JACC: HEART FAILURE VOL. 6, NO.
5, 2018
MAY 2018:439–44
Please note: Dr. Girerd has received board fees from Novartis; and honoraria
from Servier. Prof. Rossignol has received personal fees for consulting from
Novartis, Relypsa, AstraZeneca, Grünenthal, Stealth, Peptides, Fresenius, Vifor
Fresenius Medical Care Renal Pharma, Vifor, and CTMA; has received lecture
fees from Bayer and CVRx; and is a cofounder of CardioRenal. Prof. Zannad has
reported that he has no relationships relevant to the contents of this paper to
disclose.
REFERENCES
1. Girerd N, Seronde MF, Coiro S, et al. Integrative assessment of congestion in
heart failure throughout the patient journey. J Am Coll Cardiol HF 2018;6:
273–85.
2. Nunez J, Nunez E, Bayes-Genis A, et al. Long-term serial kinetics of N-
terminal pro B-type natriuretic peptide and carbohydrate antigen 125 for
mortality risk prediction following acute heart failure. Eur Heart J Acute
Cardiovasc Care 2017;6:685–96.
3. Nunez J, Sanchis J, Bodi V, et al. Improvement in risk stratification with the
combination of the tumour marker antigen carbohydrate 125 and brain
natriuretic peptide in patients with acute heart failure. Eur Heart J 2010;31:
1752–63.
4. Nunez J, Llacer P, Bertomeu-Gonzalez V, et al. Carbohydrate Antigen-125-
Guided Therapy in Acute Heart Failure: CHANCE-HF: a randomized study. J Am
Coll Cardiol HF 2016;4:833–43.
5. Briasoulis A, Androulakis E, Christophides T, Tousoulis D. The role of
inflammation and cell death in the pathogenesis, progression and treatment
of heart failure. Heart Fail Rev 2016;21:169–76.
6. Garcia-Blas S, Bonanad C, Llacer P, et al. Diuretic strategies in acute heart
failure and renal dysfunction: conventional vs carbohydrate antigen 125-
guided strategy. Clinical Trial Design. Rev Esp Cardiol (Engl Ed) 2017;70:
1067–73.
Effects of Vildagliptin
on Ventricular Function
in Patients With
Type 2 Diabetes Mellitus
and Heart Failure
We read with great interest the outcomes of the
VIVIDD (Vildagliptin in Ventricular Dysfunction
Diabetes) trial presented in the article entitled “Ef-
fects of Vildagliptin on Ventricular Function in Pa-
tients with Type 2 Diabetes Mellitus and Heart
Failure” (1). The study found that treatment with
vildagliptin in this population was associated with
increased left ventricular (LV) volumes, but the
treatment was not associated with a decrease in the
LV ejection fraction, increase in B-type natriuretic
peptide, or worsening of heart failure (HF) status.
The authors comment that the increase in ventric-
ular volumes remains an unexplained action of vil-
dagliptin on LV remodeling that most likely reflects
the play of chance.
We would like to point out that several potential
mechanisms of LV remodeling and function in type 2
diabetes (T2D) have recently emerged, providing
Letters to the Editor 443
further insights into the pathophysiology of cardiac
remodeling. The recent literature supports the
concept that accumulation of myocardial lipids in
diabetes is the cause of concentric remodeling (2).
Elevated circulating levels of fatty acids (FA) in
combination with increased capacity for myocardial
FA uptake seem to cause cardiac steatosis in patients
with T2D. As the FA supply exceeds the oxidative
capacity of the heart, lipid metabolism is diverted
from oxidative processes to nonoxidative processes,
with the production of lipotoxic intermediates such
as ceramide and diacyl-glycerol. These lipotoxic
intermediates have been shown to play a role in car-
diac remodeling by activating distinct signaling
pathways affecting adenosine triphosphate produc-
tion, myocellular contractility, and apoptosis. In
addition, it has been demonstrated that cardiac
steatosis potentiates the effects of angiotensin II on
the myocardium (3).
The link between lipotoxicity and concentric LV
remodeling has been demonstrated not only in pa-
tients with T2D, but also in patients with nonischemic
HF (4), and in patients with generalized lipodys-
trophy who exhibit severe concentric LV hypertrophy
and significant cardiac steatosis (5). In individuals
with T2DM and HF, intramyocardial lipid overload
was shown to be associated with a distinct gene
expression profile that is similar to an animal model
of lipotoxicity and cardiac dysfunction (6). Successful
reduction of myocardial steatosis with the glucagon-
like peptide-1 receptor agonist exendin-4 (7), has
been shown to reverse concentric LV remodeling.
Taken together, these studies suggest a mecha-
nistic link between cardiac steatosis, lipotoxicity,
and concentric LV remodeling in diseases of upre-
gulated FA metabolism, such as diabetes. Given that
dipeptidyl peptidase-IV inhibitors suppress the
degradation of glucagon-like peptide-1 receptor, we
suggest that, in a fashion similar to exentin, vilda-
gliptin may reverse cardiolipotoxicity in T2D, and
thereby reverse concentricity in relative terms in
patients with HF, without causing a worsening of
HF. The elimination of lipotoxicity might reverse
these distinct signaling pathways, and affect
sarcomere alignment, leading to the changes in
cardiac geometry and improvement of cardiac func-
tion demonstrated in this study. However, this
hypothesis needs to be tested in clinical studies us-
ing imaging methods such as cardiovascular mag-
netic resonance imaging that can more accurately
measure ventricular volumes and myocardial mass
to assess the effects of concentric and eccentric
hypertrophy.
444 Letters to the Editor JACC: HEART FAILURE VOL. 6, NO. 5, 2018
MAY 2018:439–44

