Low resting heart rates are associated with new-onset atrial fibrillation in patients with vascular disease: results of the ONTARGET/TRANSCEND studies.

BACKGROUND: Elevated systolic blood pressure (SBP) and high resting heart rate (HR) are associated with cardiovascular end-points. Although the association between atrial fibrillation (AF) and SBP is well established, the relation between AF and HR remains unclear. METHODS: In patients from the ONTARGET and TRANSCEND studies with high cardiovascular disease risk (n = 27 064), new-onset AF was evaluated in relation to mean SBP, visit-to-visit variation in SBP (SBP-CV; i.e. SD/mean × 100%), mean HR and visit-to-visit variation in HR (HR-CV). RESULTS: Low mean HR (P < 0.0001) and high SBP (P = 0.0021) were associated with incident AF. High SBP-CV (P = 0.031) and HR-CV (P < 0.0001) were also associated with incident AF. After adjustment for confounders, SBP and SBP-CV were no longer significantly associated with AF. The detrimental effect of low HR was particularly evident in subjects who were not receiving treatment with beta-blockers (P = 0.014 for interaction between beta-blocker use and mean HR). In addition to low HR, high HR-CV and high SBP had additive effects on incident AF. CONCLUSIONS: Low mean HR (<60 beats min(-1) ) is independently associated with incident AF, and low HR-CV and high SBP further increase the incidence of new-onset AF in patients at high risk of cardiovascular disease.

[Heart rate: clinical variable and risk marker]. / Herzfrequenz: klinische Variable und Risikomarker.

Heart rate is an easily accessible clinical variable with wide-ranging prognostic impact. Elevated resting heart rate predicts an elevated cardiovascular risk. Epidemiological studies demonstrate a relevant association between heart rate and survival in individuals without diagnosed cardiovascular disease and with cardiovascular disease like hypertension, coronary artery disease (CAD) and heart failure. Whereas a goal directed pharmacological heart rate reduction is not supported by clinical evidence for primary prevention it plays a prognostic role for patients with CAD  and chronic heart failure. Moreover heart rate can be characterized as an independent risk factor for patients with heart failure and potentially for those with CAD. As a result the common guidelines recommend heart rate reduction as a target of therapy.

[Heart rate and rate control : Prognostic value in cardiovascular diseases]. / Herzfrequenz und Frequenzkontrolle : Prognostische Bedeutung bei kardiovaskulären Erkrankungen.

Resting heart rate represents a cardiovascular risk indicator and an important target of therapy in chronic heart failure and potentially in coronary artery disease. Clinical and experimental evidence suggests that sustained elevation of heart rate - independent of the underlying trigger - plays a causal role in the pathogenesis of vascular disease. Results of the SHIFT trial support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the role of heart rate as a risk factor for patients with severe left ventricular dysfunction. Results of the BEAUTIFUL trial show that patients with ischemic heart disease and a heart rate above 70 bpm exhibit an adverse prognosis concerning coronary events.

The PPAR-gamma agonist rosiglitazone facilitates Akt rephosphorylation and inhibits apoptosis in cardiomyocytes during hypoxia/reoxygenation.

