Diabetic cardiomyopathy: the search for a unifying hypothesis

Although diabetes is recognized as a potent and prevalent risk factor for ischemic heart disease, less is known as to whether diabetes causes an altered cardiac phenotype independent of coronary atherosclerosis. Left ventricular systolic and diastolic dysfunction, left ventricular hypertrophy, and alterations in the coronary microcirculation have all been observed, although not consistently, in diabetic cardiomyopathy and are not fully explained by the cellular effects of hyperglycemia alone. The recent recognition that diabetes involves more than abnormal glucose homeostasis provides important new opportunities to examine and understand the impact of complex metabolic disturbances on cardiac structure and function.     

Pathogenesis of primary biliary cirrhosis： A unifying model

Primary biliary cirrhosis (PBC) is a disease of unknown etiology leading to progressive destruction of small intrahepatic bile ducts and eventually to liver cirrhosis and failure. It is characterised by female predominance and serum auto-antibodies to mitochondrial antigens targeting the E2 components of the 2-oxoacid dehydrogenase complex. Although they are associated with disease pathogenesis, no concrete evidence has been presented so far. Epidemiological data indicate that a geographical clustering of cases and possible environmental factors are implicated in pathogenesis. A number of genetic factors play a role in determining disease susceptibility or progression, although no definitive conclusion has been reached so far. A key factor to immune pathogenesis is considered to be the breakdown of immune tolerance, either through molecular mimicry or through the so called determinant density model. In this review, the available data regarding the pathogenesis of primary biliary cirrhosis are described and discussed. A new unifying hypothesis based on early endothelin overproduction in primary biliary cirrhosis (PBC) is presented and discussed.     

Takotsubo syndrome: the broken-heart syndrome

Takotsubo syndrome – also known as broken-heart syndrome, Takotsubo cardiomyopathy, and stress-induced cardiomyopathy – is a recently discovered acute cardiac disease first described in Japan in 1991. This review aims to update understanding on the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of Takotsubo syndrome, highlighting aspects of interest to cardiologists and general practitioners.Key words: broken-heart syndrome, stress cardiomyopathy, Takotsubo cardiomyopathy, Takotsubo syndrome     

Molecular mechanism of juxtaglomerular cell hyperplasia: a unifying hypothesis

Renin is the first enzymatic step of the renin angiotensin cascade and plays an important role in cardiovascular homeostasis. Renin is mainly expressed in and released from specialized juxtaglomerular (JG) cells in kidney. JG cells develop hyperplasia in response to various chronic stimuli while maintaining the ability to express high levels of renin. However, the molecular and cellular mechanisms of JG cell hyperplasia are unknown. Based on the authors’ previous observation that a nuclear hormone receptor, liver X receptor α, regulates renin expression as well as growth and differentiation genes such as c-myc, the authors propose the hypothesis that liver X receptor α can contribute to JG cell hyperplasia under conditions of chronic and intense induction of these genes. This hypothesis may provide a potential explanation for the observation that the JG cells can maintain a highly specialized renin-producing phenotype while undergoing hyperplasia.     

Neurogenic heart disease: A unifying hypothesis

Electrocardiographic abnormalities have been known to occur in the context of neurologic disease for a long time. These changes fall into 2 categories: arrhythmias and repolarization abnormalities. However, until relatively recently these changes were believed to represent purely electrophysiologic alterations and not real heart disease. It is now clear that some patients with neurogenic electrocardiographic changes show cardiac enzyme release and myofibrillar degeneration at autopsy. There are 4 major methods for producing myofibrillar degeneration (i.e., contraction band necrosis or coagulative myocytolysis): catecholamine infusion, stress-steroid, nervous system stimulation and reperfusion. The common thread connecting these 4 methods is the opening of receptor-operated calcium channels, resulting in intense contraction of cardiac muscle. Thus, neurogenic influence over cardiac function may represent a continuum. In the mild reversible circumstance, only the electrocardiographic change will be seen, whereas in the severe, irreversible situation, myofibrillar degeneration will ensue with release of cardiac enzymes. Cardiac cell death may be caused by oxygen free radicals produced by metabolism of catecholamines or reperfusion or both, after variable periods of ischemia. This concept represents a unifying hypothesis, tying together the clinical, physiologic, biochemical and pathologic findings in neurogenic heart disease.     

