Classification and Prognostic Evaluation of Left Ventricular Remodeling in Patients With Asymptomatic Heart Failure

Accepted Manuscript “Classification and Prognostic Evaluation of Left Ventricular Remodeling in Patients with Asymptomatic Heart Failure” Nicola Riccardo Pugliese, MD, Iacopo Fabiani, MD, Salvatore La Carrubba, MD, Lorenzo Conte, MD, Francesco Antonini-Canterin, MD, Paolo Colonna, MD, Pio Caso, MD, Frank Benedetto, MD, Veronica Santini, MD, Scipione Carerj, MD, Maria Francesca Romano, Rodolfo Citro, MD, Vitantonio Di Bello, MD, Prof. PII:

S0002-9149(16)31578-8

DOI:

10.1016/j.amjcard.2016.09.018

Reference:

AJC 22160

To appear in:

The American Journal of Cardiology

Received Date: 6 July 2016 Revised Date:

5 September 2016

Accepted Date: 6 September 2016

Please cite this article as: Pugliese NR, Fabiani I, La Carrubba S, Conte L, Antonini-Canterin F, Colonna P, Caso P, Benedetto F, Santini V, Carerj S, Romano MF, Citro R, Di Bello V, on behalf of Italian Society of Cardiovascular Echography (SIEC), “Classification and Prognostic Evaluation of Left Ventricular Remodeling in Patients with Asymptomatic Heart Failure”, The American Journal of Cardiology (2016), doi: 10.1016/j.amjcard.2016.09.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT “Classification and Prognostic Evaluation of Left Ventricular Remodeling in Patients with Asymptomatic Heart Failure” Nicola Riccardo Pugliese MD1*, Iacopo Fabiani MD1*, Salvatore La Carrubba MD2, Lorenzo Conte MD1, Francesco Antonini-Canterin MD3, Paolo Colonna MD4, Pio Caso MD5, Frank

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Benedetto MD6, Veronica Santini MD1, Scipione Carerj MD7, Maria Francesca Romano8, Rodolfo Citro MD9 and Prof. and Vitantonio Di Bello MD1, on behalf of Italian Society of Cardiovascular Echography (SIEC).

Dipartimento di Patologia Medica, Chirurgica, Molecolare e dell’Area Critica, Università di Pisa

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Ospedale Villa Sofia, Palermo, Italy

3

Ospedale di Pordenone S.Maria degli Angeli-SSD Patologia Cardiovascolare ed Aterosclerosi

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Azienda Ospedaliero Universitaria Policlinico - Bari U.O.C. Cardiologia Ospedaliera

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Azienda Ospedaliera Monaldi - Napoli

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UOC Cardiologia Clinica e Riabilitativa Azienda Ospedaliera "Bianchi-Melacrino-Morelli" Reggio Calabria

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AOU "San Giovanni di Dio e Ruggiero d'Aragona" – Salerno Scuola Superiore S.Anna , Pisa Italy

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Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Messina

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*The first two authors contributed equally to this work and are joint first authors

Running title: remodeling in asymptomatic heart failure.

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Fundings: none.

Relationships with Industry/Conflicts of interest: None. Address for Correspondence Dr. Nicola Riccardo Pugliese, MD Via Paradisa, 2 - Ospedale Cisanello, 56100 – Pisa (PI) - Italy Dipartimento di Patologia Medica, Chirurgica, Molecolare e dell’Area Critica, Università di Pisa E-mail: [email protected] Phone number: 0039-050995315. 1

ACCEPTED MANUSCRIPT ABSTRACT Patients with asymptomatic Heart Failure (HF; Stage A and B) are characterized by maladaptive left ventricular (LV) remodeling. Classic 4 groups classification of remodeling considers only LV mass index and relative wall thickness as variables. Complex remodeling classification (CRC)

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includes also LV end-diastolic volume index. Main aim was to assess the prognostic impact of CRC in Stage A and B HF. A total of 1750 asymptomatic subjects underwent echocardiographic examination as a screening evaluation in the presence of cardiovascular risk factors. LV

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dysfunction, both systolic (ejection fraction) and diastolic (transmitral flow velocity pattern), was

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evaluated, together with LV remodeling. We considered a composite end-point: all-cause death, myocardial infarction, coronary revascularizations, cerebrovascular events and acute pulmonary edema. CRC was suitable for 1729 patients (Male 53.6%; age 58.3±13 years). Two-hundred-thirtyeight patients presented systolic dysfunction (EF<50%) and 483 diastolic dysfunction. According to

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the CRC, 891 patients were normals or presented physiologic hypertrophy, 273 concentric remodeling, 47 eccentric remodeling, 350 concentric hypertrophy, 29 mixed hypertrophy, 86 dilated hypertrophy and 53 eccentric hypertrophy. Age and gender distribution was noticed

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(p<0.001). After a median follow-up of 21 months, Kaplan-Meier analysis showed different survival

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distribution (p<0.001) of the CRC patterns. In multivariate Cox-regression (adjusted for age, gender, history of stable ischemic heart disease, classic remodeling classification, systolic and diastolic dysfunction) CRC was independent predictor of primary end-point (p=0.044, HR=1.101, IC 95% 1.003-1.21), confirmed in a logistic regression (p<0.03). In conclusion, CRC could help physicians in prognostic stratification of patients in stage A and B HF.

