Table Info

Table 4.

Time varying Cox-regression models for EF reduction

A. Preliminary model
Variable	HR	95% CI	P
Clinical propensity score	1.02	0.99–1.09	0.251
Treatment arm (losartan)	0.74	0.37–1.52	0.414
Baseline EF (%)	0.88	0.20–0.95	0.001
In-treatment systolic BP (mmHg)	0.98	0.97–1.01	0.083

B. Final model
Variable	HR	95% CI	P
In-treatment heart rate (10 beats/min)	1.3	1.1–1.5	0.004
Baseline EF (%)	0.95	0.88–1.02	0.152
In-treatment LV diameter (cm)	5.19	2.58–10.41	0.0001
In-treatment mitral E/A ratio (per unit)	2.37	1.58–3.56	0.0001

Declarations

Acknowledgments

The authors thank the echo investigators who participated in the LIFE study.

Author contributions

MC, GPA, GdS and RBD contributed to the conception and design of this LIFE echocardiographic sub-study. MC, GPA and KW performed the statistical analyses. MC wrote the first draft of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

Sverre E. Kjeldsen has received ad-hoc lecture honoraria within the past 3 years from Getz, Merck Healthcare KGaA, Sanofi-Aventis and Vector-Intas. The other authors declare that they have no conflicts of interest.

Ethical approval

The LIFE study including the LIFE echocardiographic sub-study was approved by the relevant ethical committees in all countries with the participating 945 clinical centers. This manuscript complies with the Declaration of Helsinki.

Consent to participate

Written informed consent to participate in the study was obtained from all participants.

Consent to publication

Not applicable.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author (RBD) upon dire need.

Funding

Merck & Co., Inc. supported the LIFE study with an unrestricted grant from 1993. Merck had a non-voting member of the Steering Committee, which designed the study and wrote the protocol. Merck did monitoring, and data accumulated in a Merck database until study end in 2002. Merck provided the study steering committee with free access to blinded data until 2002 and then un-blinded data after the database was cleared for queries and frozen. The steering committee including a committee statistician validated independently the main outcomes. The steering committee has always been free to analyze and interpret the data, make decisions to publish and write the papers. Merck has not had any formal role after 2002 except for sporadically providing expert statistical assistance.

Copyright

References

Aurigemma GP, Silver KH, Priest MA, Gaasch WH. Geometric changes allow normal ejection fraction despite depressed myocardial shortening in hypertensive left ventricular hypertrophy. J Am Coll Cardiol. 1995;26:195–202. [DOI] [PubMed]

Inoko M, Kihara Y, Morii I, Fujiwara H, Sasayama S. Transition from compensatory hypertrophy to dilated, failing left ventricles in Dahl salt-sensitive rats. Am J Physiol. 1994;267:H2471–82. [DOI] [PubMed]

Dahlöf B, Devereux RB, Julius S, Kjeldsen SE, Beevers G, de Faire U, et al. Characteristics of 9194 patients with left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint Reduction in Hypertension. Hypertension. 1998;32:989–97. [DOI] [PubMed]

Dahlöf B, Devereux R, de Faire U, Fyhrquist F, Hedner T, Ibsen H, et al. The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study: rationale, design, and methods. The LIFE Study Group. Am J Hypertens. 1997;10:705–13. [DOI] [PubMed]

Wachtell K, Bella JN, Liebson PR, Gerdts E, Dahlöf B, Aalto T, et al. Impact of different partition values on prevalences of left ventricular hypertrophy and concentric geometry in a large hypertensive population: the LIFE study. Hypertension. 2000;35:6–12. [DOI] [PubMed]

Palmieri V, Dahlöf B, DeQuattro V, Sharpe N, Bella JN, de Simone G, et al. Reliability of echocardiographic assessment of left ventricular structure and function: the PRESERVE study. Prospective Randomized Study Evaluating Regression of Ventricular Enlargement. J Am Coll Cardiol. 1999;34:1625–32. [DOI] [PubMed]

Devereux RB, Roman MJ. Evaluation of cardiac and vascular structure and function by echocardiography and other noninvasive techniques. In: Laragh JH, Brenner BM, editors. Hypertension: pathophysiology, diagnosis, and management. 2nd ed. Raven Press Ltd; 1995. pp. 1969–85.

Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986;57:450–8. [DOI] [PubMed]

de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH. Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol. 1995;25:1056–62. [DOI] [PubMed]

10.

Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba PS, et al. Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol. 1992;19:1550–8. [DOI] [PubMed]

11.

Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence or absence of asynergy. Am J Cardiol. 1976;37:7–11. [DOI] [PubMed]

12.

Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA et al.; American Society of Echocardiography’s Nomenclature and Standards Committee; Task Force on Chamber Quantification; American College of Cardiology Echocardiography Committee; American Heart Association; European Association of Echocardiography, European Society of Cardiology. Recommendations for chamber quantification. Eur J Echocardiogr. 2006;7:79–108. [DOI] [PubMed]

13.

Shimizu G, Hirota Y, Kita Y, Kawamura K, Saito T, Gaasch WH. Left ventricular midwall mechanics in systemic arterial hypertension. Myocardial function is depressed in pressure-overload hypertrophy. Circulation. 1991;83:1676–84. [DOI] [PubMed]

14.

Wachtell K, Smith G, Gerdts E, Dahlöf B, Nieminen MS, Papademetriou V, et al. Left ventricular filling patterns in patients with systemic hypertension and left ventricular hypertrophy (the LIFE study). Losartan Intervention For Endpoint. Am J Cardiol. 2000;85:466–72. [DOI] [PubMed]

15.

Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med. 1997;127:757–63. [DOI] [PubMed]

16.

Okin PM, Devereux RB, Nieminen MS, Jern S, Oikarinen L, Viitasalo M et al.; LIFE Study Investigators. Electrocardiographic strain pattern and prediction of new-onset congestive heart failure in hypertensive patients: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study. Circulation. 2006;113:67–73. [DOI] [PubMed]

17.

Devereux RB, Bella JN, Palmieri V, Oberman A, Kitzman DW, Hopkins PN et al.; Hypertension Genetic Epidemiology Network Study Group. Left ventricular systolic dysfunction in a biracial sample of hypertensive adults: The Hypertension Genetic Epidemiology Network (HyperGEN) Study. Hypertension. 2001;38:417–23. [DOI] [PubMed]

18.

Drazner MH, Rame JE, Marino EK, Gottdiener JS, Kitzman DW, Gardin JM, et al. Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years: the Cardiovascular Health Study. J Am Coll Cardiol. 2004;43:2207–15. [DOI] [PubMed]

19.

Rame JE, Ramilo M, Spencer N, Blewett C, Mehta SK, Dries DL, et al. Development of a depressed left ventricular ejection fraction in patients with left ventricular hypertrophy and a normal ejection fraction. Am J Cardiol. 2004;93:234–7. [DOI] [PubMed]

20.

Verdecchia P, Angeli F, Gattobigio R, Sardone M, Porcellati C. Asymptomatic left ventricular systolic dysfunction in essential hypertension: prevalence, determinants, and prognostic value. Hypertension. 2005;45:412–8. [DOI] [PubMed]

21.

Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. JAMA. 1996;275:1557–62. [DOI] [PubMed]

22.

Vasan RS, Larson MG, Benjamin EJ, Evans JC, Levy D. Left ventricular dilatation and the risk of congestive heart failure in people without myocardial infarction. N Engl J Med. 1997;336:1350–5. [DOI] [PubMed]

23.

de Simone G, Gottdiener JS, Chinali M, Maurer MS. Left ventricular mass predicts heart failure not related to previous myocardial infarction: the Cardiovascular Health Study. Eur Heart J. 2008;29:741–7. [DOI] [PubMed]

24.

Yu CM, Lin H, Yang H, Kong SL, Zhang Q, Lee SW. Progression of systolic abnormalities in patients with “isolated” diastolic heart failure and diastolic dysfunction. Circulation. 2002;105:1195–201. [DOI] [PubMed]

25.

Norton GR, Woodiwiss AJ, Gaasch WH, Mela T, Chung ES, Aurigemma GP, et al. Heart failure in pressure overload hypertrophy. The relative roles of ventricular remodeling and myocardial dysfunction. J Am Coll Cardiol. 2002;39:664–71. [DOI] [PubMed]

26.

Lavine SJ, Conetta DA. Comparison of the effect of pressure loading on left ventricular size, systolic and diastolic function in canines with left ventricular dysfunction with preserved and reduced ejection fraction. Cardiovasc Ultrasound. 2008;6:57. [DOI] [PubMed] [PMC]

27.

Chinali M, De Marco M, D’Addeo G, Benincasa M, Romano C, Galderisi M, et al. Excessive increase in left ventricular mass identifies hypertensive subjects with clustered geometric and functional abnormalities. J Hypertens. 2007;25:1073–8. [DOI] [PubMed]

28.

Greve AM, Olsen MH, Bella JN, Lønnebakken MT, Gerdts E, Okin PM, et al. Contrasting hemodynamic mechanisms of losartan- vs. atenolol-based antihypertensive treatment: A LIFE Study. Am J Hypertens. 2012;25:1017–23. [DOI] [PubMed]

29.

Zile MR, Lewinter MM. Left ventricular end-diastolic volume is normal in patients with heart failure and a normal ejection fraction: a renewed consensus in diastolic heart failure. J Am Coll Cardiol. 2007;49:982–5. [DOI] [PubMed]

30.

Wachtell K, Palmieri V, Olsen MH, Gerdts E, Papademetriou V, Nieminen MS, et al. Change in systolic left ventricular performance after 3 years of antihypertensive treatment: the Losartan Intervention for Endpoint (LIFE) Study. Circulation. 2002;106:227–32. [DOI] [PubMed]

31.

Wachtell K, Gerdts E, Palmieri V, Olsen MH, Nieminen MS, Papademetriou V, et al. In-treatment midwall and endocardial fractional shortening predict cardiovascular outcome in hypertensive patients with preserved baseline systolic ventricular function: the Losartan Intervention For Endpoint reduction study. J Hypertens. 2010;28:1541–6. [DOI] [PubMed]

32.

Okin PM, Kjeldsen SE, Julius S, Hille DA, Dahlöf B, Devereux RB. Effect of changing heart rate during treatment of hypertension on incidence of heart failure. Am J Cardiol. 2012;109:699–704. [DOI] [PubMed]

33.

Wachtell K, Rokkedal J, Bella JN, Aalto T, Dahlöf B, Smith G, et al. Effect of electrocardiographic left ventricular hypertrophy on left ventricular systolic function in systemic hypertension (The LIFE Study). Losartan Intervention For Endpoint. Am J Cardiol. 2001;87:54–60. [DOI] [PubMed]

34.

Bang CN, Gerdts E, Aurigemma GP, Boman K, Dahlöf B, Roman MJ, et al. Systolic left ventricular function according to left ventricular concentricity and dilatation in hypertensive patients: the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens. 2013;31:2060–8. [DOI] [PubMed]