free PDF files on metabolic therapy in heart failure and deficiency of highly unsaturated fatty acids (HUFA) during progression of heart failure.

Heart Failure: The Ironic Failure of Success!

this statement by the late R.E. Beamish (Can J Cardiol 1994;10:603) summarizes the current therapy for heart failure. All known drugs prolong survival but cannot prevent final failure of the heart. Therefore, cardiovascular diseases have been identified as "public health enemy No. 1" by the World Health Organization. Cardiovascular diseases kill more people than any other single disease. The search for reliable preventive methods should vigorously be pursued.

Have We Missed an Important Drug Target?

How to find the magic bullet?

The image shows various drug targets during the progression of congestive heart failure (CHF). Surprisingly, various potential targets have not been explored, simply because they do not provide an acute improvement of heart function but rather alter gene expression of the cardiomyocyte.

An athlete's big heart does not fail!

PATHOLOGICAL OVERLOAD & HYPERTROPHY
A high blood pressure and coronary artery disease are the major risk factors for heart failure. Heart failure is typically associated with ventricular hypertrophy. The increase in cardiac mass can be considered as an attempt to compensate for the the reduced performance of heart muscle. It is our working hypothesis that hypertrophy should not necessarily be associated with an increased risk of cardiac failure.

ATHLETE'S HEART: NORMAL HYPERTROPHY
Because an athlete's heart does not fail, specific defects have to exist in hearts with a pathological overload. Novel drug interventions focussing at overloaded hearts should ideally restore a normal pump function by normalizing molecular structures of the cardiomyocyte. It is our working hypothesis that these 'transcriptional modulators' prevent progression of heart failure.

Progression of Heart Failure - it starts at the cardiomyocyte!

A pathological overload of the heart results in specific defects in gene expression of the hypertrophied cardiomyocyte. The resulting protein phenotype is not adapted to the e.g. increased diffusion distances of the the enlarged cardiomyocyte. The mechanical performance of the cardiomyocyte is reduced.

Because the pump function of the heart is derived from the contraction of individual cardiomyocytes, the overall function of heart muscle is reduced. This depressed function is counteracted by the body using mechanisms that are appropriate for acute adjustment of heart performance, e.g. due to postural changes or blood loss.

A vicious cycle is initiated involving neuro-endocrine activation involving the sympathetic nervous system and the renin-angiotensin II-aldosterone system (RAAS). Although the neuro-endocrine activation results in an apparently improved pump function of the heart, a remodeling of the extracellular matrix occurs further aggrevating the impaired pump function of the heart.

As a consequence of the enhanced catecholamine, angiotensin II and aldosterone influences, collagen synthesis is stimulated resulting in an enhanced collagen deposition, i.e. fibrosis of the heart. The increased collagen content of the heart has various detrimental actions on the mechanical performance, e.g. increased stiffness, and provides therefore a further stimulus for neuroendocrine activation.

Prevention of Progression of Heart Failure - the cardiomyocyte as novel drug target

A pathological overload of the heart should be avoided. Taking into account that less than 40% of hypertensives are adequately treated, the goal of preventing a pathological overload of the heart will unfortunately remain an unrealistic aim. Major efforts are needed to avoid the occurrence of hypertension and the very often associated diabetes type-2.

Any depression of cardiomyocyte function should be prevented. Currently available drugs appear not to be designed for this target. We have identified agents which selectively improve the function of overloaded hearts by interfering with the gene expression of cardiomyocytes, i.e. 'transcriptional modulators'. We hypothesize that early interference with defects in gene expression of cardiomyocytes prevents the deletrious neuro-endocrine activation.

If neuro-endocrine activation has already occurred because the progression has not been diagnosed, drugs are needed targeted at the sympathetic overactivity and activation of the renin-angiotensin II-aldosterone system. These drugs prolong life expectancy but cannot prevent congestive heart failure. A combination with selective 'transcriptional modulators' targeted at gene expression of cardiomyocytes is hypothesized to contribute to prevention of heart failure.

Metabolic Modulation of Cardiomyocyte Gene Expression

This approach is targeted at an unfavorable gene expression of a pathologically (e.g. hypertension) overloaded heart. A perturbed gene expression of ion pumps or channels of the heart muscle cell appears as a very early event in a cascade finally leading to impaired pump performance of the heart. Pharmacological strategies are developed that can increase the activity of the calcium pump of sarcoplasmic reticulum (intracellular calcium store) and thereby increase rate of ventricular contraction and relaxation. Our current lead compound is etomoxir which inhibits mitochondrial carnitine palmitoyltransferase-1 and activates PPARalpha. Since various other genes are affected in a coordinated manner, the re-programming of gene expression results in an altered protein phenotype. The unfavorable protein phenotype of an overloaded heart is thought to induce neuroendocrine activation involving catecholamines, angiotensin II and aldosterone resulting in a vicious cycle. The outcome is seen in fibrosis of the heart involving remodeling of the extracellular matrix.

Metabolic modulation of gene expression would ideally result in a heart muscle with normal molecular structures. A cartoon of this approach served as logo of the Oscar Langendorff Satellite Meeting of the International Society for Heart Research (ISHR) "Control of Cardiovascular Gene Expression. From Molecular Nutrition to Metabolic Syndromes and Shock" held in Stuttgart (June 29-July 1, 1995).

A detailed overview on drugs which could be useful for modulating cardiac metabolism and thus gene expression of cardiomyocytes can be downloaded as PDF file: The Use of Partial Fatty Acid Oxidation Inhibitors for Metabolic Therapy of Angina Pectoris and Heart Failure
A key feature of these drugs is an enhanced oxidation of glucose. Although glucose is utilized in all organs of the body, links with gene expression of the cardiomyocyte remain ill-defined.

Regression and Prevention of Cardiac Fibrosis

This approach is targeted at regression or prevention of fibrosis of the heart. Fibrosis is a deleterious event that reduces the mechanical performance of heart muscle and impairs oxygen supply to the heart muscle cell. There is increasing evidence that angiotensin II and aldosterone have crucial influences on the remodeling of the extracellular matrix. Drug interventions are needed that can specifically reduce fibrosis and have a beneficial influence on the remodeling of the extracellular matrix (cardioreparation). However, neuroendocrine activation associated with extracellular remodeling appears to be preceded by an impaired performance of the heart muscle cell itself. Various vicious cycles arise from an unfavorable protein phenotype of the heart muscle cell. Since other genes are affected in a coordinated manner, the potential of reprogramming gene expression of the heart muscle cell in a specific manner by novel drug approaches is studied actively.

For information on drug-induced modulation of gene expression of the cardiomyocyte, please contact Heinz Rupp, Ph.D., Professor of Physiology, personal data, Google Scholar Citations
Publications on cardiovascular effects of etomoxir
Patents for use of etomoxir in treatment of heart failure

For information on drug-induced modulation of extracellular matrix remodeling, please contact Christian G. Brilla, M.D., Ph.D., Professor of Medicine, personal data.

last modified August 23, 2013 by Heinz Rupp