Keywords: heart failure; echocardiography; left ventricle remodeling; left ventricular dysfunction.

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ACCEPTED MANUSCRIPT BACKGROUND The prevalence of Heart Failure (HF)1,2 in the general population ranges between 0.4% and 2%, increasing with age. Patients in Stage A and B are ideal targets for HF prevention. These individuals

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are asymptomatic patients characterized by cardiovascular risk factors (Stage A) and structural heart diseases (Stage B). These silent abnormalities may lead over time to maladaptive cardiac remodeling and HF progression3. Early detection (and potential treatment) of subclinical LV

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dysfunction is pivotal, with the aim of delaying HF evolution. In this scenario, echocardiography plays a critical role.4 In particular, we focused on LV remodeling, defined as an alteration in heart

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structure (dimension, mass, shape) in response to hemodynamic load and/or cardiac injury, and in association with neuro-hormonal activation.5 Remodeling may be described as physiologic or pathologic.6

Pathologic

remodeling

prevention/treatment

has

net

beneficial

effects.7

Echocardiography allows bedside evaluation of LV volume, mass and wall thickness.8,9 The

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universally known four-groups classification of LV remodeling,10 considers only estimation of LV mass index (LVMi) and relative wall thickness (RWT) as classifying variables.11 A recent revision improved this classification, with inclusion of indexed left ventricular end-diastolic volume (LV-

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EDVi), adding further phenotypes (9 phenotypes comprehensively)12,13. Our purposes was to

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assess the association of CRC patterns with conventional cardiovascular risk factors and the prognostic impact of CRC in a cohort of patients in stage A and B HF.14 METHODS

This is a multicenter study designed by the Italian Society of Cardiovascular Echography (SIEC): the Disfunzione Asintomatica del Ventricolo Sinistro (DAVES) study.15 It included consecutive asymptomatic HF subjects (Stage A and B)14 aged more than 18 years admitted to 19 echocardiographic laboratories for transthoracic examination in the presence of one or more cardiovascular risk factors. All laboratories were selected according to the operator’s competence 3

ACCEPTED MANUSCRIPT in agreement with the American Society of Echocardiography (ASE) requirements.16 Evidencebased HF guidelines from the American College of Cardiology/American Heart Association were used to identify 4 Stages of HF (Stage A, Stage B, Stage C and Stage D).14 The study was approved by the local research ethic committees. We enrolled subjects without a clinical history of HF with

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normal electrocardiography (ECG) tracings and 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

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complete two-dimensional echocardiographic study to evaluate LV functional and structural

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findings. Exclusion criteria were symptoms or clinical and instrumental signs of unstable 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),

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renal failure (serum creatinine > 1.3 mg/dL), endocrine disorders (in particular, hypo- and hyperthyroidism, hyper-aldosteronism). Pericardial disease, pulmonary hypertension, aortic diseases and cardiomyopathy were excluded based on echocardiography. All subjects provided written

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informed consent and detailed medical history. For study purposes, 6 cardiovascular risk factors were considered: hypertension (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90

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mm Hg, or in drug treatment), diabetes mellitus (fasting glucose > 7.0 mmol/L-1 or in drug treatment), dyslipidemia (hypercholesterolemia >200 mg/dL or in drug treatment), family history of cardiovascular disease (including CAD, cardiomyopathy, and other hereditary forms of cardiomyopathy), smoking (≥1 cigarette/day; cessation of smoking < 10 years previously was still considered as smoking) and obesity (body mass index ≥ 30 kg/m2). 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. In presence of relevant structural 4

ACCEPTED MANUSCRIPT alterations (without symptoms) revealed at echocardiography, we identified Stage B HF patients. All patients enrolled in the study underwent a physical examination, 12-lead electrocardiogram and transthoracic echocardiographic examination. Anthropometric measurements (weight, height) were obtained and body mass index (BMI) was calculated (i.e. body weight in kilograms divided by

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height in meters squared).17 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-EDV, end-systolic volume (ESV) and EF were performed using the

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modified biplane Simpson’s rule as a mean of three cardiac cycles. EF less than 53% was used as a

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cutoff for abnormal LVEF (LV systolic dysfunction). LV diastolic function was evaluated according to the standard criteria.18 Diastolic function was classified according to recommendations of ASE on diastolic functional evaluation. The grading scheme for diastolic dysfunction was mild or grade I (impaired relaxation pattern), moderate or grade II (pseudo-normalized filling), and severe

