Abstract - kinshukai.or.jp · Concept of ADHF focusing on clinical scenario Alexandre Mebazaa,...

Kinshukai the 1st CardiovascularInternational Symposium Acute Decompensated Heart Failure and Heart Failure with

Preserved Ejection Fraction

2013.11.9, Osaka

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－ A b s t r a c t －



2013.11.9, Osaka

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Concept of ADHF focusing on clinical scenario

Alexandre Mebazaa, M.D., Ph.D.

Professor of Anesthesia and Critical Care

Chiarman

Department of Anesthesia & Critical Care

Hôpital Lariboisière

Summary

The lecture will focus on new advances in the knowledge of Acute Decompensated Heart Failure

‘ADHF). This includes clinical classification system considering the initial systolic blood pressure

and other symptoms: dyspnea and/or congestion associated with 1) high systolic blood pressure 2)

systolic blood pressure in the normal range; 3) low systolic blood pressure. Those 3 scenarios likely

address different patients with different pathophysiology. This is assessed by differences in the level

of left ventricular ejection fraction and short and long term mortality.

Novelties also concern the importance of congestion rather than decrease in cardiac output in the

pathogenesis of of organ dysfunction in ADHF, this includes renal and liver congestion. Except in

cardiogenic shock in which, decrease in cardiac output and low systemic pressure are harmful,

congestion and especially the increase in venous pressure downstream of the main organ reduce

organ’s blood flow and leads to dysfunction. Indeed congestion is even more harmful on organs in

patients with low blood pressure. In that context biomarkers would be very helpful if they could

indicate in an organ with altered function whether the organ is injured (irreversible lesion) or not. We

further showed that cholestasis is related to congestion while increased transaminases is related to

hypoperfusion.

When the patient is admitted in the emergency room for AHDF, he/she is in advanced stage of organ

congestion, including pulmonary congestion and many drugs given in acute setting might be harmful.

In addition, hypoxemia and organ dysfunction might be additive to worsen patient’s situation and this

might lead to death. Increasing evidence show that appropriate treatment should be started as soon as

possible, ideally within minutes of admission. Up to now, many of the drug tested in large trials were

associated with absence of positive outcome. This might be related to the design of studies including

the delay between admission and drug administration. In fact the scenarios of ADHF are also

indicative of the location of first presentation (emergency room, cardiology or intensive care unit).

We need therefore to strengthen international multidisciplinary network such as the GREAT network

to include the patient just after admission – mostly in the emergency room – and to follow them while

hospitalized in cardiology.



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Real world patient characteristics and outcome of AHF in Japan

- From ATTEND registry -

Naoki Sato, M.D., Ph.D.

Internal Medicine, Cardiology, and Intensive Care Unit

Nippon Medical School Musashi - Kosugi Hospital

Hospitalized heart failure (HHF) is a critical issue in Japan as well as western countries. To improve

its management and outcomes, the clinical features,in-hospital management, and outcomes should be

analyzed to improve the guidelinesfor HHF.Therefore, we conducted the HHF registry, the acute

decompensated heart failure syndromes (ATTEND) registry, in Japan. The present report covers the

clinical features and in-hospital management of HHF patients. Thedata from 4,842 enrolled patients

have demonstrated that most Japanese HHF patients are elderly, with new onset,and a history of

hypertension and orthopnea on admission. During hospitalization, furosemide and carperitide

werecommonly used. Although the proportion of HHF patients with orthopnea was 63%, non-

invasive positive pressure ventilation (NPPV) was used only in 31%. The length of stay was

extremely long (mean 30 days), with 6.4% in-hospital mortality.From these findings, we learned

several issues as followings; we should treat more strictly hypertensive elderly patients to prevent

HHF and NPPV should be used more for the patients with orthopnea. And also we will need more

evidence regarding clinical benefits of carperitide and we should consider whether or not the length of

stay is appropriate.



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Treatment & evaluation of volume overload (decongestion)

in acute decompensated heart failure

Kazuhiko Hashimura, M.D.

Cardio-Vascular Center

Hanwa Memorial Hospital

Clinical congestion is the most frequent reason for heart failure hospitalizations. In the community

hospital, low output related symptoms as a cause of admission, are rare. Compared to US/European

countries, mean hospitalization stay length is relatively long in Japan, however, it appears not to be

enough to prevent readmission for recurrent heart failure.