BACKGROUND AND AIM: Results on the cardiovascular effects of PPAR-gamma agonists are conflicting. On one hand, it was suggested that the PPAR-gamma agonist rosiglitazone may increase the risk of cardiovascular events. On the other hand, PPAR-gamma agonists reduce myocardial infarct size and improve myocardial function during ischemia/reperfusion in animal studies in vivo. However, the mechanism of this effect is unclear, and it is open if PPAR-gamma agonists have a direct effect on cardiac myocyte survival in ischemia/reperfusion. The aim of this study was to determine the effect of the PPAR-gamma agonist rosiglitazone on hypoxia/reoxygenation-induced apoptosis of isolated cardiomyocytes. METHODS: Isolated rat cardiac myocytes were pretreated with rosiglitazone or vehicle for 30 min before they were subjected to hypoxia for 4 h followed by different times of reoxygenation (5 min to 12 h). Apoptosis was determined by in situ hybridization for DNA fragmentation (TUNEL) as well as detection of cytoplasmic accumulation of histone-associated DNA fragments by enzyme-linked immunosorbent assay (ELISA). Activation of apoptosis regulating intracellular signalling pathways was studied by immunoblotting using phosphospecific antibodies. RESULTS: Rosiglitazone significantly reduced apoptosis of isolated cardiomyocytes subjected to hypoxia/reoxygenation, independently determined with two methods. After 4 h of hypoxia and 12 h of reoxygenation, 34 +/- 3.6% of the vehicle treated cardiac myocytes stained positive for DNA fragmentation in the TUNEL staining. Rosiglitazone treatment reduced this effect by 23% (p < 0.01). Even more pronounced, cytoplasmic accumulation of histone-associated DNA fragments detected by ELISA was reduced by 35% (p < 0.05) in the presence of rosiglitazone. This inhibition of hypoxia/reoxygenation-induced apoptosis was associated with an increased reoxygenation-induced rephosphorylation of the protein kinase Akt, a crucial mediator of cardiomyocyte survival in ischemia/reperfusion of the heart. This effect was reversed by GW-9662, an irreversible PPAR-gamma antagonist. However, rosiglitazone did not alter phosphorylation of the MAP kinases ERK1/2 and c-Jun N-terminal kinase (JNK). CONCLUSION: It can be concluded that cardiac myocytes are direct targets of PPAR-gamma agonists promoting its survival in ischemia/reperfusion, at least in part by facilitating Akt rephosphorylation. This effect may be of clinical relevance inhibiting the reperfusion-induced injury in patients suffering from myocardial infarction or undergoing cardiac surgery.

Effects of AT1- and beta-adrenergic receptor antagonists on TGF-beta1-induced fibrosis in transgenic mice.

BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) is involved in interstitial remodelling promoting collagen synthesis and suppressing collagen degradation by inhibition of collagenases. TGF-beta1 mediates angiotensin II-dependent effects and modulates beta1-adrenergic signalling. To study the effect of neuroendocrine antagonism on TGF-beta-induced hypertrophic and fibrotic phenotype, we treated TGF-beta1 (Cys223,225Ser) transgenic mice (TGF-beta1-TG) with either the beta1-receptor blocker metoprolol (MET), the angiotensin II type I (AT1)-receptor antagonist telmisartan (TEL) or an antibody blocking TGF-beta1 signalling (TGFbeta1-sR-Ab). MATERIAL AND METHODS: Transforming growth factor-beta1-TG mice (8 weeks) overexpressing TGF-beta1 were treated with either TEL (10 mg kg(-1)), MET (350 mg kg(-1)) or a soluble TGF-beta1 receptor antibody (1 mg kg(-1)) for 6 weeks. Morphological analyses of interstitium and cardiomyocytes were related to expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) by immunoblotting and zymography. RESULTS: In TGF-beta1-TG mice, myocardial interstitial total collagen content was fourfold elevated compared to that of controls (P < 0.05) and was lowered under the treatment with TEL (P < 0.05). Protein expression of TIMP-1 and -4 was increased in TGF-beta1-TG but inhibited by TEL (TIMP-1 and TIMP-4) and MET (TIMP-1), while collagenase activity was decreased in TGF-beta1-TG and normalized by treatment with TEL (MMP-1 and MMP-13) and MET (MMP-1) (P < 0.05). Morphometric measurements of cardiomyocyte diameter and area demonstrated similar antihypertrophic effects for all treatment groups. CONCLUSION: The AT1-antagonist TEL reduced myocardial hypertrophy and interstitial fibrosis in TGF-beta1-TG mice by normalizing MMP/TIMP ratio. beta1-Adrenergic inhibition by MET as well as TGF-beta1 antagonism induced antihypertrophic rather than antifibrotic effects. Inhibition of both renin-angiotensin system and beta1-adrenergic system may exert different but synergistic effects to reduce myocardial remodelling.

