Cardiovascular prevention: lifestyle and statins--competitors or companions?

Favourable lifestyles promote cardiovascular protection. Exercise can induce beneficial changes in the genome that decrease low-density lipoprotein cholesterol (LDL-C) and increase anti-inflammatory markers. The Mediterranean dietary pattern, fortified by nuts, while not reducing weight, reduces mortality. Lifestyle changes combined with statin therapy provide potent protection against coronary heart disease, especially when used for secondary prevention after cardiovascular events. Decisions regarding the initiation of statin therapy for primary prevention are more difficult, requiring consideration of both the LDL-C level and the degree of cardiovascular risk for dyslipidaemic patients. Combining intensive exercise and statin therapy substantially reduces the mortality risk, and thus is potentially the ideal risk-reducing combination.

Sodium glucose co-transporter 2 (SGLT2) inhibitors: new among antidiabetic drugs.

Type 2 diabetes is characterized by decreased insulin secretion and sensitivity. The available oral anti-diabetic drugs act on many different molecular sites. The most used of oral anti-diabetic agents is metformin that activates glucose transport vesicles to the cell surface. Others are: the sulphonylureas; agents acting on the incretin system; GLP-1 agonists; dipetidylpeptidase-4 inhibitors; meglinitide analogues; and the thiazolidinediones. Despite these many drugs acting by different mechanisms, glycaemic control often remains elusive. None of these drugs have a primary renal mechanism of action on the kidneys, where almost all glucose excreted is normally reabsorbed. That is where the inhibitors of glucose reuptake (sodium-glucose cotransporter 2, SGLT2) have a unique site of action. Promotion of urinary loss of glucose by SGLT2 inhibitors embodies a new principle of control in type 2 diabetes that has several advantages with some urogenital side-effects, both of which are evaluated in this review. Specific approvals include use as monotherapy, when diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications, or as add-on therapy with other anti-hyperglycaemic medicinal products including insulin, when these together with diet and exercise, do not provide adequate glycemic control. The basic mechanisms are improved ß-cell function and insulin sensitivity. When compared with sulphonylureas or other oral antidiabetic agents, SGLT2 inhibitors provide greater HbA1c reduction. Urogenital side-effects related to the enhanced glycosuria can be troublesome, yet seldom lead to discontinuation. On this background, studies are analysed that compare SGLT2 inhibitors with other oral antidiabetic agents. Their unique mode of action, unloading the excess glycaemic load, contrasts with other oral agents that all act to counter the effects of diabetic hyperglycaemia.

The effect of left ventricular remodelling on soluble ST2 in a cohort of hypertensive subjects.

Soluble ST2 is a biomarker of cardiomyocyte stretch that is useful in the diagnosis and prognosis of coronary artery disease. Its role in the field of hypertension and hypertensive heart failure (HHF) has not yet been well investigated. We studied the effect of left ventricular remodelling on the concentration of soluble ST2 in a cohort of 210 subjects with hypertension (HT). Left ventricular hypertrophy (LVH) was considered present when echocardiographic left ventricular mass indexed for height in metres (m) was greater than 46.2 g m(-1 2.7) in women and 49.2 g m(-1 2.7) in men. Subjects were subdivided into three groups: those without LVH (HT, n = 83); those with LVH (hypertension with left ventricular hypertrophy (HTLVH), n = 50) and those with HHF, n=77). Plasma ST2 and NT-pro BNP were measured using electrochemiluminescence type immunoassay. Subjects with HHF had higher plasma ST2 concentrations compared to HTLVH (134.7 ± 57.3 ng ml(-1) versus 23.0 ± 8.3 ng ml(-1), P < 0.001) and those with HT (134.7 ± 57.3 ng ml(-1) versus 14.5 ± 4.9 ng ml(-1), P < 0.0001). NT-pro BNP levels were similar when HTLVH was compared with HT (P = 0.68), but subjects with HHF had significantly higher NT-pro BNP compared to HTLVH (P < 0.0002). Soluble ST2 had strong correlation with clinical and echocardiograhic parameters, and correlated well with NT-pro BNP (r = 0.41, P < 0.0001). Plasma ST2 is a useful biomarker in not only differentiating HHF from HT with or without LVH, but also distinguishes hypertensive LVH from HT without LVH.

Hypertension, the changing pattern of drug usage.

Gradually the pattern of use of antihypertensive drug agents has changed, from prime use of diuretics and beta-blockers, to preference for the inhibitors of the renin-angiotensin system and the calcium channel blockers. In assessing the value of potentially conflicting evidence, attention should be paid to the hierarchy of evidence, which works its way up through 10 steps from isolated case reports to integrated knowledge.

