Björn Redfors

Novel rat model reveals important roles of β-adrenoreceptors in stress-induced cardiomyopathy.

BACKGROUND Stress-induced cardiomyopathy (SIC), also known as Takotsubo cardiomyopathy, is an acute cardiac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular akinesia involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC but the pathophysiological pathways and receptors involved are unknown. METHODS Sprague Dawley rats (~300 g) were injected with a single dose of the β-adrenergic agonist isoprenaline (ISO, i.p.) and echocardiography was used to study cardiac function. The akinetic part of the left ventricle was biopsied in six SIC patients. Amount of intracellular lipid and glycogen as well as degree of permanent cardiac damage were assessed by histology. RESULTS In rats, ISO at doses ≥ 50 mg/kg induced severe SIC-like regional akinesia that completely resolved within seven days. Intracellular lipid content was higher in akinetic, but not in normokinetic myocardium in both SIC patients and rats. β2-receptor blockade or Gi-pathway inhibition was associated with less widespread akinesia and low lipid accumulation but significantly increased acute mortality. CONCLUSIONS We provide a novel rat model of SIC that supports the hypothesis of circulating catecholamines as initiators of SIC. We propose that the β-adrenoreceptor pathway is important in the setting of severe catecholamine overstimulation and that perturbations of cardiac metabolism occur in SIC.

Mortality in takotsubo syndrome is similar to mortality in myocardial infarction — A report from the SWEDEHEART1 registry

BACKGROUND Takotsubo syndrome is an acute cardiovascular condition that predominantly affects women. In this study, we compared patients with takotsubo syndrome and those with acute myocardial infarction with respect to patient characteristics, angiographic findings, and short- and long-term mortality. METHODS From the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) and the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA), we obtained and merged data on patients undergoing coronary angiography in Västra Götaland County in western Sweden between January 2005 and May 2013. Short- and long-term mortality in patients with takotsubo (n=302) and patients with ST-elevation myocardial infarction (STEMI, n=6595) and non-ST-elevation myocardial infarction (NSTEMI, n=8207) were compared by modeling unadjusted and propensity score-adjusted logistic and Cox proportional-hazards regression. RESULTS The proportion of the patients diagnosed with takotsubo increased from 0.16% in 2005 to 2.2% in 2012 (P<0.05); 14% of these patients also had significant coronary artery disease. Cardiogenic shock developed more frequently in patients with takotsubo than NSTEMI (adjusted OR 3.08, 95% CI 1.80-5.28, P<0.001). Thirty-day mortality was 4.1% and was comparable to STEMI and NSTEMI. The long-term risk of dying from takotsubo (median follow-up 25 months) was also comparable to NSTEMI (adjusted HR 1.01, 95% CI 0.70-1.46, P=0.955) STEMI (adjusted HR 0.83, 95% CI 0.57-1.20, P=0.328). CONCLUSIONS The proportion of acute coronary syndromes attributed to takotsubo syndrome in Western Sweden has increased over the last decade. The prognosis of takotsubo syndrome is poor, with similar early and late mortality as STEMI and NSTEMI.

Stress-Induced Cardiomyopathy in Sweden: Evidence for Different Ethnic Predisposition and Altered Cardio-Circulatory Status

Background: In this paper, we report about new insights regarding clinical course, long-term outcome, ethnic/genetic predisposition and cardio-circulatory status in the large stress-induced cardiomyopathy (SIC) cohort from Sweden. Methods and Results: We have included 115 consecutive SIC patients between January 2005 and January 2010 at Sahlgrenska University Hospital in Gothenburg. Hemodynamic status and sympathetic nerve activity were evaluated and compared with those of healthy controls. Mean age was 64, and 14% were males. Thirty-day and 3-year mortality was 6 and 10%, respectively. Eleven percent had ischemic heart disease, 3% developed thromboembolic complications, 6% had cardiac arrest and 14% developed cardiogenic shock. The great majority of SIC patients (93%) were ethnic Swedes. In three families, several close relatives developed SIC. Fourteen percent developed two or more episodes of SIC. Hemodynamic evaluation has shown subnormal systemic vascular resistance, 22% lower sympathetic activity and preserved cardiac output in SIC patients. Conclusions: SIC affects both men and women of different ages and is associated with significant short- and long-term mortality. There is a strong signal for the presence of ethnic/genetic predisposition to develop SIC. Sympathetic activity and systemic vascular resistance are lower in SIC patients, suggesting that SIC is a cardio-circulatory phenomenon.

Different catecholamines induce different patterns of takotsubo-like cardiac dysfunction in an apparently afterload dependent manner.

