Pathways involved in the transition from hypertension to hypertrophy to heart failure. Treatment strategies

Department of Psychology, Washington State University, Pullman, WA 99164-4820, USA.
Heart Failure Reviews (Impact Factor: 3.79). 10/2008; 13(3):367-75. DOI: 10.1007/s10741-007-9060-z
Source: PubMed


The renin-angiotensin-aldosterone system (RAAS) is critical in regulating systemic blood pressure, water and electrolyte balance, and pituitary gland hormones. These physiologies appear to be primarily mediated by the angiotensin II/AT(1) receptor subtype system. Overstimulation of this system can predispose cardiovascular disease (CVD) characterized by excessive vasoconstriction, fibrosis, and cardiac remodeling. If untreated, the patient typically displays a continuum of pathophysiologic conditions progressing from atherosclerosis to left ventricle hypertrophy (LVH), coronary thrombosis, myocardial infarcts, with heart failure as an endpoint. Intervention with antihypertensive therapy is necessary to inhibit this progression. RAAS blocking drugs appear to be the most effective approach. Diastolic heart failure patients benefit from treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin AT(1) receptor blockers (ARBs). Elderly CVD patients evidence age-related changes in body composition that alter the distribution and half-life of medications, thus presenting special challenges to treatment. The presence of comorbidities such as diabetes, renal dysfunction, liver insufficiency further complicates any therapeutic strategy. In addition, noncompliance because of cognitive impairment, depression, confusion due to the complexity of dose regimens, and lack of an appropriate social support system can disrupt positive outcome. The present review discusses the roles of an overactive RAAS and sympathetic nervous system as primary contributors to CVD. In addition, treatment strategies are discussed, focusing on middle aged and elderly hypertensive and heart failure patients.

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    • "Indeed, inactivation of ROCK via angiotensin II inhibition prevents stress fiber formation and hypertrophy in a cell line derived from rat heart myoblasts (Kim et al., 2013). Finally, the role of Fasudil as a potent vasodilator (Fukumoto et al., 2005) may also alleviate the fibrosis-dependent vasoconstriction of SMA hearts (reviewed in Wright et al., 2008). While it is tempting to hypothesize that overexpression of activated RhoA/ROCK during SMA pathogenesis is responsible for the observed cardiac defects, assessment of this pathway in SMA hearts and evaluation of the effects of Y-27632 and Fasudil on cardiac function and pathology have unfortunately not been performed . "
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    ABSTRACT: Spinal muscular atrophy (SMA) is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the Survival Motor Neuron 1 (SMN1) gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK), which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myoblasts, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice.
    Frontiers in Neuroscience 08/2014; 8. DOI:10.3389/fnins.2014.00271 · 3.66 Impact Factor
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    ABSTRACT: Suun kautta annosteltava kalsiumherkistäjä parantaa sydämen vajaatoimintaan liittyvää pumppausvajetta kokeellisissa sydämen vajaatoimintamalleissa Huolimatta viime vuosikymmenien lääketieteellisestä kehityksestä krooninen sydämen vajaatoiminta on silti edelleen vakava, elämänlaatua voimakkaasti rajoittava sairaus. Kalsiumherkistäjät ovat uusi, sydämen pumppausvoimaa lisäävä lääkeryhmä. Levosimendaani, kotimaista alkuperää oleva kalsiumherkistäjä, on kliinisessä käytössä akuutin vajaatoiminnan hoitoon suonensisäisesti ja lyhytaikaisesti annosteltavana valmisteena. Levosimendaanilla on aktiivinen metaboliitti, OR-1896, jonka oletetaan olevan vuorokauden mittaisen levosimendaani-infuusion jälkeen havaittujen useita päiviä kestävien hyödyllisisten vaikutuksisten