A role for the RISK pathway and K(ATP) channels in pre- and post-conditioning induced by levosimendan in the isolated guinea pig heart.

BACKGROUND AND PURPOSE: Myocardial reperfusion injury prevents optimal salvage of the ischaemic myocardium, and adjunct therapy that would significantly reduce reperfusion injury is still lacking. We investigated whether (1) the heart could be pre- and/or post-conditioned using levosimendan (levosimendan pre-conditioning (LPC) and levosimendan post-conditioning (LPostC)) and (2) the prosurvival kinases and/or the sarcolemmal or mitochondrial K(ATP) channels are involved. EXPERIMENTAL APPROACH: Isolated guinea pig hearts were treated with two 5 min cycles of levosimendan (0.1 microM) interspersed with vehicle perfusion, or two 5 min cycles of ischaemia/reperfusion, before coronary artery ligation (CAL) for 40 min at 36.5 degrees C. Hearts were treated with mitochondrial or sarcolemmal K(ATP) channel blockers before LPC or LPostC. For post-conditioning, hearts received three 30 s cycles of ischaemia/reperfusion or levosimendan/vehicle. Hearts were pretreated with levosimendan immediately before CAL (without washout). Cardiac function, infarct size and reperfusion injury salvage kinase activity was assessed. KEY RESULTS: LPC and LPostC halved the infarct size compared with controls (P<0.05). Treatment with K(ATP) channel blockers before LPC or LPostC reversed this decrease. Pretreating hearts with levosimendan increased activity of extracellular signal-regulated kinase (ERK) 42/44 on reperfusion and had the most marked infarct-lowering effect (P<0.05). CONCLUSIONS AND IMPLICATIONS: (1) Hearts could be pharmacologically pre- and post-conditioned with levosimendan; (2) levosimendan pretreatment is the most effective way to reduce infarct size, possibly by increasing ERK 42/44 activity; (3) benefits of LPC and LPostC were abolished by both K(ATP) channel blockers and (4) LPC may be useful before elective cardiac surgery, whereas LPostC may be used after acute coronary artery events.

Beta-blockers for hypertension.

BACKGROUND: Two recent systematic reviews found first-line beta-blockers to be less effective in reducing the incidence of stroke and the combined endpoint of stroke, myocardial infarction, and death compared to all other antihypertensive drugs taken together. However, beta-blockers might be better or worse than a specific class of drugs for a particular outcome measure so that comparing beta-blockers with all other classes taken together could be misleading. In addition, these systematic reviews did not assess the tolerability of beta-blockers relative to other antihypertensive medications. We thus undertook this review to re-assess the place of beta-blockade as first-line therapy for hypertension relative to each of the other major classes of antihypertensive drugs. OBJECTIVES: To quantify the effectiveness and safety of beta-blockers on morbidity and mortality endpoints in adults with hypertension. SEARCH STRATEGY: We searched eligible studies up to June 2006 in the Cochrane Controlled Trials Register, Medline, Embase, and reference lists of previous reviews, and by contacting hypertension experts. SELECTION CRITERIA: We selected randomised controlled trials which assessed the effectiveness of beta-blockers compared to placebo, no therapy or other drug classes, as monotherapy or first-line therapy for hypertension, on mortality and morbidity endpoints in men and non-pregnant women aged 18 years or older. DATA COLLECTION AND ANALYSIS: At least two authors independently applied study selection criteria, assessed study quality, and extracted data; with differences resolved by consensus. We expressed study results as relative risks (RR) with 95% confidence intervals (CI) and conducted quantitative analyses with trial participants in groups to which they were randomly allocated, regardless of which or how much treatment they actually received. In the absence of significant heterogeneity between studies (p>0.1), we performed meta-analysis using a fixed effects method. Otherwise, we used the random effects method and investigated the cause of heterogeneity by stratified analysis. In addition, we used the Higgins statistic (I(2)) to quantify the amount of between-study variability in effect attributable to true heterogeneity rather than chance. MAIN RESULTS: Thirteen randomised controlled trials (N=91,561 participants), which met our inclusion criteria, compared beta-blockers to placebo or no treatment (4 trials with 23,613 participants), diuretics (5 trials with 18,241 participants), calcium-channel blockers (CCBs: 4 trials with 44,825 participants), and renin-angiotensin system (RAS) inhibitors (3 trials with 10,828 participants). The risk of all-cause mortality was not different between first-line beta-blockers and placebo (RR 0.99, 95%CI 0.88 to 1.11, I(2)=0%), diuretics or RAS inhibitors, but was higher for beta-blockers compared to CCBs (RR 1.07, 95%CI 1.00 to 1.14, I(2)=2.2%; ARI=0.5%, NNH=200). The risk of total cardiovascular disease (CVD) was lower for first-line beta-blockers compared to placebo (RR 0.88, 95%CI 0.79 to 0.97, I(2)=21.4%, ARR=0.7%, NNT=140). This is primarily a reflection of the significant decrease in stroke (RR 0.80, 95%CI 0.66 to 0.96; I(2)=0%; ARR=0.5%, NNT=200); coronary heart disease (CHD) risk was not significantly different between beta-blockers and placebo. The effect of beta-blockers on CVD was significantly worse than that of CCBs (RR 1.18, 95%CI 1.08 to 1.29, I(2)=0%; ARI=1.3%, NNH=80), but was not significantly different from that of diuretics or RAS inhibitors. Increased total CVD was due to an increase in stroke compared to CCBs (RR 1.24, 95%CI 1.11 to 1.40, I(2)=0%; ARI=0.6%, NNH=180). There was also an increase in stroke with beta-blockers as compared to RAS inhibitors (RR 1.30, 95%CI 1.11 to 1.53, I(2)=29.1%; ARI=1.5%, NNH=65). CHD was not significantly different between beta-blockers and diuretics or CCBs or RAS inhibitors. In addition, patients on beta-blockers were more likely to discontinue treatment due to side effects than those on diuretics (RR 1.86, 95%CI 1.39 to 2.50, I(2)=78.2%, ARI=6.4% NNH=16) and RAS inhibitors (RR 1.41, 95%CI 1.29 to 1.54, I(2)=12.1%; ARI=5.5%, NNH=18), but there was no significant difference with CCBs. AUTHORS' CONCLUSIONS: The available evidence does not support the use of beta-blockers as first-line drugs in the treatment of hypertension. This conclusion is based on the relatively weak effect of beta-blockers to reduce stroke and the absence of an effect on coronary heart disease when compared to placebo or no treatment. More importantly, it is based on the trend towards worse outcomes in comparison with calcium-channel blockers, renin-angiotensin system inhibitors, and thiazide diuretics. Most of the evidence for these conclusions comes from trials where atenolol was the beta-blocker used (75% of beta-blocker participants in this review). However, it is not known at present whether beta-blockers have differential effects on younger and elderly patients or whether there are differences between the different sub-types of beta-blockers.

