Eligibility for sacubitril/valsartan in heart failure across the ejection fraction spectrum: real-world data from the Swedish Heart Failure Registry.

BACKGROUND: Randomized controlled trials (RCT) generalizability may be limited due to strict patient selection. OBJECTIVE: In a real-world heart failure (HF) population, we assessed eligibility for sacubitril/valsartan based on PARADIGM-HF (sacubitril/valsartan effective)/PARAGON-HF [sacubitril/valsartan effective in mildly reduced ejection fraction (EF)]. METHODS: Outpatients from the Swedish HF Registry (SwedeHF) were analysed. In SwedeHF, EF is recorded as <30, 30-39, 40-49 and ≥50%. In PARAGON-HF, sacubitril/valsartan was effective with EF ≤ 57% (i.e. median). We defined reduced EF/PARADIGM-HF as EF < 40%, mildly reduced EF/PARAGON-HF ≤ median as EF 40-49%, and normal EF/PARAGON-HF > median as EF ≥ 50%. We assessed 2 scenarios: (i) criteria likely to influence treatment decisions (pragmatic scenario); (ii) all criteria (literal scenario). RESULTS: Of 37 790 outpatients, 57% had EF < 40%, 24% EF 40-49% and 19% EF ≥ 50%. In the pragmatic scenario, 63% were eligible in EF < 50% (67% for EF < 40% and 52% for 40-49%) and 52% in EF ≥ 40% (52% for EF ≥ 50%). For the literal scenario, 32% were eligible in EF < 50% (38% of EF < 40%, 20% of EF 40-49%) and 22% in EF ≥ 40% (25% for EF ≥ 50%). Eligible vs. noneligible patients had more severe HF, more comorbidities and overall worse outcomes. CONCLUSION: In a real-world HF outpatient cohort, 81% of patients had EF < 50%, with 63% eligible for sacubitril/valsartan based on pragmatic criteria and 32% eligible based on literal trial criteria. Similar eligibility was observed for EF 40-49% and ≥50%, suggesting that our estimates for EF < 50% may be reproduced whether or not a higher cut-off for EF is considered.

Cardiovascular disease in women, is it different to men? The role of sex hormones.

Cardiovascular disease in women differs in clinical presentation, pathophysiology and prognosis from that in men. The role of estrogens and androgens may help explain such sex dimorphisms, being involved in cardiac function, endothelial function and vascular tone. In particular, the cardioprotective effect of estrogen replacement therapy is observed in postmenopausal women in a time-dependent manner, i.e. when it is initiated at their first menopausal symptoms. Postmenopausal women, beyond aged men, may also benefit from testosterone supplementation therapy. Testosterone has been found to be an effective and safe therapy for elderly women with chronic heart failure. However, further studies are needed to clarify doses and routes of administration of androgens in postmenopausal women.

Androgens and cardiovascular disease in postmenopausal women: a systematic review.

Androgens play a pivotal role in cardiovascular function and their effects differ between men and women. In postmenopausal women, testosterone replacement within physiological levels is associated with overall well-being. However, a definitive explanation as to how androgens have an impact on cardiovascular health in postmenopausal women and whether they may be used for cardiovascular treatment has yet to be established. With these aims, a systematic review of the existing studies on the link between androgens and cardiovascular disease and the effects of testosterone therapy on cardiovascular outcomes in postmenopausal women has been conducted. The few existing studies on cardiovascular outcomes in postmenopausal women indicate no effect or a deleterious effect of increasing androgens and increased cardiovascular risk. However, there is evidence of a favorable effect of androgens on surrogate cardiovascular markers in postmenopausal women, such as high density lipoprotein cholesterol, total cholesterol, body fat mass and triglycerides. Further studies are therefore needed to clarify the impact of therapy with androgens on cardiovascular health in postmenopausal women. The cardiovascular effect of testosterone or methyltestosterone with or without concomitant estrogens needs to be elucidated.

Effects of testosterone on the Q-T interval in older men and older women with chronic heart failure.