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(restrictive pattern) or grade III. Diastolic dysfunction, was a dichotomous definition (yes/no for any of the previous 3 grades). A random sample of 5% was centrally re-analyzed by two independent observers. The mean and standard deviation of variability between the two readings

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and by the same observer for the echocardiographic parameters were as follows: the intra-

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observer variability mean +/- standard deviation values for EF were 64% +/- 4% versus 66% +/- 5% (p <0.06), and the inter-observer values were 62% +/- 6% versus 67% +/- 7% (p <0.07). If the interobserver and intra-observer variability were considered in the identification of LV systolic or diastolic dysfunction, inter-observer variability was 8.2% and intra-observer variability was 7.8% for systolic dysfunction, while inter-observer variability was 8.7% and intra-observer variability was 7.5% for diastolic dysfunction. Remodeling classification was performed based on RWT, LVMass (classic classification) and LV-EDVi (complex classification). RWT was calculated as the ratio of 2*Posterior wall thickness (PWT) and End-diastolic diameter (EDD), while LV-Mass was 5

ACCEPTED MANUSCRIPT calculated according to Devereux formula.16,19 Both LV-EDV and LV-Mass were indexed for BSA. According to the subdivision proposed by Gaasch,12 the non-dilated ventricle is characterized as having “concentric hypertrophy” whether LVMi is >115 g/m2 in men or >95 g/m2 in women and RWT is > 0.42. Conversely, the absence of LV dilation and LVH identifies a “concentric remodeling”

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(RWT > 0.42), a “normal morphology” (RWT 0.32–0.42), or “cardiac atrophy” (RWT <0.32, typically after prolonged bed rest, space flight or anorexia). A dilated ventricle without LVH and with RWT <0.32 distinguishes the “eccentric remodeling”, while the presence of LVH identifies the

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conceptual framework of hypertrophy. In particular, we can describe a “mixed hypertrophy” (RWT

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> 0.42), an “eccentric hypertrophy” (RWT <0.32) and a “dilated hypertrophy” (RWT 0.32–0.42). The latter framework should be distinguished by “physiologic hypertrophy”, as athlete’s heart, pregnant state or an early stage of a compensated mitral regurgitation. Based on the above classification, we considered physiologic hypertrophy as part of normal remodeling pattern, due to

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its relatively low prevalence in our population. All 19 echocardiographic laboratories involved in the study agreed to follow up the recruited patients. Patients follow-up was performed using clinical controls (cardiologic visit), the hospital database and phone contact to obtain information

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on clinical data and adverse events. The present study considered a composite end-point: all-

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cause death, myocardial infarction, coronary artery bypass grafting or percutaneous coronary intervention, cerebrovascular events (including stroke and transient ischemic attack), and acute pulmonary edema. For the diagnosis of myocardial infarction, stroke/transient ischemic attack, and acute pulmonary edema, standard laboratory, ECG, or examination criteria were used. Only 29 patients (1.5%) were lost to follow-up, leading to little bias20. Continuous variables are presented as mean±2 standard deviations (95% confidence intervals) or median and interquartile range (1st – 3rd quartile), as appropriate. Categorical variables are presented as percentages and were compared using the Chi-square test. We searched for a statistical correlation between 6

ACCEPTED MANUSCRIPT cardiovascular risk factors and different remodeling pattern, according to the complex classification. Overall event-free survival was described by the Kaplan–Meier method for the different remodeling groups. Cox regression analysis was performed to establish independent predictors of outcomes, using age, gender, systolic and diastolic function (normal or abnormal),

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SIHD and remodeling group pattern (both classic and complex classification) as variables. To confirm predictive factors for occurrence of end-point, we performed a model of logistic regression analysis with the previous variables. Then, to establish the incremental value of

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remodeling group classification, we stepwise divided subjects according to age, gender (Step 1), LV

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systolic dysfunction (Step 2), diastolic dysfunction, classic LV remodeling classification, SIHD (Step 3) and CRC (Step 4). For each step, we tested the differences using the Chi-square test. A twotailed p value <0.05 was considered significant. All data were analyzed using SPSS software (version 13.0; SPSS, Inc., Chicago, IL).

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RESULTS

Of the total population (n=1950), 1729 patients (Male 53.6%; BMI 26.2±5.6; age 58.3±13 years) were suitable for complex remodeling classification and were thus included in the study.