Cardiologists are living through exciting times. The example of postconditioning to protect the human heart during revascularization.

The exciting work the group of Jennings, published in Circulation in 1986, has established a new and powerful form of cardioprotection, whereby exposure to short bouts of repeated ischemia interspersed by reperfusion protects from a subsequent prolonged and potentially very serious major ischemic attack. Similar protection by postconditioning can be achieved by short bursts of ischemia just after the onset of mechanical reperfusion in acute myocardial infarction. Of interest, it has taken almost 20 years of intense work to bring all the important preconditioning ideas to clinical reality in the form of postconditioning. Once cardiologists are fully awoken to the idea of attacking reperfusion induced myocardial cell death, then this area will be set to develop as a major and novel target in the therapy of acute myocardial infarction.

[Sphingolipid signaling: a potential pathway for TNF-alpha induced preconditioning]. / TNF alpha mime un effet de préconditionnement ischémique: un rôle pour la voie des sphingolipides.

Although cytokine activation has long been recognized to associate with cardiac ischemia and reperfusion, the concept that these cytokines may enhance some cardioprotective mechanisms has only recently been considered. Ischemic preconditioning is a biologic phenomenon that activates innate cytoprotective programs in the heart. Ischemic preconditioning has been described where a transient non-lethal ischemic "trigger" or endogenous molecules produced/released by ischemia enables the tissue to become more resistant/tolerant to subsequent potentially lethal ischemia. The mechanisms and signalling events involved in this cytoprotective program still remain obscure. Recently, it has been suggested that cytokine activation including tumour necrosis factor (TNF alpha) may play a key role in the preconditioned phenotype. Moreover, new studies have given the evidence that the exploration of cytokine-activated sphingolipid signalling pathways may enhance our understanding of the preconditioning program.

Increased glycolysis during ischaemia mediates the protective effect of glucose and insulin in the isolated rat heart despite the presence of cardiodepressant exogenous substrates.

