Use Instructions

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APPENDIX VI
Scientific Background About Heart Failure and Cardiac Contractility
Modulation
Heart failure is a condition wherein the heart muscle does not pump blood as well as it
should, generally resulting in reduced cardiac output, possibly due to reduced contraction
force or impaired relaxation or other deficiencies. Chronic heart failure is associated with
cardiac muscle remodeling, which is the result of abnormal genomic, molecular, cellular, and
structural changes that typically manifest clinically as changes in size, shape, and function of
the heart’s ventricles. The reduced cardiac function is associated with multiple symptoms,
such as fatigue, shortness of breath (dyspnea), co-morbidities, and limited ability to walk,
exercise, or tolerate effort. The severity of symptoms is often classified by the physician in
accordance with New York Heart Association (NYHA) classification (for example, NYHA class
II represents moderate symptoms and class IV represents severe symptoms). Over time,
chronic heart failure is a leading cause for hospitalizations and mortality. There are several
medications that are used for treating heart failure according to the guidelines. In patients that
are symptomatic despite appropriate medication, further evaluation of left ventricular ejection
fraction (usually valuated by echocardiography) and QRS duration (evaluated by ECG) are
useful in determining the possible need for an ICD, in cases having low ejection fraction, or a
CRT, in cases with wide QRS, respectively.
Cardiac Contractility Modulation therapy is based on the delivery of non-excitatory electrical
signals to the ventricles during the ventricular absolute refractory period. Published scientific
research on cardiac contractility modulation therapy in animals and in humans explored
various properties and effects. Some data suggests that cardiac contractility modulation has
immediate effects on heart failure tissue, including potentially increasing the contraction force
(contractility) of the muscle, possibly by immediate (i.e. less than a minute) improvement in
the activity of the intracellular proteins that are associated with calcium cycling, for example
by increased phosphorylation of the phospholamban protein, which is believed to modify the
activity level of SERCA-2a, a protein responsible for intracellular calcium handling. Other data
in heart failure animals and in humans suggest that after treating with cardiac contractility
modulation for several hours, there may be normalization of mRNA expression levels of
plurality of cardiac genes that are associated with heart failure (e.g. SERCA-2a, ANP, BNP,
a-MHC, and others). Some data suggest that these changes and improvements in
contraction are not associated with increase in myocardial oxygen consumption. Other data
in animals over a period of a few months of cardiac contractility modulation delivery suggest
the potential for improvements in the expression levels of several proteins that are associated
with heart failure. In addition, some data suggest that with a few months of cardiac
contractility modulation delivery, cardiac dimensions, structure, function (e.g. LVEDD,
LVESD, and LVEF), cellular function, and/or tissue behavior may improve, providing the
potential for reverse remodeling. Other studies explored clinical benefits with cardiac
contractility modulation therapy in chronic heart failure patients, typically with a narrow QRS
and New York Heart Association (NYHA) class of at least II, and suggest that several months
(e.g. at least 3 months) of treatment potentially result in improvements in exercise tolerance
(e.g. by six minute walk tests or by peak oxygen consumption in cardio pulmonary tests) and
in quality of life (e.g. by NYHA classification or by questionnaire), which could be indicative of
clinically significant improvements in cardiac function. Various studies explored effects of
cardiac contractility modulation in patients with NYHA classes II, III, and IV, some with EF up
to 35%, some with higher EF (e.g. 40%, 45%). The studies usually included population with a
range of age, gender, etiology (e.g. ischemic, idiopathic) and other characteristics.
With regard to use of cardiac contractility modulation outside the United States, the 2016
European Society of Cardiology practice guidelines has reviewed clinical studies of cardiac
contractility modulation in heart failure patients and mentioned cardiac contractility
modulation as a treatment option that may be considered in selected patient population.
Summaries of some of these studies are available on Impulse Dynamics’ website
(http://www.impulse-dynamics.com/int/for-physicians/clinical-data/).