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Table 1 summarizes clinical characteristics of study population, together with risk factors and

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comorbidities. A clinical history of stable ischemic heart disease (SIHD, defined as history of angina or previous coronary revascularization) was found in 323 patients (16.6% of the population). Only 238 patients (12.2%) presented systolic dysfunction (EF<50%), 483 (24.8%) diastolic dysfunction (First degree or more), with 642 patients (32.9%) presenting a systolic or diastolic dysfunction. Echocardiography-derived parameters were summarized in Table 2. First, we studied the population with the classic remodeling classification: 518 (29.9%) patients had hypertrophy (139, 8% eccentric and 379, 21.9% concentric), while 938 (54.2%) showed a normal pattern and 273 7

ACCEPTED MANUSCRIPT (15.7%) a concentric remodeling. According to the CRC, 891 patients (45.7%) presented normal or physiologic hypertrophy, 273 (14%) concentric remodeling, 47 (2.41%) eccentric remodeling, 350 (18%) concentric hypertrophy, 29 (1.5%) mixed hypertrophy, 86 (4.4%) dilated hypertrophy and 53 (2.7%) eccentric hypertrophy. There were no patients with cardiac atrophy. A significant gender

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specificity in remodeling pattern distribution (p<0.001) was noticed, with higher prevalence of men in mixed hypertrophy (23, 79%), dilated hypertrophy (61, 71%) and eccentric remodelling (32, 68%). The prevalence of women was higher than men only in normal pattern or physiologic

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hypertrophy (463, 52%). An age trend was also observed (p<0.001), with oldest patients in the

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mixed hypertrophy (15, 52%) and the youngest ones in the normal pattern (285, 32%). In the CRC classification, we observed a significantly different distribution of some of the reported cardiovascular risk factors. In particular, diabetes mellitus was associated to concentric (RR 1.5; CI 95% 1.1-2.1; p=0.007) and dilated hypertrophy (RR 2.7; CI 95% 1.7-4.4; p<0.001). Hypertension showed

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association with concentric (RR 2.6; CI 95% 1.9-3.3; p<0.001), dilated (RR 2.1; CI 95% 1.3-3.5; p<0.002) and eccentric hypertrophy (RR 2.0; CI 95% 1.1-3.7; p=0.025), while obesity was associated to concentric remodeling (RR 1.5; CI 95% 1.1-2.0; p=0.005). During the follow-up (20.9 ±

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10 months), we observed a total of 151 (7.7%) events (Table 3). Considering CRC, the highest rates

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of events (in particular acute pulmonary edema and all-cause death) were observed in the 4 patterns of hypertrophy. In addition, Kaplan-Meier analysis showed a significant different eventfree survival distribution (log rank test: p<0.001) of the remodeling patterns (Figure 1): the worst prognosis was reported for patients with concentric hypertrophy, followed by eccentric hypertrophy and mixed hypertrophy. Cox-Regression analysis including each remodeling pattern, identified eccentric hypertrophy (p=0.011, HR=3.173, IC 95% 0.53-3.53), concentric hypertrophy (p=0.011, HR=1.908, IC 95% 1.16-3.14) and dilated hypertrophy (p=0.038, HR=2.1; IC 95% 1.14.1;) as independent predictors of composite end-point. Both older individuals (4th quartile, patients 69 8

ACCEPTED MANUSCRIPT ≥ year old) and male patients were significantly associated with composite end-point (p<0.001). Then, a multivariate Cox-regression analysis was used to observe the occurrence of the composite end-point, adjusting for age, gender, systolic and diastolic dysfunction, SIHD, classic (4 groups) and complex (7 groups in our study) LV remodeling pattern classification (Table 4). We observed

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systolic LV dysfunction (p=0.001), Complex LV remodeling classification (p=0.044), age (p=0.001) and gender (p=0.001) as independent predictive factors. Finally, a logistic regression analysis considering the previous variables in a stepwise fashion was performed. The analysis confirmed

DISCUSSION The main findings of our study are:

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(incremental Chi-square: p<0.03, Figure 2).

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the added prognostic value of complex LV remodeling pattern in composite end-point prediction

clinical data and cardiovascular risk factors are significantly associated with LV remodeling;

2.

assessment of LV remodeling pattern has an independent prognostic value respective to

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1.

age, gender, history of SIHD, systolic and diastolic LV function in patient with asymptomatic HF; 3.

in our population CRC produces a better risk stratification in comparison to the classic one.

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Identification and treatment of asymptomatic HF individuals, aiming to prevention of disease

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progression, has been the objective of the DAVES study developed by SIEC. Previous studies already confirmed the prognostic impact of systolic and diastolic dysfunction, as well as increased LV mass in HF population5,7,21. Moreover, as previously demonstrated by our group, in Stage A, even a single risk factor is significantly associated to both systolic (8.5%) and diastolic (32.5%) dysfunction15. Even in subjects with apparently normal systolic/diastolic function at echocardiography, single or multiple risk factors play a significant prognostic role.9 One of the reasons could be the impact of these risk factors on LV remodeling that preceded LV dysfunction. In fact, risk factors affect remodeling in different ways, inducing hypertrophy and ischemia, wall 9

ACCEPTED MANUSCRIPT stress and fibrosis, pressure and volume overload.12,16,22,23 That’s why the assessment of LV remodeling in every heart disease should be one of the cornerstones for a correct and outright comprehension of underlying pathophysiological mechanisms. LV dilatation or hypertrophy and evidence of systo-diastolic impairment are significantly associated with an increased likelihood of