*Eylem Levelt, MBBS, DPhil cardiac steatosis and oxidative stress in type 2 diabetes. Am J Physiol Heart
Circ Physiol 2013;305:H295–304.
Gerry P. McCann, MD
Jurgen E. Schneider, PhD
Sven Plein, MD, PhD REPLY: Effects of Vildagliptin on
Ventricular Function in Patients With
*British Heart Foundation
Type 2 Diabetes Mellitus and Heart Failure
Cardiovascular Research Centre
University of Leicester
Dr. Levelt and colleagues (1) present an interesting
Glenfield Hospital
hypothesis linking diabetes to cardiac remodeling
Groby Road
through cardiolipotoxicity. Whether vildagliptin
Leicester LE3 9QP
reverses cardiolipotoxicity and whether this would
United Kingdom
lead to left ventricular dilation without a change in
E-mail: eylem@doctors.org.uk
left ventricular mass or ejection fraction, as seen in
https://doi.org/10.1016/j.jchf.2018.01.017
the present trial, is unknown but would certainly be
Ó 2018 by the American College of Cardiology Foundation. Published by Elsevier.
better studied by using cardiac magnetic resonance
Please note: The authors have reported that they have no relationships relevant imaging and spectroscopy.
to the contents of this paper to disclose.

*John V. McMurray, BSc(Hons), MBChB(Hons), MD

REFERENCES *Institute of Cardiovascular and Medical Sciences
1. McMurray JJV, Ponikowski P, Bolli GB, et al. Effects of vildagliptin on BHF Glasgow Cardiovascular Research Centre
ventricular function in patients with type 2 diabetes mellitus and heart failure: University of Glasgow
a randomized placebo-controlled trial. J Am Coll Cardiol HF 2018;6:8–17.
126 University Place
2. Levelt E, Mahmod M, Piechnik SK, et al. Relationship between left ven-
tricular structural and metabolic remodelling in type 2 diabetes mellitus.
Glasgow, Scotland G12 8TA
Diabetes 2016;65:44–52. United Kingdom
3. Glenn DJ, Cardema MC, Ni W, et al. Cardiac steatosis potentiates angiotensin E-mail: john.mcmurray@glasgow.ac.uk
II effects in the heart. Am J Physiol Heart Circ Physiol 2015;308:H339–50. https://doi.org/10.1016/j.jchf.2018.01.023
4. Sharma S, Adrogue JV, Golfman L, et al. Intramyocardial lipid accumulation in the Ó 2018 by the American College of Cardiology Foundation. Published by Elsevier.
failing human heart resembles the lipotoxic rat heart. FASEB J 2004;18:1692–700.
Please note: Glasgow University received financial support from Novartis for
5. Nelson MD, Victor RG, Szczepaniak EW, Simha V, Garg A, Szczepaniak LS.
participation in VIVIDD and a number of other clinical trials. Dr. McMurray has
Cardiac steatosis and left ventricular hypertrophy in patients with generalized
reported that he has no relationships relevant to the contents of this paper to
lipodystrophy as determined by magnetic resonance spectroscopy and im-
disclose.
aging. Am J Cardiol 2013;112:1019–24.

6. Finck BN, Lehman JJ, Leone TC, et al. The cardiac phenotype induced by
PPARa overexpression mimics that caused by diabetes mellitus. J Clin Invest
2002;109:121–30.
7. Monji A, Mitsui T, Bando YK, Aoyama M, Shigeta T, Murohara T. Glucagon-
like peptide-1 receptor activation reverses cardiac remodeling via normalizing
REFERENCE
1. Levelt E, McCann GP, Schneider JE, Plein S. Effects of Vildagliptin on
Ventricular Function in Patients With Type 2 Diabetes Mellitus and Heart
Failure. J Am Coll Cardiol HF 2018;6:443–4.