The Q-Tc interval duration on the electrocardiogram is recognized to differ between the sexes. In vitro data and data from humans before and after puberty and menopause suggest that sex hormones play a role in the longer Q-Tc intervals in women, or conversely, the shorter Q-Tc intervals in men. Direct investigations of sex hormone effects on the Q-Tc interval in humans, however, are limited and reach conflicting conclusions. Our objective was to determine effects of testosterone on ECG Q-T intervals of older men and older women. ECG's from 84 older men and older women in double-blind placebo-controlled investigations of testosterone supplementation for the treatment of chronic heart failure (CHF) were analysed. Thirty men received 1000mg intramuscular long-acting testosterone undecanoate and 28 men received saline at 0, 6 and 12weeks. ECG's were recorded at baseline and 12weeks. Sixteen women received transdermal testosterone (33µg) and 10 women received matching placebo twice weekly for 24 weeks with ECG's at baseline and after 24weeks. Testosterone, but not placebo, shortened Q-T and Q-Tc intervals without heart rate changes. Q-T intervals decreased from 385±28 (mean±SD) to 382±28 ms (p<0.002) and Q-Tc intervals decreased from 398±26 to 392±27 (p<0.006) in men on testosterone. In women, Q-T intervals decreased from 400±25 to 397±23ms (p=0.06) and Q-Tc intervals from 415±26 to 409±27ms (p=0.3) on testosterone. Q-T intervals were longer in women compared with men under all conditions (p<0.03). The data support a direct effect of testosterone to shorten Q-T intervals in older men and older women in the absence of HR changes or hypogonadal status. Mean decreases are small and unlikely to affect risks of arrhythmic events in patients receiving Q-T prolonging medications.

Gender-specific aspects in primary and secondary prevention of cardiovascular disease.

Gender differences in biological substrates of disease determine different clinical manifestations of CV disease with important implications for prevention, diagnosis and therapy in the two sexes. In women, the activity of sex hormones reduces the influence of CV risk factors during the reproductive age, and delays the onset of CHD of 2 decades compared to men. However, women as men suffer from CV events, and in women mortality from all CV causes and have greater than the sum of the others 7 causes of death together. Women are more likely than men to die of a first myocardial infarction a probability of developing heart failure or a second infarction than their male counterparts. The levels of lipid components vary in different ages of life and in the two genders. TC and LDL increase in men between 35 and 50 years of age. On the contrary LDL levels do not change significantly in fertile women in which they have a lower predictive value for CHD than in men, HDL levels are higher in premenopausal women than in men of the same age and their role in predicting CHD is considerably higher in women. High triglycerides and Lp(a) are more important as a risk factor in women than in men. Because of the greater incidence of cardiovascular diseases in men until the early 80s, the information about the importance of risk factors associated with an increased risk of cardiovascular events has been gathered mainly in men and transferred to women. Most studies on lipid-lowering therapy did not have the adequate statistical power to show significant reductions in CV events in women. Regarding the indications for use of statins in daily practice, current data suggest that in secondary prevention statins are equally effective in both genders while in primary prevention the CV benefits of lipid-lowering therapy in women are less clear than in men and therefore should be used according to the degree of risk calculated from the available score systems.

Cardiovascular aspects of menopausal hormone replacement therapy.

Cardiovascular disease is the leading cause of death in postmenopausal women in Western countries. Despite preventive strategies, in the past decades, the incidence of cardiovascular events has shown a decline in men but a rise in women, matching the growth of the population of postmenopausal women. Several epidemiological findings suggest the causative role of ovarian hormone deficiency in the development of cardiovascular disease in women. Observational and randomized studies have suggested that initiation of hormone replacement therapy in early postmenopause could be beneficial from a cardiovascular point of view. Conversely, aging, time since menopause and presence of cardiovascular risk factors or cardiovascular disease may decrease its efficacy and increase the risk of cardiovascular events. It is plausible that the unfavorable effects of the estrogen/progestin combination used in the randomized studies are not related to the hormone preparation per se but rather to the use of hormones in the less receptive group of women, older and with cardiovascular risk factors. Clinical judgement, choice of the right dose and estrogen/progestin combination are of pivotal importance to maximize the beneficial effect of estrogen or estrogen-progestin replacement therapy, especially if given within a reasonably short time after the menopause to those women that need this therapy for the relief of menopausal symptoms. In these women, continuation of estrogen or estrogen-progestin replacement therapy may be beneficial.