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overt HF and adverse events.24–27 Anyway, a better classification of remodeling patterns, capable of improving prognostic stratification, may refine clinical strategies. Starting from these standpoints, we adopted both the classic and the complex remodelling pattern definition

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suggested by Gaasch12. Conforming to the inclusion criteria, half of the study population was

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classified as normal or with a physiological hypertrophy. The main cardiovascular risk factors, such as diabetes mellitus, hypertension and obesity, were significantly associated with more advanced remodeling patterns, above all concentric hypertrophy and dilated hypertrophy. As stated before, a clear gender distribution was noted12, with a significantly higher prevalence of women in normal

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or physiologic hypertrophy. On the other hand, men exceeded female subjects in all the other adverse remodeling patterns. In agreement with our premises, we observed a significantly different survival distribution of remodeling pattern: in line with pre-existing literature,28

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hypertrophic patterns showed the worst prognosis (early events); in particular, concentric,

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eccentric and dilated hypertrophy were independent predictive factors. On the same time, not surprisingly, many patients having normal or physiologic remodeling finally had events in follow up. If we look at risk factor distribution, we can see normal/physiologic hypertrophy group is characterized by an intermediate-high risk profile (50% Hypertensive; 11% Diabetics; 23% Smokers), that can explain the burden of adverse events in itself. Besides, the survival analysis showed this group had a worse prognosis respective to patients with concentric remodeling, probably due to an initial compensatory mechanism associated to this latter pattern. In order to clarify the relationship between the LV remodeling and LV function, we included a functional 10

ACCEPTED MANUSCRIPT evaluation of patients (standard echo parameters for systole and diastole). Then, to adjust the survival analysis for the clear influence played by aging and gender, both variables were introduced in the multivariate analysis, together with a history of SIHD. Finally, we wanted to demonstrate the additional value of the complex LV remodeling classification in comparison to the

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standard classification. The leading result of this study was that CRC was a significant and independent prognostic indicator also in asymptomatic stages of HF (together with systolic LV dysfunction, age and gender), outdoing and refining classic LV remodeling classification. To further

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emphasize this result, we demonstrated in a logistic regression analysis the incremental value of

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the complex LV classification, including in a stepwise fashion all the previously described variables. Then, we may infer that a global analysis of LV geometry, together with functional (at least systolic function) and clinical evaluation offers the appealing, convenient and reproducible opportunity of a better prognostic stratification. Noteworthy, all these data can be obtained with a single medical

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examination in an accredited echocardiography laboratory. This kind of evaluation is suitable for all contexts, form valve heart disease to cardiomyopathy and from ischemic heart disease to asymptomatic patients with an intermediate-high cardiovascular risk profile. Finally, it is important

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to remember that LV remodeling is a dynamic process and each pattern can potentially change

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throughout the course of the disease. In this scenario, a positive LV remodeling (reverse remodeling) could became a therapeutic goal with a dedicated analysis during the follow-up process.

A study limitation was the use of composite outcomes. The use of standard echocardiographic assessment instead of more sophisticated methods (e.g., strain imaging) could be considered both a limitation and a strength of the study. The limitation is that strain imaging has proved to be more sensitive for detecting subclinical abnormalities of both systolic and diastolic function. Anyway, the strength is that the present study was focused on the utility of 11

ACCEPTED MANUSCRIPT currently established and widely available echocardiographic techniques. About LV mass and volume, a potential limitation may derive from the use of M-mode and 2D echo, when gold standard (three-dimensional echocardiography; magnetic resonance imaging) have been introduced and validated. Again, this is a real world study, based on widespread, well-defined and

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validated echocardiographic acquisition techniques. The low prevalence of adverse events described in the present study, because of the study population size and length of follow-up, could be considered another limitation. However, this is not totally surprising if we consider patient

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inclusion criteria (asymptomatic HF). Another limit of the study is represented by the lack of

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determination of natriuretic peptide (B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide) levels. In fact, recent works demonstrated that increased concentrations of both these biochemical markers could accurately detect asymptomatic LV systolic dysfunction.9 Finally, unfortunately, the current complex LV remodeling classification suggested by Gaasch and

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Zile is not the “Holy Grail”, because it does not address all parameter possibilities. For example, there can be twelve (2×2×3) possible combinations from the three variables (LV-EDVi, LVMi and RWT), but and the authors suggest only 9 combinations, ignoring the other 3, meaning that some

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patients (12.8% in our study population) cannot be properly classified. Anyway, this gap in the classification is not new in cardiology, if we consider, for example, the diagnosis of diastolic

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dysfunction by current joint guidelines29. Whether this misclassification can lead to errors and pitfalls in clinical practice should be tested in larger clinical trials.

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ACCEPTED MANUSCRIPT 1. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 2007;93:1137–1146.