[Treatment of peri- and postoperative hypertensive emergencies]. / Therapie des peri- und postoperativen hypertensiven Notfalls.

Acute hypertensive emergencies occur in 5 to 35 % of the patients in perioperative care. This is associated with an increase in perioperative complications: the rate of bleedings, myocardial infarctions, cerebral ischemia and overall mortality is increased 4-fold. Before an operation, it is of utmost importance to recognize predictors for hypertensive emergencies and to achieve an adequate blood pressure control. There has so far been no agreement on a blood pressure threshold at which blood pressure needs to be reduced. Antihypertensive therapy is a bedside decision of the responsible physician. It aims at a rapid decrease of hypertensive peaks without risking a reduced organ perfusion. The optimal drug for the treating hypertensive emergencies should have a rapid and safe action. Antihypertensives of first choice are esmolol, metoprolol, urapidil or clonidin. The oral therapy with nifedipine or nitrendipine has the risk of abrupt hypotensive episodes and should therefore only be administered after exclusion of an acute coronary syndrome or cardiac failure Because of its toxicity sodium nitroprusside is an antihypertensive drug of second choice. Nitrates or diuretics are supplementary drugs for patients with angina pectoris, cardiac failure or renal insufficiency. Newer substances (fenoldopam, nicardipine, clevidipine) have promising kinetic properties but are not as yet been approved for antihypertensive treatment in Germany.

The role of heart rate in the development of cardiovascular disease.

Heart rate is an independent risk factor for patients with cardiovascular disease, in particular with arterial hypertension, myocardial infarction, coronary artery disease and heart failure. This relation is supported by a large number of animal studies as well as clinical trials which are summarized in this article. These studies demonstrated detrimental effects of increased heart rate on the function and structure of the cardiovascular system. Heart rate can be easily detected during physical examination of the patient and therefore allows a simple conclusion on prognosis and efficiency of therapy.

Insights from knock-out models concerning postischemic release of TNFalpha from isolated mouse hearts.

The inflammatory cytokine tumor necrosis factor alpha (TNFalpha) is controversially discussed in ischemia/reperfusion damage of the heart. Purpose of this study was to elucidate cellular sources of TNFalpha and parameters which possibly influence its release in the heart following ischemia. Isolated hearts of mice were subjected to 15 min of global ischemia and 90 min of reperfusion. We employed hearts of various mice knock-out strains (interleukin-6(-/-), matrix metalloprotease-7(-/-), mast-cell deficient WBB6F1-Kit(W)/Kit(W-v), TNF-R1(-/-)) and wildtype mice, the latter perfused without and with infusion of cycloheximide or TNFalpha-cleaving-enzyme inhibitor (TAPI-2). Normoxic control hearts showed basal release of TNFalpha during the whole experiment. Immunohistology identified cardiac mast cells, macrophages and endothelial cells as main sources. TNFalpha release was stimulated during postischemic reperfusion, occurring in a two-peak pattern: directly after ischemia (0-10 min) and again after 60-90 min. The first peak mainly reflects tissue washout of TNFalpha accumulated during ischemia. The second, protracted peak arose continuously from the basal level and was abolished by protein synthesis inhibitor cycloheximide. Both properties are characteristic for de novo synthesis of TNFalpha, e.g., in cardiac muscle cells. However, immunohistological staining for TNFalpha failed in cardiomyocytes after 90 min of reperfusion. In contrast to hearts of TNF-R1(-/-) and Kit(W/W-v)-mice, those of IL-6(-/-) and MMP-7(-/-) mice lacked the late TNFalpha peak. TAPI did not suppress release of TNFalpha. While autostimulation via TNF-R1 also does not seem obligatory and mast cell can be ignored as source of the second peak, IL-6 may support de novo synthesis of TNFalpha. Additionally, TNFalpha release may essentially involve cleavage of membrane bound TNFalpha by MMP-7.