Chronic administration of Sildenafil improves markers of endothelial function in men with Type 2 diabetes.

OBJECTIVE: Diabetic patients have a reduced endothelial response to phosphodiesterase-5 inhibitors. The aim of this study was to determine the effects of chronic therapy with sildenafil on endothelial function in patients with Type 2 diabetes mellitus (DM2). METHODS: In a double-blind, placebo-controlled parallel design, 20 patients without erectile dysfunction randomly received a loading dose of sildenafil (100 mg) for 3 days, followed by either sildenafil 25 mg three times a day (t.d.s.) for 4 weeks or sildenafil 25 mg t.d.s. for 4 days followed by placebo t.d.s. for 3 weeks. RESULTS: After 1 week, flow-mediated dilatation (FMD) improved significantly (> 50% compared with baseline) in patients allocated to both sildenafil arms (62 and 64%, respectively). In patients allocated to chronic sildenafil, a progressive increase in percentage of patients with FMD improvement was noted (78, 86 and 94% at 2, 3 and 4 weeks, respectively) while a progressive decrease in the placebo group occurred (45, 18 and 6% at 2, 3 and 4 weeks, respectively). At the end of the study, a significant improvement in FMD compared with baseline was noted after chronic sildenafil (FMD from 6.8 +/- 0.5 to 12.5 +/- 0.7%, P = 0.01 vs. baseline). A decrease in endothelin-1 levels and an increase in nitrite/nitrate levels were found after chronic sildenafil; significant changes from baseline in C-reactive protein, interleukin 6, intercellular adhesion molecule and vascular adhesion molecule levels were also found. CONCLUSIONS: In DM2 patients, daily sildenafil administration improves endothelial function and reduces markers of vascular inflammation, suggesting that the diabetes-induced impairment of endothelial function may be improved by prolonged phosphodiesterase-5 inhibition.

Gender-specific characteristics of atherosclerosis in menopausal women: risk factors, clinical course and strategies for prevention.

Cardiovascular disease is the leading cause of mortality and morbidity in women after the age of 50 years in most developed countries. Epidemiology, symptoms and progression of cardiovascular disease are different in women than in men. Indeed, women develop cardiovascular disease when they are about 10 years older than men and typically after the menopause. Risk factors have a different impact in determining cardiovascular risk in the two sexes. In men, cholesterol is more important than in women, in whom arterial hypertension, diabetes and their combination has a greater importance in determining cardiovascular risk. Menopause is an important cardiovascular risk factor both for the negative effect of ovarian hormone deprivation on cardiovascular function and for the consequent worsening of cardiovascular risk factors. Marked gender differences also exist in the clinical manifestations of atherosclerosis and in the pattern of symptoms in the two sexes. Angina, the most common manifestation of coronary heart disease, is frequently uncomplicated in women, whereas in men it tends to evolve to an acute coronary syndrome. The clinical presentation of acute ischemic syndromes is also different in men and women and, because of the frequent atypical symptoms, women tend to underestimate the importance of them. Because of the different impact of cardiovascular risk factors in men and women, the strategies for prevention should be different in the two sexes. In women, the control of blood pressure and glucose metabolism should be a priority. Furthermore, hormone replacement therapy may still have a role in the prevention of cardiovascular diseases if given to the right woman and at the right time.

Menopause and cardiovascular disease: the evidence.

Menopause is a risk factor for cardiovascular disease (CVD) because estrogen withdrawal has a detrimental effect on cardiovascular function and metabolism. The menopause compounds many traditional CVD risk factors, including changes in body fat distribution from a gynoid to an android pattern, reduced glucose tolerance, abnormal plasma lipids, increased blood pressure, increased sympathetic tone, endothelial dysfunction and vascular inflammation. Many CVD risk factors have different impacts in men and women. In postmenopausal women, treatment of arterial hypertension and glucose intolerance should be priorities. Observational studies and randomized clinical trials suggest that hormone replacement therapy (HRT) started soon after the menopause may confer cardiovascular benefit. In contrast to other synthetic progestogens used in continuous combined HRTs, the unique progestogen drospirenone has antialdosterone properties. Drospirenone can therefore counteract the water- and sodium-retaining effects of the estrogen component of HRT via the renin-angiotensin-aldosterone system, which may otherwise result in weight gain and raised blood pressure. As a continuous combined HRT with 17beta-estradiol, drospirenone has been shown to significantly reduce blood pressure in postmenopausal women with elevated blood pressure, but not in normotensive women. Therefore, in addition to relieving climacteric symptoms, drospirenone/17beta-estradiol may offer further benefits in postmenopausal women, such as improved CVD risk profile.