2. Chen J, Normand S-LT, Wang Y, Krumholz HM. National and regional trends in heart failure hospitalization and mortality rates for Medicare beneficiaries, 1998-2008. JAMA 2011;306:1669–

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1678.

3. Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, Keulenaer G De, Leite-Moreira AF, Borbély A, Edes I, Handoko ML, Heymans S, Pezzali

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N, Pieske B, Dickstein K, Fraser AG, Brutsaert DL. How to diagnose diastolic heart failure: a

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consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28:2539–2550.

4. Marwick TH, Raman S V, Carrió I, Bax JJ. Recent developments in heart failure imaging. JACC

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Cardiovasc Imaging 2010;3:429–439.

5. Konstam MA, Kramer DG, Patel AR, Maron MS, Udelson JE. Left ventricular remodeling in heart

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2011;4:98–108.

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failure: current concepts in clinical significance and assessment. JACC Cardiovasc Imaging

6. Grant C, Greene DG, Bunnell IL. Left ventricular enlargement and hypertrophy. A clinical and angiocardiographic study. Am J Med 1965;39:895–904.

7. Krumholz HM, Larson M, Levy D. Prognosis of left ventricular geometric patterns in the Framingham Heart Study. J Am Coll Cardiol 1995;25:879–884.

8. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer

13

ACCEPTED MANUSCRIPT KT, Tsang W, Voigt J-U. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16:233–270. Available at:

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http://ehjcimaging.oxfordjournals.org/content/16/3/233. Accessed April 3, 2016.

9. Carerj S, Carrubba S La, Antonini-Canterin F, Salvo G Di, Erlicher A, Liguori E, Monte I, Badano L, Pezzano A, Caso P, Pinto F, Bello V Di. The incremental prognostic value of echocardiography in

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asymptomatic stage a heart failure. J Am Soc Echocardiogr 2010;23:1025–1034. Available at:

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http://www.ncbi.nlm.nih.gov/pubmed/20659788. Accessed July 25, 2015.

10. Huwez FU, Pringle SD, Macfarlane PW. A new classification of left ventricular geometry in patients with cardiac disease based on M-mode echocardiography. Am J Cardiol 1992;70:681–688.

11. Dumesnil JG, Shoucri RM. Quantitative relationships between left ventricular ejection and wall

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thickening and geometry. J Appl Physiol 1991;70:48–54.

12. Gaasch WH, Zile MR. Left ventricular structural remodeling in health and disease: with special

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emphasis on volume, mass, and geometry. J Am Coll Cardiol 2011;58:1733–1740. Available at:

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http://www.sciencedirect.com/science/article/pii/S0735109711028397. Accessed July 2, 2015.

13. Ciampi Q, Villari B. Role of echocardiography in diagnosis and risk stratification in heart failure with left ventricular systolic dysfunction. Cardiovasc Ultrasound 2007;5:34.

14. Members WC, Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Konstam M a, Mancini DM, Michl K, Oates J a, S P, Silver M a, Stevenson LW, Yancy CW, M E, Smith SC, Adams CD, Anderson JL, P D, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult. J Am Coll Cardiol 2005;46:e1-82. 14

ACCEPTED MANUSCRIPT 15. Carerj S, Penco M, Carrubba S La, Salustri A, Erlicher A, Pezzano A, Investigators of the DAVES Study. The DAVES (Disfunzione Asintomatica VEntricolare Sinistra) study by the Italian Society of Cardiovascular Echography: rationale and design. J Cardiovasc Med (Hagerstown) 2006;7:457–463.

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16. Marwick TH, Gillebert TC, Aurigemma G, Chirinos J, Derumeaux G, Galderisi M, Gottdiener J, Haluska B, Ofili E, Segers P, Senior R, Tapp RJ, Zamorano JL. Recommendations on the use of echocardiography in adult hypertension: a report from the European Association of Cardiovascular

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Imaging (EACVI) and the American Society of Echocardiography (ASE)†. Eur Heart J Cardiovasc Imaging 2015;16:577–605. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25995329.

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Accessed April 17, 2016.

17. Wang H-T, Liu C-F, Tsai T-H, Chen Y-L, Chang H-W, Tsai C-Y, Leu S, Zhen Y-Y, Chai H-T, Chung SY, Chua S, Yen C-H, Yip H-K. Effect of obesity reduction on preservation of heart function and

Transl Med 2012;10:145.

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attenuation of left ventricular remodeling, oxidative stress and inflammation in obese mice. J

2010;23:1035–1038.

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18. Kirkpatrick JN. ABCD’s of heart failure: Echo-ing through the first stage. J Am Soc Echocardiogr

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19. Jafary FH. Devereux Formula for Left Ventricular Mass-Be Careful to Use the Right Units of Measurement. J Am Soc Echocardiogr 2007;20:783.