As of November/2013, tolvaptan has been in clinical use for almost three years. Compared with

conventional diuretics (loop, thiazide), tolvaptan use facilitated to prevent 1) intravascular

dehydration, which leads to symptomatic hypotension, 2) electrolyte abnormalities (ie. hyponatremia,

hypokalemia), 3) worsening renal function, 4) sympathetic nerve stimulation, 5) RAAS stimulation.

To what degree, do we have to withdraw volume overload? If we withdraw much more fluid than

necessary, it can lead dehydration, hypotension, worsening renal function. If we withdraw fluid

insufficiently, though it might improve signs/symptoms of heart failure, it would raise readmission

rate, mortality and morbidity.

The following index for decongestion will be discussed. 1)Body weight loss, net fluid loss, 2)

hemoconcentration, 3) biomarkers (BNP, NGAL etc), 4)Bio Z ICG monitor, which noninvasively can

detect intra-thoracic extra cellular fluid content, 5) transient elastography, which can measure right

atrial pressure noninvasively.



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Heart Failure with preserve Ejection Fraction : Basic and Clinical Aspects

Barry A. Borlaug, M.D.

Mayo Clinic, Rochester, MN, USA

Half of patients with heart failure (HF) have a preserved ejection fraction (HFpEF) and the

prevalence is increasing. In contrast to HF with reduced EF, there is no proven effective treatment for

HFpEF. A significant barrier in the development of effective treatments has been incomplete

understanding of basic disease mechanisms. In this talk, I will review the complex pathophysiology

of HFpEF starting with clinical vignettes followed by review of physiological studies from our group

and others. I will show how the pathophysiology of HFpEF is far more complex than previously

recognized, and while abnormalities in diastolic function clearly play a role, there are additional

limitations in ventricular systolic reserve as well as heart rate, vasodilation, endothelial function, right

heart-pulmonary artery coupling, neural signaling, and peripheral limitations including the skeletal

muscle and microvasculature. These abnormalities coexist in individual patients to varying degrees,

introducing additional heterogeneity that confounds treatment and diagnosis. I shall conclude by

exploring what overarching processes may underlie these pleiotropic abnormalities in cardiovascular

and peripheral reserve, including changes in cardiovascular function associated with aging, obesity,

and within women as compared with men.



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Epidemiology and pathophysiology

Hiroyuki Tsutsui, M.D., Ph.D.

Department of Cardiovascular Medicine,

Hokkaido University Graduate School of Medicine, Sapporo, Japan

Heart failure (HF) is primarily caused by the abnormalities of systolic function of the heart;

i.e. reduced left ventricular ejection fraction (HFrEF). However, recent studies have shown that HF

with preserved EF (HFpEF) is common with reported prevalence rates of ranging from 30 to 50% of

the total HF population in clinical practice.

We compared the characteristics and outcomes in patients with HFrEF versus HFpEF by

using the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), a prospective

observational cohort study in a broad sample of patients hospitalized with worsening HF symptoms.

Patients with HFpEF (EF≥50% by echocardiography) were more likely to be older, female, have

hypertension and atrial fibrillation, and less likely to have ischemic etiology compared with those

with HFrEF (EF<40%). Unadjusted risk of in-hospital mortality as well as post-discharge mortality

was slightly higher in patients with HFpEF, which, however, did not differ after multivariable

adjustment. Patients with HFpEF had similar hospitalization rates compared with those with HFrEF.

The mode of death included cardiovascular (CV) in 63% (including 17% sudden, 36% HF,

3% myocardial infarction, and 3% stroke), non-CV in 23%, and unknown in 14%. The prevalence of

CV death including sudden death was high in patients with HFrEF compared to HFpEF. HF death,

the most common mode of death, was similar between HFrEF and HFpEF. In contrast, non-CV

mortality was significantly higher in HFpEF than HFrEF.

Diastolic dysfunction has been recognized as an important contributor to HFpEF and its

central hemodynamic disturbances involve the abnormalities in myocardial relaxation and

compliance. However, other aspects of cardiac remodeling also contribute to its pathophysiology.

Even though growing body of data has delineated the clinical features of HFpEF, its

pathophysiological basis and, most importantly, effective treatment strategies remain uncertain.