Low testosterone levels are associated with coronary artery disease in male patients with angina.

Historically, high androgen levels have been linked with an increased risk for coronary artery disease (CAD). However, more recent data suggest that low androgen levels are associated with adverse cardiovascular risk factors, including an atherogenic lipid profile, obesity and insulin resistance. The aim of the present study was to evaluate the relationship between plasma sex hormone levels and presence and degree of CAD in patients undergoing coronary angiography and in matched controls. We evaluated 129 consecutive male patients (mean age 58+/-4 years, range 43-72 years) referred for diagnostic coronary angiography because of symptoms suggestive of CAD, but without acute coronary syndromes or prior diagnosis of hypogonadism. Patients were matched with healthy volunteers. Out of 129 patients, 119 had proven CAD; in particular, 32 of them had one, 63 had two and 24 had three vessel disease, respectively. Patients had significantly lower levels of testosterone than controls (9.8+/-6.5 and 13.5+/-5.4 nmol/l, P<0.01) and higher levels of gonadotrophin (12.0+/-1.5 vs 6.6+/-1.9 IU/l and 7.9+/-2.1 vs 4.4+/-1.4, P<0.01 for follicle-stimulating hormone and luteinizing hormone, respectively). Also, both bioavailable testosterone and plasma oestradiol levels were lower in patients as compared to controls (0.84+/-0.45 vs 1.19+/-0.74 nmol/l, P<0.01 and 10.7+/-1.4 vs 13.3+/-3.5 pg/ml, P<0.05). Hormone levels were compared in cases with one, two or three vessel disease showing significant differences associated with increasing severity of coronary disease. An inverse relationship between the degree of CAD and plasma testosterone levels was found (r=-0.52, P<0.01). In conclusion, patients with CAD have lower testosterone and oestradiol levels than healthy controls. These changes are inversely correlated to the degree of CAD, suggesting that low plasma testosterone may be involved with the increased risk of CAD in men.

Managing cardiovascular risk in menopausal women.

Blood pressure control and prevention of glucose intolerance are primary factors in overcoming the increased cardiovascular risks in menopausal women. This heightened risk may partially be explained by the metabolic syndrome - a precursor of type 2 diabetes - in which the renin-angiotensin-aldosterone system may play a pivotal role. Once diabetes occurs, the cardiovascular risk is considerably greater in postmenopausal women than in men - especially if hypertension is also present. An additional risk factor, weight gain, is common in postmenopausal women not treated with hormone replacement therapy. Rigorous control of blood pressure has been shown to be particularly beneficial in women with metabolic syndrome; a reduction in blood pressure can reduce the mortality rate of ischemic stroke. The administration of hormone replacement therapy can also reduce the likelihood of coronary heart disease in postmenopausal women; therefore therapy should be started early in the menopausal transition to maximize cardiovascular protection. As such, an ideal hormone replacement therapy that can overcome hypertension, prevent body weight gain and control serum triglycerides offers an important advance in cardiovascular risk management during the menopause.

Metformin improves endothelial function in patients with metabolic syndrome.