20. Dettori JR. Loss to follow-up. Evid Based Spine Care J 2011;2:7–10. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22956930. Accessed July 4, 2016.

21. Peterson LR, Waggoner AD, Schechtman KB, Meyer T, Gropler RJ, Barzilai B, Dávila-Román VG. Alterations in left ventricular structure and function in young healthy obese women. J Am Coll Cardiol 2004;43:1399–1404. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15093874. 15

ACCEPTED MANUSCRIPT Accessed October 17, 2015.

22. Gardin JM, Siscovick DS, Anton-Culver H, Lynch JC, Smith VE, Klopfenstein HS, Bommer WJ, Fried L, O’Leary D, Manolio TA. Sex, age, and disease affect echocardiographic left ventricular mass

RI PT

and systolic function in the free-living elderly. Circulation 1995;91:1739–1748.

23. Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C, Escaned J, Hammes HP, Huikuri H, Marre M, Marx N, Mellbin L, Ostergren J, Patrono C, Seferovic P, Uva MS, Taskinen

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MR, Tendera M, Tuomilehto J, Valensi P, Zamorano JL. ESC Guidelines on diabetes, pre-diabetes,

M AN U

and cardiovascular diseases developed in collaboration with the EASD - Summary The Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in col. Diabetes Vasc Dis Res 2014;11:133–173. Available at: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed12&NEWS=N&AN=20143244

TE D

23.

24. Wang TJ, Evans JC, Benjamin EJ, Levy D, LeRoy EC, Vasan RS. Natural history of asymptomatic

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left ventricular systolic dysfunction in the community. Circulation 2003;108:977–982.

25. Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J, Kitzman D. Predictive value of systolic

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and diastolic function for incident congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol 2001;37:1042–1048.

26. Greenberg B, Quinones MA, Koilpillai C, Limacher M, Shindler D, Benedict C, Shelton B. Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiography substudy. Circulation 1995;91:2573–2581.

27. Schocken DD, Benjamin EJ, Fonarow GC, Krumholz HM, Levy D, Mensah GA, Narula J, Shor ES, Young JB, Hong Y. Prevention of heart failure: a scientific statement from the American Heart 16

ACCEPTED MANUSCRIPT Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research. Circulation 2008;117:2544.

28. Vakili BA, Okin PM, Devereux RB. Prognostic implications of left ventricular hypertrophy. Am

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Heart J 2001;141:334–341.

29. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD,

Flachskampf FA, Pellikka PA, Evangelisa A. Recommendations for the evaluation of left ventricular

SC

diastolic function by echocardiography. Eur J Echocardiogr 2009;10:165–193. Available at:

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http://ehjcimaging.oxfordjournals.org/content/10/2/165. Accessed May 23, 2016.

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ACCEPTED MANUSCRIPT Figure Legends Figure 1. Kaplan–Meier overall event-free survival curves. Patient population (n=1729), assigned according to the complex left ventricle remodeling classification (log rank test: p<0.001).

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Figure 2. Incremental Chi-square analysis. Incremental value of complex LV remodeling classification obtained in stepwise fashion. Step 1: age + gender. Step 2: Step 1 + systolic dysfunction. Step 3: Step 2 + diastolic dysfunction + classic LV remodeling classification + SIHD.

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Step 4: Step 3 + complex LV remodeling classification. LV: left ventricle. Ns: non-significant. SIHD:

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stable ischemic heart disease.

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ACCEPTED MANUSCRIPT Table 1. Clinical characteristics of study population, risk factors and comorbidities. Men

904 (46.4%)

Women

1.046 (53.6%) 57 ± 13.6

Weight (Kg, Mean and 95% CI)

72.6 ± 14.1

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Age (Years, Mean and 95% CI)

Height (cm, Mean and 95% CI)

166.5 ± 8.7

Body mass index (kg/m2, Mean and 95% CI)

26.2 ± 45.6

Body surface area (m2, Mean and 95% CI) Systolic Arterial Pressure (mmHg, Mean and 95% CI)

Smoker

135.2 ± 18.5 80.9 ± 9.9

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Diastolic Arterial Pressure (mmHg, Mean and 95% CI)

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1.8 ± 0.2

449 (23.0%)

Family history of cerebro-vascular disease Diabetes Mellitus

698 (35.8%) 272 (13.9%)

Hypertension

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1.111 (57.0%)

Total serum cholesterol >200mg/dL

711 (36.5%)

Body mass index > 30Kg/m2

421 (21.6%)

Pectoris Angina

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Previous Stroke

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Previous coronary revascularization

21 (1.1%) 142 (7.3%) 209 (10.7%)

Chronic obstructive pulmonary disease

39 (2.0%)

Cerebro-vascular disease

57 (2.9%)

Peripheral artery disease

50 (2.6%)

THERAPHY Diuretics

315 (16.2%)

ACE inhibitors

647 (33.2%)

Digoxin

27 (1.4%)

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143 (7.3%)

Dihydropyridine Ca-channels blockers

239 (12.3%)

Verapamil/Diltiazem

82 (4.2%) 481 (24.7%)

Alfa-blockers

74 (3.8%)

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Beta-blockers

Nitroderivates

273 (14.0%)

Aspirin/clopidogrel

637 (32.7%)

Anticoagulants

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84 (4.3%)

Antiarrhytmics

74 (3.8%)

Statins

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414 (21.2%)

ACE: Angiotensin-converting enzyme; ARB: angiotensin receptor blockers; CI: confidence

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intervals.