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Medical treatments of HFpEF

- Real-World Practice and Challenges in Japan -

Yoshihiko Seino, M.D., Ph.D.

Department of Cardiovascular Medicine, Cardiovascular Center

Nippon Medical School Chiba - Hokusoh Hospital, Chiba, Japan

Medical treatments with evidence-proven benefit for patients with HFrEF have almost failed to

improve outcomes in those with HFpEF. The different pathophysiology of HFpEF are described as

the diastolic dysfunction (prolonged relaxation and increased diastolic stiffness), the ventricular-

vascular stiffening (systolic hypertension and LV concentric remodeling), the abnormalcardiovascular

reservefunction, systolic dysfunction, and the chronotropic incompetence (Borlaug 2009, 2013).

In terms of “Challenges in Japan”, recent reports regarding the real-worldobservational studies of

carvedilol (Mori et al. 2013) and carperitide (Suwa et al. 2007, and Nomura et al. 2008), the

multicenter clinical trial using pitavastatin for chronic HF (PEARL study, 2013), and the non-

pharmacological intervention using ASV: adaptive-servo ventilation (SAVIOR-R study, 2012, and

Yoshihisa et al. 2013) are reviewed.

The earlier, but not late, and comprehensive treatments should be established.



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Molecular Mechanism for Cardiorenal Connection

Yoshihiko Saito, M.D., Ph.D.

First department of Internal Medicine Nara Medical University

Kashihara, Japan

CKD is a strong risk for cardiovascular events. Worsening of atherosclerosis is highly associated

with CKD, but its molecular mechanism has not been fully understood.

Placental growth factor (PlGF) is a member of the VEGF family that activates macrophages via its

specific receptor, fms-like tyrosine kinase-1 (Flt-1), and then plays a role in the development of

atherosclerosis. The gene encoding Flt-1 generates a soluble form of Flt-1 (sFlt-1), consisting of 6

extracellular immuneglobulin-like domains by alternating splicing, which acts as an endogenous

antagonist against PlGF. So PlGF is a proatherogenic molecule but sFlt-1 is anti-atherogenic one.

The expression of sFlt-1 was reduced in the lung and kidney of both patients with CKD and 5/6

nephrectomized mice. In human endothelial cell culture, addition of serum from patients with

hemodialysis significantly reduced the expression of sFlt-1 mRNA. Atherosclerosis was exaggerated

by 5/6 nephrectomy in ApoE knockout mice, and a 10-week administration of recombinant sFlt-1

attenuated this renal dysfunction-induced worsening of atherosclerosis. Furthermore, sFlt-1 specific

knockout mice, which express authentic full length Flt-1, showed no atherosclerotic changes at basal

condition. However, when crossing ApoE kockout mice with sFlt-1 specific knockout mice,

atherosclerosis was more severe in the double knockout mice than in ApoE knockout mice, without

any deterioration of renal function.

The present study provides a new insight that PlGF/sFlt-1/Flt-1 system is involved in worsening of

atherosclerosis accompanied by renal dysfunction.



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Clinical Concept of Heart Failure

Mihai Gheorghiade, M.D.

Center for Cardiovascular Innovation

Northwestern University Feinberg School of Medicine

Savina Nodari, M.D.

Hospital of Brescia



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Protecting the heart from ischaemic & reperfusion injury :

from laboratory bench to hospital bedside

Derek M. Yellon, M.D., Ph.D.

The Hatter Cardiovascular Institute, University College London

Coronary heart disease (IHD) is set to become the leading world-wide cause of death by the year

2020. Acute myocardial infarction is a major cause of such mortality and the best hope of salvaging

viable myocardium is rapid reperfusion of the ischaemic myocardium, by either thrombolysis or

primary percutaneous coronary intervention (PCI). However, despite these effective reperfusion

strategies, the long-term benefit is suboptimal in that only one-third of the life-years lost by

myocardial infarction is regained by reperfusion. This is due to the injury that occurs as a

consequence of the reperfusion procedure itself and is termed "lethal reperfusion-induced injury".