Pathogenesis of secondary hypertrophic osteoarthropathy: a hypothesis

Wide ranges both in the location and the pathological state of the primary disease associated with hypertrophic osteoarthropathy (HO) have been noted. The combined distribution of the glossopharyngeal and vagus nerves appears to coincide with the range of locations of the primary disease associated with HO. These two nerves are believed to contribute to the innervation of the blood vessels in this same area. This hypothesis states that: i) some of this innervation is part of a blood volume control system; and ii) by an inappropriate stimulation of this system, as a result of blood-flow in an anomalous vascular rearrangement lying close to the primary disease associated with HO, a cerebral salt centre is stimulated to retain extra-cellular sodium. A secondary atrial natriuretic peptide over-secretion ensues and a "near steady-state" is established, with the presence of excess fluid and dilated vessels in all four limbs. Thus, the pathogenesis of HO and the distribution of an extra-renal volume control system are reciprocal facets of the same question.     

Takotsubo syndrome

The Takotsubo Syndrome was first described by Japanese investigators approximately 20 years ago and has been increasingly recognized in all countries. It occurs almost exclusively in postmenopausal women and is triggered by a severe emotional stress. Severe chest pain is common and the electrocardiogram often mimics that seen with an acute myocardial infarction. An echocardiogram or a left ventriculogram resembles a Takotsubo, a Japanese octopus fishing pot. In Japanese 'Takotsubo' means a 'fishing pot for trapping octopus.' These traps have a round bottom with a narrow neck. When the octopus enters the Takotsubo it is most often trapped while the fisherman pulls the device to the surface. The syndrome is reversible and over the next several weeks to months all electrocardiographic and echocardiographic changes revert to normal. It is likely that the emotionally induced catecholamine surge in an estrogen-deficient woman causes a combination of epicardial coronary artery constriction, constriction of the myocardial microvasculature, and direct cardiomyocyte toxicity producing a temporary stunning effect on the left ventricular myocardium.     

Takotsubo syndrome

Takotsubo syndrome is a reversible acute heart failure frequently precipitated by an emotional or physical stress. The clinical presentation resembles acute coronary syndrome. Pathogenesis is complex and may involve brain-heart axis and neuro-hormonal stunning of the myocardium. Coronary angiography reveals normal epicardial arteries with no obstruction or spasm. NT-ProBNP maybe remarkably elevated. Regional wall motion akinesia (RWMA) of left ventricle extends beyond the territory of one coronary artery. Reduced left ventricle ejection fraction (LVEF) and RWMA recover in 6–12 weeks. Prognosis is generally good. Recent meta-analysis shows in-hospital mortality of 1–4.5% and recurrence rate of 5–10% during five year follow-up.     

The pathogenesis of heartburn in nonerosive reflux disease: a unifying hypothesis

Heartburn is a symptom complex that has traditionally been accepted as an acid-mediated event and a reliable indicator of gastroesophageal reflux disease. Recently, however, these concepts have been questioned because patients with endoscopy-negative "heartburn" have lower response rates to acid suppression with proton pump inhibitors than do patients with endoscopy-positive "heartburn," ie, erosive esophagitis. As explanation for this, 3 different mechanisms have been proposed to explain the occurrence of heartburn in the endoscopy-negative setting. They are: esophageal visceral hypersensitivity, sustained esophageal contractions, and abnormal tissue resistance. In this report, we review the observations in support of each concept and propose a means for reconciling them under one hypothesis: abnormal tissue resistance. Essential to this review and to the conclusions drawn about the pathogenesis of heartburn in nonerosive reflux disease is a reaffirmation of the definition of reflux-associated "heartburn" as an acid-mediated event requiring "relief by antacids" as a necessary component of the history.     