takana. Levosimendaanin kroonisen, suun kautta tapahtuvan annostelun vaikutuksista tieto on vähäisempää, mutta sillä näyttää olevan positiivisia vaikutuksia potilaiden raportoimana. FM Marjut Louhelainen on selvittänyt väitöskirjassaan suun kautta annosteltavan levosimendaanin ja sen pitkäkestoisen aktiivisen metaboliitin vaikutuksia kroonisen vajaatoiminnan hoidossa käyttämällä sekä hypertensiivisen sydäntaudin että 2 tyypin diabeteksen komplisoimaan sydäninfarktin kokeellisia malleja. Tutkimuksessa selvitettiin lisäksi vajaatoimintaan johtavia molekyylitason tapahtumia sydänlihaksessa. Tutkimuksessa osoitettiin, että krooninen suun kautta annosteltu hoito sekä kalsiumherkistäjä levosimendaanilla että sen aktiivisella metaboliitilla estää hypertensiiviseen sydämen vajaatoiminnan aikaasaamaa sydämen uudelleenmuovaantumista ja siihen liittyvää kuolleisuutta. Nämä vaikutukset välittyivät vähentyneen sydänlihassoluhypertrofian, solukuolleisuuden ja neurohumaraalisen aktivaation kautta. Levosimendaanin ja OR-1896:n osoitettiin myös parantavan sydämen pumppausfunktiota tyyppi 2 diabeteksen komplisoimassa sydäninfarktissa. Ei-diabeettiseen tilanteeseen verrattuna diabetekseen liittyvä infarktin jälkeinen vajaatoiminnan kehitys oli yhteydessä lisääntyneeseen tulehdukseen, fibroosiin, solukuolemaan, neurohumoraaliseen aktivaatioon ja ennenaikaiseen kudoksen vanhenemiseen. Sekä levosimendaani, että OR-1869 vähensivät tulehduksen, fibroosin ja solukuoleman merkkejä ja vaimensi neurohumoraalista aktivaatiota. OR-1896 myös vähensi solujen vanhenemiseen liittyvien merkkiaineiden ilmentymistä. Väitöskirjassa todettiin, että suun kautta annosteltuna sekä levosimendaani, että sen aktiivinen metaboliitti OR-1896, omaavat terapeuttista potentiaalia sekä hypertensiivisen sydäntaudin hoitoon että sydäninfarktin jälkeisen vajaatoiminnan estoon. FM Marjut Louhelaisen farmakologian alaan kuuluva väitöskirja Effects of oral calcium sensitizers on experimental heart failure tarkastetaan Helsingin yliopiston Lääketieteellisessä tiedekunnassa perjantaina 29.01.2010 klo 12 (Biomedicum Helsinki, luentosali 2, Haartmaninkatu 8, Helsinki). Vastaväittäjänä toimii professori Raimo Tuominen, Helsingin yliopiston Farmasian tiedekunnasta ja kustoksena professori Eero Mervaala Helsingin yliopiston Lääketieteellisestä tiedekunnasta. Oral calcium sensitizer levosimendan and its active metabolite OR-1896 improve cardiac functions and prevent harmful cardiac remodeling in an experimental heart failure Calcium sensitizers is a novel class of inotropic agents that may possess potential advantages for the treatment of acute decompensated heart failure and other low output heart failure situations as compared with conventional inotropic drugs. Levosimendan, the only calcium sensitizer in clinical use at the moment, mediates its cardiac effect by the calcium sensitization of the contractile protein troponin C. Besides increasing the strength of cardiac contractions, levosimendan also exerts vasodilatory effects through opening of the sarcolemmal and mitochondrial ATP-sensitive potassium channels. The major elimination route of levosimendan is conjugation with glutathione to cysteine and cysteinylglycine conjugates. A minor metabolism route is reduction of levosimendan in intestine by bacteria into metabolite OR-1855, which is further acetylated to OR-1896, a long-lasting metabolite sharing the pharmacological properties of the parent compound. Currently levosimendan is used only as 24-h systemic infusion. The present study aimed at exploring the cardiovascular effects of oral calcium sensitizers in two different animal models of heart failure, namely in hypertensive and salt-sensitive Dahl/Rapp rats on high salt diet (a model of hypertensive heart failure with preserved systolic function), and in spontaneously diabetic Goto-Kakizaki rat with experimental myocardial infarction induced by coronary artery ligation (a model of post-infarct heart failure with impaired systolic functions). We were able to demonstrate