Treatment strategies which directly target the reperfusion phase could provide a novel approach to

cardio-protection. Such strategies which have significant consequences for the future management of

acute myocardial infarction are the phenomenon of Ischaemic Conditioning (both mechanical &

pharmacological). Mechanical conditioning is achieved by (i) by short repetitive periods of

ischaemia-reperfusion immediately prior to a lethal ischaemic insult (Ischaemic Preconditioning) (ii)

by short repetitive periods of coronary reperfusion and occlusion in the early minutes of

revascularization (Ischaemic Postconditioning) (iii) by ischaemia-reperfusion in another organ or

muscle (Remote Conditioning) or (iv) by giving pharmacological agents at the time of reperfusion

after a prolonged ischaemic insult (Pharmacological Conditioning).

It is also important to appreciate that in addition to the above, co-morbidities such as diabetes, the

metabolic syndrome and age can significantly influence the ability to protect the myocardium from

such injury.

Recent studies have identified a signalling pathway that is recruited at the time of reperfusion and

which is central to the protection observed from both mechanical and pharmacological conditioning

in both the normal & diabetic heart. This signalling pathway comprises the survival kinases PI3K-Akt

and Erk1/2, components of what has been termed the “Reperfusion Injury Salvage Kinase” (RISK)

pathway. In addition, and of equal importance, is the identification that a non-specific pore of the

inner mitochondrial membrane, called the mitochondrial permeability transition pore (MPTP) whose

opening in the first few minutes of myocardial reperfusion, mediates cell death during reperfusion.

The phenomenon of Remote Ischemic Preconditioning represents the best chance of translating this

endogenous cardioprotective effect to potential clinical use, with a number of large clinical studies

now underway in this area. However the exact mechanism of how Remote Conditioning elicits its

protective effect is still not clear. New hypothesis with respect to activation of humoral substances

such as the chemokine, Stromal derived factor-1α (SDF-1α) and/or the importance of endogenous

nanoparticles (exosomes) will be discussed.



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Targeting and understanding the biological events occurring within the cell and at the mitochondrial

level, is enabling us to translate these basic laboratory findings directly to the benefit patients at risk

of myocardial infraction.



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- Pre- and Post-conditioning

Tetsuji Miura, M.D., Ph.D.

Department of Cardiovascular, Renal and Metabolic Medicine

Sapporo Medical University School of Medicine, Sapporo, Japan

Cardioprotective effects of pre- and post-conditioning have been established in animal models of

myocardial infarction, and benefits of the two interventions in human hearts are also supported by

results of several clinical studies. Although timings of conditioning ischemia are different between

pre- and post-conditioning (i.e., before ischemia vs. after ischemia), there are overlaps between

intracellular signaling upon reperfusion in preconditioned and postconditioned hearts, and the

mitochondrial permeability transition pore (mPTP) is a common target of the overlapped signal

pathways. The mPTP is a physiologically-closed megachannel in the inner mitochondrial membrane

and its opening under pathological conditions induces collapse of mitochondrial membrane potential.

During ischemia, the mPTP remains closed, and reperfusion induces mPTP opening by calcium

overload and burst production of reactive oxygen species. Irreversible opening of the mPTP

incapacitates mitochondria to generate ATP and prevents cell recovery from ischemic injury. In a

series of studies, we have characterized roles of glycogen synthase kinase-3beta (GSK-3beta) in

regulation of the mPTP. GSK-3beta is constitutively active and reperfusion induces its mitochondrial

translocation and binding to the mPTP, which facilitates mPTP opening. Pro-survival signaling

inactivates GSK-3beta by phosphorylation at Ser9, which inhibits mPTP opening. Recently, we

found that re-closure of the mPTP following oxidant stress is also a mechanism by which phospho-

GSK-3beta protects cardiomyocytes from necrosis. Contribution of necroptosis, a programmed

necrosis, to ischemia/reperfusion has been shown in various organs, including the heart, and a recent

study indicated that RIP-1-mediated pathway and mPTP opening-mediated pathway can be

independent mechanisms of necrosis. In conclusion, significant cardioprotection can be achieve by

modulating mPTP directly or indirectly via GSK-3beta, but additional strategy to prevent necroptosis

appears to be necessary for maximizing cardioprotection from ischemia/reperfusion injury.