BACKGROUND: Exogenous insulin is known to protect against ischaemia-reperfusion injury of the myocardium. We investigated whether these benefits of insulin could be explained by increased glycolysis during the ischaemic period, even in the presence of potentially cardiodepressant substrates such as fatty acids and lactate. Increased cardiac output during post-ischaemic reperfusion was used as a marker of protection by insulin. METHODS: Isolated hearts from fasted rats were subjected to 5 minutes of Langendorff perfusion followed by a 15-minute working heart pre-ischaemic perfusion with glucose (11 mmol/l), followed by a 30-minute 0.2 ml/min low-flow Langendorff ischaemic period, using glucose(11 mmol/l) or glucose plus fatty acids (1 mmol/l), or lactate (10 mmol/l), or lactate plus glucose as substrates. During reperfusion, the hearts were again perfused with glucose. Insulin (1 mU/ml), when added, was present throughout the experimental protocol. RESULT: Post-ischaemic reperfusion cardiac output recovery was depressed in hearts perfused with glucose plus fatty acids or with lactate alone, when compared with glucose alone (p<0.01). In each case, cardiac output improved (p < 0.01) with insulin pre-treatment despite added fatty acids, or in hearts perfused with lactate alone during ischaemia. Improved cardiac output could be linked to improved glucose uptake (p < 0.05) during ischaemia and increased pre-ischaemic glycogen stores (p < 0.01). In hearts perfused with lactate alone, increased glycolysis occurred via glycogen breakdown as confirmed by increased cardiac tissue lactate levels at the end o the ischaemic period. CONCLUSION: Insulin treatment before ischaemia and throughout ischaemia and reperfusion, abolished the depressant effects of fatty acids added to glucose or of lactate alone, on reperfusion cardiac output. The consistent feature common to the protective effects of insulin in the various conditions tested was increased glycolysis, whether achieved by increased glucose uptake during the ischaemic period or by glycogen preloading. Increased glycolysis could also explain the protective effect of glucose added to lactate in the absence of insulin.

Calcium channel blockers in hypertension: reappraisal after new trials and major meta-analyses.

This review evaluates the current position of calcium channel blockers (CCB) in antihypertensive treatment in the light of three major comparative studies and two extensive meta-analyses. The latter both show that CCB are equivalent to conventional (initial beta-blocker or diuretic therapy) when total and cardiovascular mortality are the end points. Divergent points between the meta-analyses include stroke and myocardial infarction (MI). One meta-analysis compared CCB with conventional therapy, to find a small 13% reduction in stroke and a small, nonsignificant 12% increase in MI. The other meta-analysis found a 26% increase in MI when CCB were compared with all other therapies including the angiotensin converting enzyme (ACE) inhibitors. This increase was most robust (P < .001) when comparing CCB with ACE inhibitors, consonant with proposed protective effects of ACE inhibitors on cardiovascular risk. At present, only the comparison of CCB with conventional therapy, and not that with ACE inhibitors, rests on secure comparative data. When cost is compelling, conventional therapy is less expensive. For the individual patient, issues of quality of life (for example, impotence with diuretics and beta-blockers) might be decisive. Nonetheless, beta-blockers are preferred in postinfarct patients or in those with heart failure or unstable angina (a contraindication to dihydropyridines in the absence of beta-blockade). In others, the benefits of only a borderline stroke reduction with CCB versus an equally borderline increase in MI should be evaluated for each individual patient, taking into account the age group and the patient's preferences. In conclusion, overall CCB are neither better nor worse than conventional therapy, allowing for possible small differences in stroke and MI. The ACE inhibitors may protect better, although data are incomplete.

The choice of first-line therapy: rationale for low-dose combinations of an angiotensin converting enzyme inhibitor and a diuretic.

More than 50% of patients with mild uncomplicated hypertension will need combination therapy to reach target blood pressure, as defined by the Joint National Committee. This percentage is even higher in hypertensive patients with diabetes, renal impairment and congestive heart failure in whom target blood pressures are lower. Combination therapy of angiotensin converting enzyme inhibitor and low dose diuretic offers distinct advantages in the treatment of essential hypertension. The two drug classes may have a synergistic effect on hypertensive target organ disease and blood pressure. Triple therapy with a calcium antagonist may be needed to achieve blood pressure control in more severely hypertensive patients.

Relation of cyclic nucleotide ratios to ischemic and reperfusion injury in nitric oxide-donor treated rat hearts.