BACKGROUND: Metabolic Syndrome (MS) is associated with impaired endothelial function and increased cardiovascular risk. Insulin resistance is a key feature of MS and plays an important role in the pathogenesis of endothelial dysfunction. Aim of the present study was to evaluate the effect of metformin on endothelial function and insulin resistance, assessed by the homeostasis model (HOMA-IR, homeostasis model assessment-insulin resistance), in patients with MS. METHODS: Sixty-five subjects (37 men and 28 women, mean age 54 +/- 6 years) with MS were allocated to receive metformin 500 mg twice daily (n = 32) or placebo (n = 33) for 3 months. Before and after treatment we assessed endothelial function, using flow-mediated dilatation of the brachial artery, and HOMA-IR. RESULTS: Patients who received metformin demonstrated statistically significant improvement in endothelium-dependent vasodilation compared with those treated with placebo (from 7.4 +/- 2.1% to 12.4 +/- 1.9% vs. 7.3 +/- 2.5% to 6.9 +/- 2.7%, P = 0.0016, metformin vs. placebo respectively), without significant effect on endothelium-independent response to sublingual glyceryl trinitrate (P =0.32). Metformin improved insulin resistance compared with placebo group (HOMA-IR from 3.39 to 2.5 vs. 3.42 to 3.37; 26% reduction in HOMA-IR, P = 0.01). An association between the improvement in insulin resistance and the improvement in endothelial function (r = -0.58, P = 0.0016) was found. CONCLUSION: Metformin improves both endothelial function and insulin resistance in patients with MS. These findings support the central role of insulin resistance in the development of endothelial dysfunction and the role of metformin for the treatment of patients with MS.

Effects of androgens on the cardiovascular system.

The evidence that men have a greater incidence of coronary artery disease than women of similar age, together with the fact that android fat distribution is associated with a greater incidence of coronary heart disease, have suggested that high testosterone levels are associated with an increased risk for coronary artery disease. The possible causal role of androgens in the development of cardiovascular disease has not been proven and, to date, there are no epidemiological and pathophysiological evidences to support that an hyper-androgenic state or androgen replacement is associated with cardiovascular disease in both sexes. Clinical studies have suggested that physiological testosterone supplementation in ageing males has a positive effect upon lipid profile. Additional potential protective cardiovascular effects of androgens may be related to their effect upon endothelial function and vasomotor tone. Few data are currently available on the correlation between plasma testosterone levels and coronary artery disease in men. Cross-sectional studies reported either reduced or similar plasma testosterone levels and/or androgens in patients with coronary artery disease as compared to controls without cardiovascular symptoms. Epidemiological studies addressing the importance of androgen levels upon cardiovascular mortality and morbidity have gathered inconclusive results. Prospective studies found no significant association between plasma testosterone and cardiac events in both sexes, while most cross-sectional studies have repetitively found an association between hypotestosteronemia and cardiovascular morbidity. In conclusion, androgens in general and testosterone in particular may have some protective effects on the cardiovascular system through their metabolic and direct effects upon human vasculature.

Comparative vascular effects of hormone replacement therapy and raloxifene in women at increased cardiovascular risk.

Hormone replacement therapy (HRT) improves endothelial function in postmenopausal women while the effects of raloxifene, a selective estrogen receptor modulator, are still under debate. The aim of this study was to evaluate endothelium-dependent flow-mediated vasodilatation in the brachial artery and plasma levels of nitrite, nitrate and endothelin-1 in 20 postmenopausal women with increased cardiovascular risk treated with either HRT or raloxifene for 4 weeks in a randomized double-blind single cross-over study. Patients had an endothelium-dependent flow-mediated dilatation of 4% prior to initiation of the study. Treatment with HRT resulted in a 67% increase in dilatation compared with baseline (from a 7.4% increase to a 12.4% increase, p < 0.01). Raloxifene treatment resulted in no change in vasodilatation from baseline. Endothelium-dependent dilatation was significantly improved by HRT compared with raloxifene treatment (12.4+/-0.6% vs. 6.1+/-2.0%; p < 0.01). Compared with baseline values, nitrate plus nitrite levels increased significantly (p < 0.05) with HRT but not with raloxifene. Similarly, endothelin-1 decreased from baseline with both treatments, but only the HRT-induced decrease was statistically significant (p < 0.05). In conclusion, HRT improved endothelial function and reduced plasma levels of endothelin-1 in postmenopausal women at risk of coronary artery disease. These beneficial effects were not shared by raloxifene.

Effects of estradiol on myocardial global performance index in hypertensive postmenopausal women.