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Potential effects of anti-diabetic drugs for heart failure

Masanori Asakura, M.D., Ph.D., Ayako Takahashi, Shin Ito, Kyung-Duk Min, Kazuhiro Shindo,

Miki Imazu, Madoka Ihara, Satoru Yamazaki, Hiroshi Asanuma, Masafumi Kitakaze

National Cerebral and Cardiovascular Center

Heart failure is a leading cause of death in Japan as well as in other countries. The associations

between heart failure anddysfunction of other tissues such as kidney and brain havereceived a great

deal of attention in recent years.We have also been trying to elucidate this associationfor over a

decade. We performed data mining analysis using a database of patients with heart failure. The

analysis suggested that histamine receptor blockers and alpha-glucosidase inhibitorsmight attenuate

the severity of heart failure. Moreover, our clinical research revealed that approximately 90% of

patients with chronic heart failure had impaired glucose tolerance. On the basis of these results, we

focused our research on the association between heart failure and diabetes mellitus (DM). We

investigated the effects of anti-diabetic drugs such as alpha-glucosidase inhibitors and metformin

using animal models of heart failure. Recently, dipeptidyl peptidase IV (DPP-IV) inhibitors have

been widely used to treat patients with DM. Therefore, we examined the cardioprotective effects of a

DPP-IV inhibitor in a murine heart failure model via transverse aortic constriction .We found that the

DPP-IV inhibitor had a slight restorative effect on cardiac dysfunction, and also improved the overall

survival in our murineheart failure model.These results imply that the treatment of DM mayhave

important implications for the management for heart failure.



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Left Ventricular Diastolic Function

William C. Little, M.D., FACC

Patrick Lehan Professor of Cardiovascular Medicine

Chair of the Department of Medicine

The University of Mississippi Medical Center

Jackson, Mississippi, USA.

Left Ventricular (LV)diastolic function has been understood based on the end-diastolic pressure-

volume relation (EDPVR), which is thought to represent the LV’s passive properties. In this paradigm,

diastolic dysfunction is due to an upward and leftward shift of the LVEDPVP, where a higher left

atrial pressure is required to distend the LV to any volume. Patients with heart failure (HF) with a

reduced ejection fraction (rEF) have a LV EDPVR that is shifted to the right, indicating a more

distensible LV, where a lower pressure is required to distend the LV to any volume. However,

patients with HFrEFdo not have enhanced diastolic function but instead have the highest left atrial

(LA) pressures and most abnormal filling dynamics. Thus, the LV EDPVR does not explain diastolic

dysfunction in HFrEF. Normally, the LV acts as a suction pump. In fact, it will fill from a zero LA

pressure. This is also not explained by the LV EDPVR.

The suction function of the LV results from elastic elements compressed during ejection that recoil

during diastole. Thus, some of the energy of cross-bridge cycling is stored and used to drive rapid

early diastolic filling. The most important contributor to normal LV filling is long axis shortening that

pulls the mitral annulus towards the apex during ejection. Early in diastole, the mitral annulus rapidly

moves up into the left atrium, trans-locating blood that was above the mitral valve at end-systole into

the LV. In addition, the annular motion produces a progressive pressure difference from the left

atrium to the LV apex that accelerates blood into the LV, producing rapid early diastolic filling.

During exercise or other stress, LV filling can increase due to enhanced suction without an increase in

LA pressure.

Normal long axis shortening and recoil and the resulting diastolic suction is lost in all forms of HF,

both HFpEF and HFrEF. In order for the LV to function as a suction pump there are four

requirements: 1.) systolic ejection must compress elastic elements which is predominantly due to long

axis shortening, 2.)the elastic elements must store the energy (collagen and titan), 3.) relaxation must

be rapid to release recoil, and 4.) the LV must have an ellipsoidal configuration that enhances

energetically efficient filling. Thus, LV suction is lost with any myocardial abnormality, and is most

impaired in patients with HFrEF who have abnormalities in all four of the requirements for suction. In

the absence of normal suction function, LV filling is critically dependent on LA pressure. Thus, LA

pressure increases during exercise or other stress that enhances venous return.



2013.11.9, Osaka

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In conclusion, normal LV diastolic function is more than passive LV distention and cannot be

understood by only considering the LV EDPVR. Normally, the LV is a suction pump and filling can

increase without increases in LA pressure. This protects against the development of pulmonary

congestion. In HFpEF and HFrEF, LV suction function is impaired and LV filling is dependent on

LA pressure. Thus, patients with HFpEF and HFrEFare prone to develop pulmonary congestion.