Takotsubo Syndrome: Clinical Manifestations,Etiology and Pathogenesis

The purpose of the review is the analysis of clinical and experimental data on the etiology and pathogenesis of takotsubo syndrome (TS). TS is characterized by contractile dysfunction, which usually affects the apical region of the heart without obstruction of coronary artery, moderate increase in myocardial necrosis markers, prolonged QTc interval (in 50% of patients), sometimes elevation of ST segment (in 19% of patients), increase N-Terminal Pro-B-Type Natriuretic Peptide level, microvascular dysfunction, sometimes spasm of the epicardial coronary arteries (in 10% of patients), myocardial edema, and life-threatening ventricular arrhythmias (in 11% of patients). Stress cardiomyopathy is a rare disease, it is observed in 0.6 - 2.5% of patients with acute coronary syndrome. The occurrence of takotsubo syndrome is 9 times higher in women, who are aged 60-70 years old, than in men. The hospital mortality among patients with TS corresponds to 3.5% - 12%. Physical or emotional stress do not precede disease in all patients with TS. Most of patients with TS have neurological or mental illnesses. The level of catecholamines is increased in patients with TS, therefore, the occurrence of TS is associated with excessive activation of the adrenergic system. The negative inotropic effect of catecholamines is associated with the activation of β₂ adrenergic receptors. An important role of the adrenergic system in the pathogenesis of TS is confirmed by studies which were performed using ¹²⁵I-metaiodobenzylguanidine (¹²⁵I -MIBG). TS causes edema and inflammation of the myocardium. The inflammatory response in TS is systemic. TS causes impaired coronary microcirculation and reduces coronary reserve. There is a reason to believe that an increase in blood viscosity may play an important role in the pathogenesis of microcirculatory dysfunction in patients with TS. Epicardial coronary artery spasm is not obligatory for the occurrence of TS. Cortisol, endothelin-1 and microRNAs are challengers for the role of TS triggers. A decrease in estrogen levels is a factor contributing to the onset of TS. The central nervous system appears to play an important role in the pathogenesis of TS.     

Transient mid-ventricular dyskinesia: a variant of Takotsubo syndrome

Takotsubo Cardiomyopathy is characterized by a reversible systolic left ventricular apical ballooning. A new pattern of dyskinesia in the absence of angiographic evidence of coronary artery stenosis has been indicated like a variant of takotsubo cardiomiopathy: mid-ventricular akinesis with preservation of apical and basal contractilities revealed at echocardiograms and ventriculographies. We report the case of a 65 years old patient with this pattern, reverted in 4 weeks.     

Body fluid volume regulation in health and disease: a unifying hypothesis

In studies in experimental animals and in edematous patients, the nonosmotic release of vasopressin has been found to be consistently associated with activation of the sympathetic nervous and renin-angiotensin-aldosterone systems. Moreover, the sympathetic nervous system is known to modulate the nonosmotic release of vasopressin and activation of the renin-angiotensin-aldosterone system. These findings led to our proposal that body fluid volume regulation involves dynamic interaction between cardiac output and peripheral arterial resistance. In this context, neither total extracellular fluid volume nor total blood volume are determinants of renal sodium and water excretion. With a decrease in effective arterial blood volume (EABV) initiated by either decreased cardiac output or peripheral arterial vasodilation, the acute response involves vasoconstriction mediated by angiotensin, sympathetic mediators, and vasopressin. The renal vasoconstriction, which accompanies either decreased cardiac output or peripheral arterial vasodilation, causes a decreased distal tubular delivery of sodium and water, thus maximizing the water-retaining effect of vasopressin and impairing normal escape from the sodium-retaining effect of aldosterone. The elevated glomerular filtration rate and filtered sodium load seen in pregnant women allow increased distal sodium and water delivery despite a decrease in EABV, thus limiting edema formation during gestation.     

The path of calcium in cytosolic calcium oscillations: a unifying hypothesis.

Data from 42 systems have been assembled in which the overall spatial course of relatively natural, intracellular calcium pulses has been or can be determined. These include 21 cases of solitary pulses in activating eggs and 21 cases of periodic (as well as solitary) pulses in various fully active cells. In all cases, these pulses prove to be waves of elevated calcium that travel from one pole of a cell to the other or from the periphery inward. The velocities of these waves are remarkably conserved--at approximately 10 microns/sec in activating eggs and approximately 25 microns/sec in other cells at room temperature. Moreover, in three cases, the data suffice to show that these velocities fit the Luther equation for a reaction/diffusion wave of calcium through the cytosol. It is proposed that (i) natural intracellular calcium pulses quite generally take the form of cytosolic calcium waves and (ii) cytoplasmically controlled calcium waves are triggered and then propagated by the successive action of two distinct modes of calcium-induced calcium release. First, in the lumenal mode, a slow increase of calcium within the lumen of the endoplasmic reticulum reaches a level that triggers fast lumenal release as well as fast localized release into the cytosol. Then, the well-known cytosolic mode drives a reaction/diffusion wave across or into the cell.