The objective of this study was to assess the acute and chronic effects of estradiol on the myocardial performance index (MPI) in hypertensive postmenopausal women. There are conflicting reports on the effects of estrogen on left ventricular function in postmenopausal women, and we are unaware of any study on the myocardial performance index in the postmenopausal state. We undertook a prospective, randomized, double-blind, placebo-controlled study in 34 women, distributed into an estradiol group or a placebo group. After 90 min and at 12 weeks of administration of 1 mg of oral estradiol we evaluated, by Doppler echocardiography, its effects on the MPI. The estradiol group showed no alteration in the MPI after 90 min of the administration of estradiol. On the other hand, after 12 weeks of treatment we observed a statistically significant decrease of isovolumic relaxation time, from 127+/-23 ms to 106+/-16 ms (p < 0.001 and of the MPI from 0.63+/-0.13 to 0.48+/-0.09 (p < 0.01) and an increase in ejection time, from 297+/-32 ms to 330+/-31 ms (p < 0.01). In conclusion, estrogen replacement therapy over a period of 12 weeks showed a significant improvement in the MPI in hypertensive postmenopausal women, whereas the acute administration did not have any effect.

Effect of estradiol valerate alone or in association with cyproterone acetate upon vascular function of postmenopausal women at increased risk for cardiovascular disease.

OBJECTIVES: a large body of evidence has been accumulated suggesting that impairment of vascular endothelial function is an initial step in the development of atherosclerosis. Recent studies have shown that estrogen replacement therapy in postmenopausal women (PMW) improves endothelium-dependent, flow-mediated dilatation (FMD) while the cyclical adjunct of a progestin may reverse this effect. METHODS: the purpose of this study was to evaluate endothelium-dependent, FMD in the brachial artery and the plasma levels of Endothelin-1 in menopausal females treated with estradiol valerate with and without cyclical cyproterone acetate in 20 PMW (mean age 64+/-6 years) with more than one risk factor for coronary artery disease. After a baseline evaluation, PMW entered a double-blinded, placebo controlled single cross-over study and were randomized to receive either estradiol valerate (2 mg) for 21 days or estradiol valerate (2 mg) for 11 days and estradiol valerate (2 mg) and cyproterone acetate (1 mg) for 10 days. Patients were crossed-over the complementary treatment 7 days after completing the first treatment phase. The study of forearm blood flow was repeated at the end of each treatment period. RESULTS: estradiol valerate significantly increased FMD as compared with baseline (12+/-3 vs. 7+/-4%, P<0.01) the adjunct of cyproterone acetate did not affect the effect of estradiol valerate upon FMD (12+/-3 vs. 11+/-4%, P=NS). Similarly reactive hyperemic flow increased after estradiol valerate alone (24%) or in association with cyproterone acetate (24%) compared with baseline. Plasma levels of Endothelin-1 were significantly reduced by estradiol valerate alone or in association with cyproterone acetate. CONCLUSIONS: in conclusion hormone replacement therapy with estradiol valerate and cyproterone acetate improves endothelial function and reduces plasma levels of Endothelin-1 in PMW at risk of coronary artery disease. These effects may be relevant for cardioprotection.

Can menopause be considered an independent risk factor for cardiovascular disease?

Following the menopause, women develop coronary artery disease at the same rate as men. The best documented change observed in the risk factors linked to ovarian exhaustion is an alteration in lipid composition. More recent studies, however, suggest that the increased cardiovascular morbidity and mortality after menopause cannot be fully explained by changes in plasma lipoproteins, and support the concept that ovarian hormone deprivation has a widespread impact on the cardiovascular system, with a direct harmful effect on vessel-wall physiology. After the menopause, subjects free from cardiovascular diseases show vascular hyperactivity and a poor vasodilator reserve; the rate of increase in the incidence of arterial hypertension in women is higher than that observed among males of the same age; altogether, cardiovascular diseases become the number one cause of death among women. A large number of mechanistic studies have shown that estrogens, through either direct or genomic-dependent activities, produce beneficial effects on the factors controlling blood flow and plaque formation. Nevertheless, results from recent randomized clinical trials are challenging the belief that postmenopausal hormone therapy protects against coronary artery disease.