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Pathophysiology : Heart Failure with Preserved Ejection Fraction

as Acute Decompensated Heart Failure

Katsuya Onishi, M.D., Ph.D., FACC, FESC

Director, Onishi Heart Clinic

Associated Professor, Department of Cardiology, Mie University School of Medicine

The pathophysiology of acute decompensated heart failure (ADHF) remains incompletely understood,

especially with respect to the differences between patients with HF and a reduced ejection fraction

(EF) (HFrEF) and those with HF and a preserved ejection fraction (HFpEF). The American College

of Cardiology/American Heart Association (ACC/AHA) guidelines cite 3 profiles of patients

presenting with ADHF: volume overload, low cardiac output, and a combination of fluid overload

and shock.

The rate of increase in pulmonary arterial diastolic pressure was more rapid in the HFpEF patients

than the HFrEF patients because ofmore increased left ventricularstiffness in HFpEF.In patients with

HFpEF, only a small increase in diastolic volume can result in a marked increase in diastolic

pressure.Early stages of congestion in ADHF often occur in the absence of significant changes in

body weight. Shifts between total extracellular fluid volume and effective circulating volume

underlie the development of ADHF

The venous system contains approximately 70% of total blood volume, is about 30 times more

compliant than the arterial system, and is sensitive to stimulation by the sympathetic stimulus. A

relatively minor increase in sympathetic outflow stimulates splanchnic reservoir of blood resulting in

a shift of volume from the capacitance vessels into the systemic circulation, increasing effective

circulatory volume and causing congestion. Nitroglycerin is effective in the setting of ADHFpartly

due to its venodilating effect.



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HFpEF as a cause of ADHF

Treatment

Kazuhiro Yamamoto, M.D., Ph.D.

Division of Cardiovascular Medicine, Endocrinology and Metabolism

Faculty of Medicine, Tottori University

Epidemiologic studies have revealed that 40 to 50 % of ADHF patients have normal or minimally

impaired left ventricular (LV) ejection fraction (EF) in many industrialized countries. This phenotype

of heart failure is termed heart failure with preserved EF (HFpEF). Its prognosis remains poor, and

the rate of rehospitalization and the cost of health care associated with HFpEF rival those associated

with heart failure with reduced EF (HFrEF). Although angiotensin converting enzyme inhibitor and

angiotensin receptor blocker have been proven effective in HFrEF, previous clinical studies have

failed to show their benefits in HFpEF, andthe therapeutic approach to HFpEF has not yet been

established.

Our experimental studies have demonstrated that the promotion of LV stiffening plays an important

role in the transition from asymptomatic hypertrophic stage to HFpEF in a hypertensive heart disease,

and that progression of LV fibrosis plays a crucial role in LV stiffening. Therefore, anti-fibrotic

therapy may be effective to improve the prognosis of HFpEF.Our and other experimental studies

have reported that -blockers attenuate LV fibrosis and improve the survival rate of the animal model

for HFpEF. Our recent clinical trial, J-DHF study, has suggested benefits of -blocker if prescribed

at standard doses.

Another candidate for the treatment of HFpEF is L-carnitine. Metabolomics with capillary

electrophoresis time-of-flight mass spectrometry revealed that plasma free-carnitine level was

decreased in HFpEF model rats.LV free-carnitine levels were also decreased with the down-

regulation of organic cation/carnitine transporter 2 which transports free-carnitine into cells. L-

carnitine treatment restored LV free-carnitine levels, attenuated LV fibrosis and stiffening, and

improved survival in the HFpEF model. These effects were accompanied with increased expression

of fatty acid desaturase (FADS) 1/2, rate-limiting enzymes in forming arachidonic acid (AA), and

enhanced production of AA, a precursor of prostacyclin, and prostacyclin in the LV. In cultured

cardiac fibroblasts, L-carnitine attenuated the angiotensin II-induced collagen production with

increased FADS1/2 expression and enhanced production of AA and prostacyclin. We have

confirmed that serum free-carnitine levels were decreased in HFpEF patients at the ADHF stage.

Conclusion: 1) The standard-dose, not low-dose, prescription of -blocker is likely effective in

HFPEF. 2) L-carnitine may be a new therapeutic strategy in this phenotype of heart failure.



2013.11.9, Osaka

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Abstract - kinshukai.or.jp · Concept of ADHF focusing on clinical scenario Alexandre Mebazaa,...

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