that, in Dahl/Rapp rats, both levosimendan and OR-1896 prevented mortality, produced a transient decrease in blood pressure, prevented cardiac hypertrophy and improved cardiac contractility. These beneficial effects were associated with decreased cardiac ANP mRNA expression, a marker of pressure/volume overload, attenuation of oxidative stress, inflammatory response and cellular senescence. In Goto-Kakizaki rats, levosimendan and OR-1896 prevented MI-induced systolic heart failure, pronounced cardiac hypertrophy in the remote area, and sustained cardiomyocyte apoptosis. The beneficial effects of calcium sensitizers were associated with decreased myocardial ANP, inflammatory IL-6, and fibrogenic CTGF mRNA expressions, and corrections of MI-induced disturbances in calcium-handling proteins (SERCA2, Na+-Ca2+-exhanger). In conclusion, findings from the present study suggest a therapeutic role for oral calcium sensitizers in the treatment of hypertension-induced heart failure with preserved systolic function as well as in the prevention of post-infarct heart failure with decreased systolic function.
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    ABSTRACT: RESUMO A hipertrofia ventricular esquerda (HVE) representa uma resposta adaptativa do coração à hipertensão arterial. Embora considerada compensatória, a HVE é um preditor independente de maior morbimortalidade cardiovascular. Em concordância com essas observações, diversas evidências clínicas e epidemiológicas demonstraram que a HVE é um importante fator de risco para o desenvolvimento de insuficiência cardíaca (IC) sistólica e diastólica. Além da massa miocárdica, a geometria ventricular também influen - cia o desenvolvimento de IC. Nesse contexto, a hipertrofia concêntrica corresponde ao padrão geométrico que tem sido mais associado à progressão para IC. Diversos meca- nismos têm sido propostos para explicar a transição de HVE para IC. Entre eles, destacam-se as alterações na micro e na macrocirculação coronária e a fibrose intersticial, as quais comprometem o suprimento de oxigênio e nutrientes para os miócitos cardíacos e impedem um desempenho mecânico satisfatório dessas células. Esses fatores modificam tanto a contratilidade quanto o relaxamento miocárdico, sugerindo que as disfunções sistólica e diastólica relacionadas à HVE podem representar um continuum. Por outro lado, eventos isquêmicos também podem precipitar o desenvolvimento de IC, demonstrando que a progressão de HVE para IC tem origem multifatorial e é resultante de uma complexa interação entre fatores intrínsecos e extrínsecos ao miocárdio. PALAVRAS-CHAVE Hipertrofia ventricular esquerda, insuficiência cardíaca, ecocardiografia, disfunção ventricular esquerda. ABSTRACT Left ventricular hypertrophy (LVH) is an adaptive respon- se to systemic hypertension. Nevertheless, it has been extensively demonstrated that LVH is an independent predictor of increased cardiovascular risk and heart failure (HF) development. In this regard, not only myocardial mass but also left ventricular geometric pattern have been shown to influence left ventricular performance. For instance, concentric hypertrophy displays the major risk to HF progression, especially to its diastolic form. Conversely, several mechanisms have been proposed to explain the transition from LVH to overt HF. They include coronary micro and macrovascular changes and myo- cardial interstitial fibrosis, which may lead to a reduced supply of oxygen and nutritional factors to myocytes and to a mechanical impairment of myocyte function. These alterations impair either contractile or relaxing performance, thus suggesting that LVH-related systolic and diastolic dysfunction may represent a continuum. On the other hand, coronary atherothrombotic events may also precipitate left ventricular dysfunction, demonstra- ting that transition from LVH to HF is a complex process that results from the interaction between extrinsic and intrinsic myocardial factors.
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