 7.8% for systolic dysfunction, and interobserver variability was 8.7% and intraobserver variability was 7.5% for diastolic dysfunction.

Follow-Up and Outcome Events

All 19 echocardiographic laboratories involved in the study agreed to follow up the recruited patients. Thus, follow-up data were available for 905 subjects (82.4% of the initial sample) (mean duration 26 ± 11 months, range 16–60 months). Follow-up of patients was performed by using clinical controls (cardiologic visit), the hospital database, and phone contact to obtain information on clinical data and adverse events. The present study considered the following primary end points: cardiac death, myocardial infarction, coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, stroke, transient ischemic attack, and acute pulmonary edema. Secondary end points were (1) the HF hospitalization due to a clear change of normal clinical state of the patients (acute progression of HF stage) realized with a minimum of one night of hospitalization and involving at least two of the major Framingham criteria for the Clinical Diagnosis of Congestive Heart Failure; and (2) cardiologist-made diagnosis of chronic progression of HF (HF stage C). For the diagnosis of myocardial infarction, stroke/transient ischemic attack, and acute pulmonary edema, standard laboratory, ECG, or examination criteria were used.

Statistical Analysis

Continuous variables are presented as mean ± standard deviation or median and interquartile range, as appropriate. Categoric variables are presented as percentages and were compared using the chi-square test. Kruskal–Wallis one-way analysis of variance by ranks was used to examine differences of continuous variables among risk factor groups. The Mann–Whitney test was used to examine the difference of continuous variables between dichotomy variables. To identify predictive factors for occurrence of primary or secondary end points, we first performed three models of logistic regression analyses with cardiovascular risk factors and LV (systolic and diastolic) dysfunction as covariates, adjusting for age and gender, and with the outcomes mentioned above as dependent variables. Second, we calculated several survival curves using the Kaplan–Meier method for predicting primary or secondary end points according to cardiovascular risk factors (stratifying in three groups of subjects with one, two, or more cardiovascular risk factors), systolic function (normal or abnormal EF), and diastolic function (normal or abnormal). To establish the incremental value of echocardiography, we divided subjects with normal or abnormal systolic function according to the three groups of cardiovascular risk factors and tested the differences of primary end points, secondary end points, and combined, using the chi-square test. A two-tailed P value less than .05 was considered significant. All data were analyzed using SPSS software (version 13.0; SPSS, Inc., Chicago, IL).

Follow-up

During the follow-up period, 38 primary end points (3.3%) were observed; secondary end points were observed in 47 subjects (5.2%). The details of their distribution are shown in Table 3 . Univariate analysis of possible predictors of primary, secondary, or combined end points is shown in Table 4 . Primary end points are related to gender ( P < . 002) and age ( P < . 001). Diabetes, obesity, and dyslipidemia are the more important risk factors in predicting primary end points. From a structural point of view, LV mass and LV systolic and diastolic volumes, indexed to height, are significant predictors of primary end points ( Table 5 ). The multivariate analysis for independent predictors of cardiovascular primary end points showed that age ( P = .001), gender ( P = .02), dyslipidemia ( P = .01), obesity ( P = .001), and systolic dysfunction ( P = .048) represented the significant predictors ( Table 5 ). The multivariate logistic regression analysis for independent predictors of secondary end points showed that gender ( P = .02), LV systolic dysfunction ( P = .01), and LV diastolic dysfunction ( P < . 01) represented the significant predictors ( Table 6 ). The multivariate analysis for independent predictors of combined end points showed that only age ( P < . 003), gender (male: P < . 001), obesity ( P < . 04), and systolic dysfunction ( P < . 001) represented the significant predictors ( Table 7 ).

Table 4

Univariate analysis of possible predictors of primary or secondary end points or combined

		Secondary end points		Primary end points		Combined
	Overall	n (%) or median, IQR	P <	n (%) or median, IQR	P <	n (%) or median, IQR	P <
Male	476	35 (7.4)	.003	27 (5.7)	.002	52 (10.9)	.000
Diabetes	111	11 (9.9)	.020	10 (9)	.002	17 (15.3)	.001
Hypertension	583	36 (6.2)	.078	21 (3.6)	.924	46 (7.9)	.353
Current smokers	236	12 (5.1)	.930	8 (3.4)	.807	17 (7.2)	.951
Dyslipidemia	315	22 (7)	.079	21 (6.7)	.001	33 (10.5)	.008
Obesity	167	13 (7.8)	.099	15 (9)	.000	20 (12)	.011
Family history of CAD	360	17 (4.7)	.604	13 (3.6)	.963	25 (6.9)	.743
1 risk factor	355	11 (3.1)	.048	6 (1.7)	.001	15 (4.2)	.005
2 risk factors	312	18 (5.8)		9 (2.9)		24 (7.7)
≥3 risk factors	238	18 (7.6)		18 (7.6)		27 (11.3)
Diastolic dysfunction	277	16 (8.1)	.028	7 (3.6)	.847	20 (10.2)	.074
Systolic dysfunction	94	17 (18.1)	.000	8 (8.5)	.011	18 (19.1)	.000
Age (y)	57 (46–65)	59 (52–65)	.001	68 (64–69)	.000	61 (53–68)	.000
BMI	25 (23–28)	26 (24–30)	.015	30 (25–32)	.002	26 (24–31)	.005
SBP (mm Hg)	140 (125–150)	140 (130–150)	.611	135 (130–140)	.405	140 (130–146)	.867
DBP (mm Hg)	80 (80–90)	80 (75–90)	.119	80 (70–80)	.002	80 (74–90)	.016
EF (%)	64 (58–69)	49 (45–59)	.001	49 (42–75)	.209	49 (44–60)	.060
LVM bsa	93 (77–113)	124 (107–148)	.000	134 (91–156)	.022	120 (101–149)	.000
LVM h	43 (35–52)	56 (53–66)	.000	61 (41–77)	.013	55 (43–67)	.000
EDV (mL)	93 (71–117)	107 (92–144)	.000	126 (69–141)	.002	111 (92–141)	.000
ESV (mL)	32 (23–45)	57 (42–74)	.000	49 (28–75)	.009	57 (33–74)	.000
LVDD (mm)	50 (46–53)	53 (50–55)	.000	51 (48–54)	.007	52 (49–55)	.000
LVSD (mm)	30 (28–34)	36 (30–42)	.000	29 (23–40)	.036	35 (29–40)	.000
LA diameter (mm)	37 (33–41)	41 (37–46)	.000	40 (34–44)	.062	41 (36–44)	.000

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