Nitric oxide (NO) donors given during ischemia possibly protect the myocardium by increasing tissue cyclic guanosine monophosphate (cGMP) and decreasing cytosolic Ca2+ levels. However, NO donors also elevate ischemic cyclic adenosine monophosphate (cAMP) levels, which exacerbates ischemic-reperfusion injury. The authors propose that suppression of this NO donor-induced increase in cAMP would improve the cardioprotective properties of these compounds. Langendorff perfused rat hearts were treated with sodium nitroprusside (SNP, 0.1 mM ) or glyceryl trinitrate (GTN, 1.0 microM ) and/or adenylyl cyclase (SQ, 50 microM ) or guanylyl cyclase (ODQ, 30-300 microM ) inhibitors during 40-min low-flow (0.2 ml/min) ischemia. Control reperfusion rate-pressure product (RPP) recoveries were 47 +/- 3% (n = 9) and improved to 59 +/- 1% (n = 11) (p < 0.05) with SNP treatment. Ischemic ODQ treatment decreased RPP recovery to 33 +/- 3% (n = 10) (p < 0.05). ODQ eliminated the cardioprotective effects of SNP (RPP recovery: 40 +/- 5% [n = 7] vs. 59 +/- 1% [p < 0.05]). Adenylyl cyclase inhibition improved RPP recovery from 59 +/- 1% (SNP) to 72 +/- 4% (SNP + SQ) (n = 11) (p < 0.05). The authors conclude that (a) suppression of the NO donor-induced elevations in ischemic cGMP levels (ODQ) worsened reperfusion RPP, (b) suppression of the NO donor-induced elevation in ischemic cAMP levels (SQ) further improved reperfusion RPP in NO donor-treated hearts, and (c) the severity of ischemic-reperfusion injury in the NO donor-treated heart was inversely related to ischemic-tissue cGMP levels and often directly related to the ischemic-tissue cAMP-to-cGMP ratio.

Screening for primary aldosteronism--normal ranges for aldosterone and renin in three South African population groups.

OBJECTIVE: To establish normal ranges for plasma aldosterone, renin and aldosterone/renin (A/R) ratio in South African normotensives under typical outpatient conditions, and to estimate the prevalence of primary aldosteronism (PA) among hypertensives in primary care settings. DESIGN AND METHODS: One hundred and thirty-six normotensive subjects and 154 sex- and age-matched hypertensives at three primary care clinics had measurements of blood pressure, plasma creatinine, K+, aldosterone, plasma renin activity, and spot urine for urinary Na+/creatinine ratio. Medication was not withdrawn before testing. RESULTS: Mean plasma renin activity in black normotensive subjects (0.95 +/- 1.25 ng/ml/h, mean +/- standard deviation (SD)) was significantly lower than in white (2.09 +/- 1.12 ng/ml/h; P < 0.0001) and coloured (1.81 +/- 1.86 ng/ml/h, P = 0.013) normotensives. Mean plasma aldosterone in black normotensives (306 +/- 147 pmol/l) was also significantly lower than in white (506 +/- 324 pmol/l, P = 0.0002) and coloured (418 +/- 304 pmol/l, P = 0.0148) normotensives. In hypertensives, there were no significant differences in renin or aldosterone levels between the three population groups. Urinary Na+/creatinine ratios, an index of Na+ intake, were not significantly different in the three population groups. None of the normotensives had an A/R ratio > or = 1,000 plus aldosterone > or = 750, while 7.1% of hypertensives exceeded these levels, suggesting that they are appropriate criteria for screening for PA. CONCLUSIONS: A large fraction of black normotensive subjects had low renin and aldosterone levels compared with whites, suggesting a salt-retaining tendency in black subjects. These results have important implications for the interpretation of plasma renin and aldosterone levels in hypertensive patients. In primary care settings, 7.1% of hypertensives had biochemical results indicating the need for investigation of PA.

Nicorandil decreases postischemic actin oxidation.

This study examined the hypothesis that preconditioning can decrease postischemic oxidative protein damage. Isolated rat hearts were subjected to 25 min of normothermic global ischemia followed by 45 min of reperfusion. These were compared with hearts pretreated with 20 microM nicorandil or preconditioned with two cycles of ischemia. Changes in the high energy phosphates, ATP and phosphocreatine, were followed using (31)P-NMR spectroscopy. Protein carbonyls were assessed using an immunoblot technique. Postischemic hemodynamic function and high energy phosphates recovered to significantly (p <.05) higher levels in nicorandil-treated and ischemic preconditioned hearts as compared to controls. Postischemic protein carbonyl formation was highest in control reperfused hearts but reduced to intermediate between control and preischemic hearts by ischemic preconditioning and virtually prevented by nicorandil pretreatment, with a prominent band at 43 kDa significantly affected (p <.05). Based on immunoshift and immunoprecipitation studies, this band was identified as a mixture of actin isoforms. These studies support the conclusion that nicorandil diminishes protein oxidative damage in general, and specifically actin oxidation, which in the presence of improved supply of high energy phosphates, leads to enhanced postischemic contractile function.