ACCEPTED MANUSCRIPT Table 2. Echocardiographic parameters (n, % or Mean and 95% confidence intervals) LV end-diastolic diameter (mm, Mean and 95% CI)

50.1 ± 6.0 100.5 ±37.7

LV end-diastolic volume indexed (ml/m2, Mean and 95% CI)

54.8 ± 18.9

Inter-ventricular septum (mm, Mean and 95% CI)

10.6 ± 2.1

Posterior wall (mm, Mean and 95% CI)

9.7 ± 1.8

RWT (Mean and 95% CI)

0.4 ± 0.1

E-wave velocity (cm/s, Mean and 95% CI)

71.3 ± 26.9

A-wave velocity (cm/s, Mean and 95% CI)

Ejection Fraction (%, Mean and 95% CI) LV mass indexed (g/m², Mean and 95% CI)

Diastolic dysfunction

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Estimated sPAP (mmHg, Mean and 95% CI)

73.2 ± 19.9

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Average E/e’ ratio (Mean and 95% CI)

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Systolic and/or distolic dysfunction

17.2 ± 5.4

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Atrial end-systolic area (cm2, Mean and 95% CI)

Systolic dysfunction (EF<50%)

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LV end-diastolic volume (ml, Mean and 95% CI)

15.5 ± 20.6 61.2 ± 9.9 104.2 ± 30.3 29.3 ± 7.9 238 (12.2%) 483 (24.8%) 642 (32.9%)

CI: confidence intervals; LV: left ventricle; RWT: relative wall thickness; sPAP: systolic

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pulmonary artery pressure.

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Table 3-Rates of cumulative adverse events in total population and different patterns of complex remodeling classification during a median follow up of 21 months. Normal Morphology/

Concentric

Eccentric

Concentric

Mixed

Dilated

Eccentric

population

Physiologic

Remodeling

Remodeling

Hypertrophy

Hypertrophy

Hypertrophy

Hypertrophy

n=1729

Hypertrophy n=891

n=273

n=47

n=350

n=29

n=86

n=53

All-cause death

72(3.7%)

34 (3.8%)

10 (3.7%)

16 (4.6%)

2 (6.9%)

5 (5.8%)

2 (3.8%)

Cardiac death

19 (1.0%)

10 (1.1%)

1 (0.4%)

2 (4.3%)

3 (0.9%)

0

2 (2.3%)

1 (1.9%)

Non-cardiac death

53(2.7%)

24 (2.7%)

9 (3.3%)

1 (2.1%)

13 (3.7%)

2 (6.9%)

3 (3.5%)

1 (1.9%)

Acute pulmonary edema

23(1.2%)

5 (0.6%)

2 (0.7%)

0

7 (2%)

1 (3.4%)

3 (3.5%)

5 (9.4%)

Myocardial infarction

11(0.6%)

2 (0.2%)

3 (1.1%)

0

3 (0.8%)

1 (3.4%)

1 (1.2%)

1 (1.9%)

Cerebrovascular event

6(0.3%)

2 (0.2%)

0

0

2 (0.6%)

0

0

2 (3.8%)

PCI/CABG

48(2.5%)

18 (2%)

4 (1.5%)

2 (4.3%)

12 (3.4%)

0

4 (4.7%)

3 (5.7%)

All events

151 (7.7%)

61 (6.8%)

19 (7%)

5 (10.6%)

42 (12%)

4 (13.4%)

13 (15.1%)

13 (24.5%)

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Total

3 (6.4%)

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Events

CABG: coronary artery by-pass graft PCI: percutaneous coronary intervention

ACCEPTED MANUSCRIPT Table 4. Cox proportional hazard model: independent predictive factors for composite end-point.

95% CI

p

Systolic LV dysfunction

2.344

1.435 - 3.828

0.001

Diastolic LV dysfunction

1.45

0.944 - 2.227

0.09

Classic LV remodeling classification

1.23

0.845 - 3.227

0.12

Complex LV remodeling classification

1.101

1.003 - 1.21

0.044

Age

1.032

1.013 - 1.052

0.001

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HR

Gender

SIHD

1.029

1.010 - 1.045

0.001

1.56

0.847 - 3.227

0.15

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CI: confidence intervals; HR: hazard ratio; LV: left ventricle; SIHD: stable ischemic heart disease

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