BACKGROUND Takotsubo cardiomyopathy (TCM) is characterized by regional left ventricular dysfunction that cannot be explained by an occlusive lesion in a coronary artery. Catecholamines are implicated in the pathogenesis of TCM but the mechanisms involved are unknown. Because the endogenous and the most commonly used exogenous catecholamines have well defined adrenoceptor subtype affinities, inferences can be made about the importance of each adrenoceptor subtype based on the ability of different catecholamines to induce TCM. We therefore studied which of five well-known catecholamines, that differ in receptor subtype affinity, are able to induce TCM-like cardiac dysfunction in the rat. METHODS 255 rats received intraperitoneally isoprenaline (β1/β2-adrenoceptor agonist), epinephrine (β1/β2/α-adrenoceptor agonist), norepinephrine (β1/α-adrenoceptor agonist), dopamine (α/β1/β2-adrenoceptor agonist) or phenylephrine (α-adrenoceptor agonist). Each catecholamine was given in five different doses. We measured blood pressure through a catheter inserted in the right carotid artery and studied cardiac morphology and function by echocardiography. RESULTS All catecholamines induced takotsubo-like cardiac dysfunction. Isoprenaline induced low blood pressure and predominantly apical dysfunction whereas the other catecholamines induced high blood pressure and basal dysfunction. In another set of experiments, we continuously infused hydralazine or nitroprusside to rats that received epinephrine or norepinephrine to maintain systolic blood pressure < 120 mm Hg. These rats developed akinesia of the apex instead of the base. Infusion of phenylephrine to maintain blood pressure > 120 mm Hg after isoprenaline administration prevented apical TCM-like dysfunction. CONCLUSIONS Catecholamine-induced takotsubo-like cardiac dysfunction appears to be afterload dependent rather than depend on stimulation of a specific adrenergic receptor subtype.

A mouse model reveals an important role for catecholamine-induced lipotoxicity in the pathogenesis of stress-induced cardiomyopathy

Stress‐induced cardiomyopathy (SIC), also known as takotsubo cardiomyopathy, is an acute cardiac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular dysfunction (akinesia) involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC, but the pathomechanisms involved are unknown. We tested the hypothesis that excessive catecholamines cause perturbation of myocardial lipid metabolism and that cardiac lipotoxicity is responsible for the pathogenesis of SIC.

Current hypotheses regarding the pathophysiology behind the takotsubo syndrome

Takotsubo syndrome is an increasingly recognized acute cardiac affliction which is characterized by severe regional left ventricular dysfunction that cannot be explained by one or more occlusive culprit lesions of a coronary artery. A preceding somatic and/or emotional stressor can be identified in a majority of these patients and older women are overrepresented among the afflicted. Catecholamine levels are elevated in patients with takotsubo and exogenous catecholamine administration may cause or exacerbate the condition. Hence, catecholamines appear implicated in the pathogenesis. However, beyond catecholamine the pathogenesis of the takotsubo syndrome is unclear. Five distinct hypotheses have been postulated which attempt to explain why specific regions within the left ventricle are affected in takotsubo. In this manuscript we critically review these hypotheses in light of the available data. We discuss how the different hypotheses may be complementary to each other and to which extent they are contradicting one another.

Contrast echocardiography reveals apparently normal coronary perfusion in a rat model of stress-induced (Takotsubo) cardiomyopathy.

AIMS Stress-induced cardiomyopathy (SIC) is an important differential diagnosis to acute myocardial infarction (AMI) that is associated with significant morbidity and mortality. The typical hallmark of SIC is left-ventricular apical akinesia but preserved function in basal segments. Catecholamines are postulated to play an important role in SIC but the precise pathophysiology is incompletely understood. Whether myocardial perfusion of the affected segments is impaired in SIC has been debated and remains unknown. METHODS AND RESULTS Myocardial contrast echocardiography (MCE) was used to study regional myocardial perfusion in a rat model of SIC. Twelve rats received 50 mg/kg isoproterenol (ISO) i.p. and were continuously monitored by MCE. Apical and basal perfusion were estimated and expressed as a ratio at baseline, 5, 10, 20, 30, 40, 50, 60, 70, 80, and 90 min post-ISO. The rats developed typical apical ballooning after 43 ± 9 min post-ISO injection. The ratio of apical:basal perfusion was close to 1.00 at all time-points and never dropped below 0.89 (95% CI never extended below 0.73). Light and electron microcoscopical investigation revealed no structural damage of myocardial vessels. CONCLUSION Apical perfusion is not impaired in the early phase of SIC in this rat model.

Stress-induced cardiomyopathy (Takotsubo) - broken heart and mind?

Stress-induced cardiomyopathy (SIC), also known as Takotsubo cardiomyopathy, is characterized by severe but potentially reversible regional left ventricular wall motion abnormalities, ie, akinesia, in the absence of explanatory angiographic evidence of a coronary occlusion. The typical pattern is that of an akinetic apex with preserved contractions in the base, but other variants are also common, including basal or midmyocardial akinesia with preserved apical function. The pathophysiology of SIC remains largely unknown but catecholamines are believed to play a pivotal role. The diverse array of triggering events that have been linked to SIC are arbitrarily categorized as either emotional or somatic stressors. These categories can be considered as different elements of a continuous spectrum, linked through the interface of neurology and psychiatry. This paper reviews our current knowledge of SIC, with focus on the intimate relationship between the brain and the heart.

Trends in publications on stress-induced cardiomyopathy.

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Targeting filamin A reduces K-RAS–induced lung adenocarcinomas and endothelial response to tumor growth in mice

BackgroundMany human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro.MethodsFirst, we used a Cre-adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells.ResultsKnockout of Flna significantly reduced K-RAS–induced lung tumor formation and the proliferation of oncogenic K-RAS–expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors.ConclusionsWe conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics.