Elke Lehmkuhl

Gender differences in the metabolic syndrome and their role for cardiovascular disease

SummaryWomen live longer than men and develop cardiovascular disease (CVD) at an older age. The metabolic syndrome represents a major risk factor for the development of CVD, and gender1 differences in this syndrome may contribute to gender differences in CVD.In recent years, the metabolic syndrome has been more prevalent in men than in women. Prevalence is increasing and this increase has been steeper in women, particularly in young women, during the last decade. The contributions of the different components of the metabolic syndrome differ between genders and in different countries.In a recent survey in Germany, 40% of the adult population had been diagnosed with disturbed glucose tolerance or type 2 diabetes. Undiagnosed diabetes was more frequent in men than in women, and risk factors for undiagnosed diabetes differed between the sexes. Worldwide, in individuals with impaired glucose tolerance, impaired fasting glucose was observed more frequently in men, whereas impaired glucose tolerance occurred relatively more often in women. Lipid accumulation patterns differ between women and men. Premenopausal women more frequently develop peripheral obesity with subcutaneous fat accumulation, whereas men and postmenopausal women are more prone to central or android obesity. In particular, android obesity is associated with increased cardiovascular mortality and the development of type 2 diabetes. Visceral adipocytes differ from peripheral adipocytes in their lipolytic activity and their response to insulin, adrenergic and angiotensin stimulation and sex hormones. Visceral fat is a major source of circulating free fatty acids and cytokines, which are directly delivered via the portal vein to the liver inducing insulin resistance and an atherogenic lipid profile. Inflammation increases cardiovascular risk particularly in women. A relatively greater increase in cardiovascular risk by the appearance of diabetes in women has been reported in many studies.Thus, the presently available data suggest that the pathophysiology of the metabolic syndrome and its contribution to the relative risk of cardiovascular events and heart failure show gender differences, which might be of potential relevance for prevention, diagnostics, and therapy of the syndrome.

Gender Aspects of the Role of the Metabolic Syndrome as a Risk Factor for Cardiovascular Disease

BACKGROUND The interaction of the risk factors of abdominal obesity, disturbed glucose homeostasis, dyslipidemia, and hypertension is believed to represent a distinct entity, termed the metabolic syndrome (MetS), that leads to a greater increase in cardiovascular risk than does the sum of its components. OBJECTIVE We reviewed currently available information regarding gender differences in the role of the MetS as a risk factor for cardiovascular disease (CVD). METHODS Using the search terms women, men, sex, gender, sex differences, and gender differences in combination with the metabolic syndrome, we conducted a systematic review of the available literature on sex differences in the MetS. The National Institutes of Health, PubMed, and MEDLINE databases were searched retrospectively from 2007 to 1987. Reference lists of identified articles were also used as a source, and articles were not restricted to the English language. RESULTS In recent years, the MetS has been more prevalent in men than in women but has risen particularly in young women, where it is mainly driven by obesity. Diagnostic criteria for the MetS vary for the cutoff points and definition of its components in a gender-specific manner. Based on the definition of impaired glucose homeostasis and pathologic abdominal circumference or waist/hip ratio, more or fewer women are included. Glucose and lipid metabolism are directly modulated by estrogen and testosterone, with a lack of estrogen or a relative increase in testosterone inducing insulin resistance and a proatherogenic lipid profile. Hypertension is a strong risk factor in both sexes, but the prevalence of hypertension increases more rapidly in aging women than in men. Menopause and polycystic ovary syndrome contribute to the development of MetS by the direct effects of sex hormones. Some components of the MetS (eg, diabetes and hypertension) carry a greater risk for CVD in women. CONCLUSIONS Future gender-related clinical and research activities should focus on the identification of sex- and gender-specific criteria for risk management in patients with the MetS. We propose small, focused, mechanistic studies on sex-specific surrogate end points and sex-specific studies in animal models for diabetes and aging.

Regression of Myocardial Hypertrophy After Aortic Valve Replacement Faster in Women

Background— In patients with aortic stenosis, pressure overload induces cardiac hypertrophy and fibrosis. Female sex and estrogens influence cardiac remodeling and fibrosis in animal models and in men. Sex differences and their molecular mechanisms in hypertrophy regression after aortic valve replacement have not yet been studied. Methods and Results— We prospectively obtained preoperative and early postoperative echocardiography in 92 patients, 53 women and 39 men, undergoing aortic valve replacement for isolated aortic stenosis. We analyzed in a subgroup of 10 patients matrix gene expression in left ventricular (LV) biopsies. In addition, we determined the effect of 17&bgr;-estradiol on collagen synthesis in isolated rat cardiac fibroblasts. Preoperatively, women and men had similar ejection fraction. Similar percentages of women and men had increased LV diameters (37% and 38%). Women more frequently exhibited LV hypertrophy than men (women: 86%; men: 56%; P<0.01). Postoperatively, increased LV diameters persisted in 34% of men but only in 12% of women (P<0.023). LV hypertrophy reversed more frequently in women than in men, leading to a similar prevalence of LV hypertrophy after surgery (women: 45%; men: 36%). In surgical biopsies, men had significantly higher collagen I and III and matrix metalloproteinase 2 gene expression than women. In isolated rat cardiac fibroblasts, 17&bgr;-estradiol significantly increased collagen I and III gene expressions in male cells but decreased it in female cells. Conclusion— Women adapt to pressure overload differently from men. Less fibrosis before surgery may enable faster regression after surgery.

Screening for depression: Rasch analysis of the dimensional structure of the PHQ-9 and the HADS-D

BACKGROUND Both the depression modules of the Hospital Anxiety and Depression Scale (HADS-D) and the Patient Health Questionnaire (PHQ-9) are widely used for the screening of depression. We analyzed the dimensionality and the item fit of both scales individually and across the scales. Moreover, we sought to identify items which evidenced item response bias associated with age and gender. METHODS The depression subscales HADS-D and the PHQ-9 were administered to 1271 patients (mean age 67.2; 22.5% women) undergoing coronary artery bypass graft surgery (CABG). Rasch analyses were performed to assess the overall fit of the model, individual item fit and differential item functioning (DIF). RESULTS Rasch analysis revealed that the HADS-D and the PHQ-9 feature a common core construct containing six items of the HADS-D and three items of the PHQ-9. Two of these items are identical with the 2-item short form of the PHQ-9. In addition, fatigability was the only somatic item that fitted the model. No substantial DIF was observed. LIMITATIONS The generalizability of these results might be restricted to patients awaiting CABG. CONCLUSIONS The short form of the PHQ-9 seems to be an economic and valid instrument for the screening of depression, which indicates the same latent construct that is captured by six items of the HADS-D. Further studies are needed to evaluate whether the addition of fatigability might enhance the validity of the PHQ-2 in this patient population.

Incidence rates and predictors of major and minor depression in patients with heart failure

AIMS Depression is common in heart failure (HF) and associated with adverse outcomes. This study aimed to investigate incidence rates and predictors of depression in patients sampled from four subprojects of the German Competence Network Heart Failure. METHODS Eight hundred thirty nine symptomatic HF patients free of depression at baseline underwent repeat depression screening (Patient Health Questionnaire, PHQ-9) after 12 months. Ordered logistic regression analysis was employed to search for predictors of incident depression. RESULTS Incident minor (major) depression was observed in 61 (7.3%) and 47 (5.6%) of the population. Depression was recurrent in 15 (25%) and 16 (34%), respectively. Multiple regression analysis revealed seven variables predicting minor or major depression: Previous depressive episode (odds ratio [OR] 4.04, 95% confidence interval [CI] 2.37-6.89, p ≤ 0.001), previous resuscitation (OR 2.44, CI 1.23-4.81, p=0.010), current smoking (OR 2.06, CI 1.08-3.50, p=0.008), >4 visits/year to general practitioner (OR 1.67, CI 1.06-2.63, p=0.026), New York Heart Association class (OR 1.54/class, 95% CI 1.05-2.25, p=0.027), PHQ-9 baseline sum-score (OR 1.18/point, CI 1.11-1.27, p<0.001), and SF-36 physical functioning (OR 1.08/-5 points, CI 1.03-1.13, p=0.002). CONCLUSIONS In these HF patients initially free of depression annual incidence rates were high. Several independent predictors allowed identification of patients at particular risk. Although obtained in a selected cohort these findings call, in view of the grave prognosis of HF patients with comorbid depression, for regular depression screening and development of specific supportive strategies to improve patient care and outcomes in HF.

Heart Failure and its Treatment in Women Role of Hypertension, Diabetes, and Estrogen

AbstractLarge differences exist between women and men in the syndrome of heart failure (HF).In contrast to men, hypertension and diabetes represent the major risk factors for development of HF in women and hypertension is also the major cause of left ventricular hypertrophy and stroke. Left ventricular hypertrophy in women increases the risk for mortality to a higher degree than it does in men. The clinical course of HF is generally more benign and more frequently characterized by HF with preserved systolic function.Estrogen receptors are present in the human heart. Based on data from rodent models, they are believed to modulate hypertrophy and the progression of HF. Some of the signaling pathways have been described and involve phosphorylation of intracellular kinases and production of nitric oxide. Interestingly, estrogen receptors are upregulated in human hypertrophy and HF.The clinical course of HF in women is characterized by the more frequent occurrence of diastolic HF. Myocardial remodeling with age and, as a consequence, of mechanical load is different in both genders.Adherence to guidelines in the diagnosis and treatment of HF is less strict in women than in men, leading to undertreatment with inhibitors of the renin–angiotensin system. Women are generally underrepresented in clinical trials in HF and gender–specific analyses have been neglected in most older large survival trials. In some of the large survival studies angiotensin–converting enzyme inhibitors or β–receptor blockers did not reach significant endpoints in women. However, meta–analyses show overall positive effects for these groups of substances. Angiotensin receptor blockers were effective in large studies including high percentages of women.ZusammenfassungFrauen und Männer unterscheiden sich deutlich in den Risikofaktoren und dem Verlauf einer Herzinsuffizienz.Im Gegensatz zu Männern sind bei Frauen arterieller Hypertonus und Diabetes mellitus die führenden Risikofaktoren für die Entwicklung einer Herzinsuffizienz. Hypertonus ist bei Frauen auch die Hauptursache für linksventrikuläre Hypertrophie und Schlaganfall. Linksventrikuläre Hypertrophie tritt bei Frauen später auf, erhöht jedoch die Mortalität in stärkerem Maße als bei Männern. Der klinische Verlauf einer Herzinsuffizienz ist bei Frauen im Allgemeinen jedoch benigner und häufiger durch eine gut erhaltene systolische Ventrikelfunktion gekennzeichnet.Im weiblichen und männlichen menschlichen Herzen finden sich Östrogenrezeptoren. Aufgrund von Tiermodellen geht man heute davon aus, dass diese die Entstehung der myokardialen Hypertrophie und die Progression von Herzinsuffizienz modulieren. Einige der zugrundeliegenden Stoffwechselschritte sind mittlerweile bekannt und umfassen u.a. die Phosphorylierung intrazellulärer Kinasen und die Produktion von Stickstoffmonoxid (NO). Interessanterweise kommt es bei Hypertrophie und Herzinsuffizienz beim alten Menschen zu einer Zunahme der Östrogenrezeptoren im Myokard.Der klinische Verlauf einer Herzinsuffizienz ist bei Frauen durch das häufigere Auftreten einer diastolischen Funktionsstörung charakterisiert. Eine Ursache dafür ist möglicherweise, dass myokardiales Remodeling – Fibrose und Apoptose – im Alter und als Konsequenz mechanischer Belastung bei Frauen und Männern unterschiedlich verlaufen.Die Einhaltung von Leitlinien zur Diagnose und Therapie der Herzinsuffizienz wird bei Frauen weniger konsequent verfolgt als bei Männern. Frauen sind insgesamt in klinischen Studien zur Herzinsuffizienz unterrepräsentiert, und in fast allen älteren großen Überlebensstudien wurden keine geschlechtsspezifischen Auswertungen durchgeführt. In einigen Studien mit Angiotensin–Converting– Enzym–Hemmern erreichten Analysen hinsichtlich der Endpunkte keine statistische Signifikanz bei Frauen. Allerdings weisen Metaanalysen auf eine insgesamt positive Wirkung dieser Substanzgruppen bei Frauen hin. Für die β–Blocker wurde die Wirksamkeit bei Frauen in Metaanalysen belegt. Angiotensinrezeptorblocker erwiesen sich in großen Studien mit hohem Frauenanteil als effektive Therapie in der Behandlung der Herzinsuffizienz. Digitaliswirkungen sind in hohem Maß blutspiegelabhängig – es ist möglich, dass dies die Übersterblichkeit der Frauen unter Digitalistherapie erklärt.

Heart transplantation in women with dilated cardiomyopathy.

Background. Dilated cardiomyopathy (DCM) is responsible for over half of all heart transplants. Fewer women with DCM undergo heart transplants than men with DCM; the reasons for this state of affairs are unclear. Methods and Results. We analyzed prospectively a cohort of 698 DCM patients who were referred to our heart transplant center. Only 15.5% of them were women. Women and men did not differ in age or ejection fraction (24%). Women were more frequently in New York Heart Association class III-IV, had lower exercise tolerance, worse pulmonary function, and poorer kidney function (all P<0.05) than men. Women were less commonly diabetic (14% vs. 23%; P<0.05). Similar percentages of women and men who were referred were transplanted; the women spent less time on the waiting list (153±37 days for women and 314±29 days for men; P<0.05). The 10-year survival rate of women and men after transplantation was similar (57% and 45%, respectively; P<0.203). We compared our current data to our overall experience from 1985 till date (n=972), and also with the Eurotransplant heart dataset. Similar to our current findings, far lower percentages of DCM patients in both cohorts were women, although the 10-year survival of female and male DCM patients after transplantation was not different. Conclusions. Because women were referred with more severe heart failure but fewer relative contraindications, it seems that the option of transplantation is less intensely considered for women, particularly for those with comorbidities, by the referring physicians. Because women with DCM do as well as men after transplantation, efforts should be undertaken to improve referral of women.

Thrombosis and cable damage in the HeartWare pump: clinical decisions and surgical technique.

Exchange of the HeartWare HVAD made necessary by thrombosis or cable damage is rare, but it is a complex procedure associated with morbidity. Less invasive exchange procedures may contribute to faster postoperative recovery and early mobilization. Between September 2009 and April 2012, 225 patients (median age 55.4 years, range 7–82 years, 40 of them women) were supported with the HeartWare HVAD at our institution. Cumulative follow-up in all 225 patients was 151.9 patient/years. In six patients, early pump thrombosis (<30 days) requiring pump exchange occurred after a median time of 7 (2–9) days. In six patients, late pump thrombosis requiring pump exchange occurred after a median of 380 (84–705) days. The overall incidence was 5.3% with 0.079 thromboses per year. In two instances of accidental cable damage as a result of massive external mechanical impact, pump exchange was necessary. We describe a safe and less invasive technique for the explantation and exchange of the HeartWare HVAD through a left thoracotomy. Pump thrombosis of the HeartWare HVAD is a very rare condition caused mostly by new onset of heparin-induced thrombocytopenia type II, mismanagement of anticoagulation, or hypercoagulability in the case of severe sepsis. Since the introduction of the sintered inflow cannula no early thrombosis has occurred. Pump exchange in the case of hemolysis should not be delayed. The cable of the HeartWare HVAD is very reliable and breaks only after excessive external impact. A minimally invasive approach for pump exchange on cardiopulmonary bypass for pump thrombosis and off-pump for cable damage or pump explantation is recommended.

Herzinsuffizienz und ihre Behandlung bei Frauen. Rolle von Hochdruck, Diabetes und Östrogen

AbstractLarge differences exist between women and men in the syndrome of heart failure (HF).In contrast to men, hypertension and diabetes represent the major risk factors for development of HF in women and hypertension is also the major cause of left ventricular hypertrophy and stroke. Left ventricular hypertrophy in women increases the risk for mortality to a higher degree than it does in men. The clinical course of HF is generally more benign and more frequently characterized by HF with preserved systolic function.Estrogen receptors are present in the human heart. Based on data from rodent models, they are believed to modulate hypertrophy and the progression of HF. Some of the signaling pathways have been described and involve phosphorylation of intracellular kinases and production of nitric oxide. Interestingly, estrogen receptors are upregulated in human hypertrophy and HF.The clinical course of HF in women is characterized by the more frequent occurrence of diastolic HF. Myocardial remodeling with age and, as a consequence, of mechanical load is different in both genders.Adherence to guidelines in the diagnosis and treatment of HF is less strict in women than in men, leading to undertreatment with inhibitors of the renin–angiotensin system. Women are generally underrepresented in clinical trials in HF and gender–specific analyses have been neglected in most older large survival trials. In some of the large survival studies angiotensin–converting enzyme inhibitors or β–receptor blockers did not reach significant endpoints in women. However, meta–analyses show overall positive effects for these groups of substances. Angiotensin receptor blockers were effective in large studies including high percentages of women.ZusammenfassungFrauen und Männer unterscheiden sich deutlich in den Risikofaktoren und dem Verlauf einer Herzinsuffizienz.Im Gegensatz zu Männern sind bei Frauen arterieller Hypertonus und Diabetes mellitus die führenden Risikofaktoren für die Entwicklung einer Herzinsuffizienz. Hypertonus ist bei Frauen auch die Hauptursache für linksventrikuläre Hypertrophie und Schlaganfall. Linksventrikuläre Hypertrophie tritt bei Frauen später auf, erhöht jedoch die Mortalität in stärkerem Maße als bei Männern. Der klinische Verlauf einer Herzinsuffizienz ist bei Frauen im Allgemeinen jedoch benigner und häufiger durch eine gut erhaltene systolische Ventrikelfunktion gekennzeichnet.Im weiblichen und männlichen menschlichen Herzen finden sich Östrogenrezeptoren. Aufgrund von Tiermodellen geht man heute davon aus, dass diese die Entstehung der myokardialen Hypertrophie und die Progression von Herzinsuffizienz modulieren. Einige der zugrundeliegenden Stoffwechselschritte sind mittlerweile bekannt und umfassen u.a. die Phosphorylierung intrazellulärer Kinasen und die Produktion von Stickstoffmonoxid (NO). Interessanterweise kommt es bei Hypertrophie und Herzinsuffizienz beim alten Menschen zu einer Zunahme der Östrogenrezeptoren im Myokard.Der klinische Verlauf einer Herzinsuffizienz ist bei Frauen durch das häufigere Auftreten einer diastolischen Funktionsstörung charakterisiert. Eine Ursache dafür ist möglicherweise, dass myokardiales Remodeling – Fibrose und Apoptose – im Alter und als Konsequenz mechanischer Belastung bei Frauen und Männern unterschiedlich verlaufen.Die Einhaltung von Leitlinien zur Diagnose und Therapie der Herzinsuffizienz wird bei Frauen weniger konsequent verfolgt als bei Männern. Frauen sind insgesamt in klinischen Studien zur Herzinsuffizienz unterrepräsentiert, und in fast allen älteren großen Überlebensstudien wurden keine geschlechtsspezifischen Auswertungen durchgeführt. In einigen Studien mit Angiotensin–Converting– Enzym–Hemmern erreichten Analysen hinsichtlich der Endpunkte keine statistische Signifikanz bei Frauen. Allerdings weisen Metaanalysen auf eine insgesamt positive Wirkung dieser Substanzgruppen bei Frauen hin. Für die β–Blocker wurde die Wirksamkeit bei Frauen in Metaanalysen belegt. Angiotensinrezeptorblocker erwiesen sich in großen Studien mit hohem Frauenanteil als effektive Therapie in der Behandlung der Herzinsuffizienz. Digitaliswirkungen sind in hohem Maß blutspiegelabhängig – es ist möglich, dass dies die Übersterblichkeit der Frauen unter Digitalistherapie erklärt.

Gender Differences in Health-related Quality of Life After Coronary Bypass Surgery: Results From a 1-year Follow-up in Propensity-matched Men and Women

Objective: To examine whether the predictive value of gender for health-related quality of life (HRQoL) is independent of clinical health status and depression. Women undergoing coronary bypass surgery generally report a poorer HRQoL than men. Methods: A total of 990 (20% women) patients completed study questionnaires 1 day before coronary bypass surgery and 1 year after surgery. Physical aspects of HRQoL were assessed with the Short Form 36 Health Survey. Depression was measured with the self-reported Patient Health Questionnaire. Propensity score matching was applied to match men and women with respect to 65 clinical variables. Of 198 women, 157 (79.3%) could be matched to a partner, resulting in an excellent balance of clinical variables between the matched groups. Results: At baseline, propensity-matched men and women differed in physical functioning (p < .001) and role functioning (p = .007), but not in bodily pain and general health perception. In both men and women, HRQoL outcomes improved over 1 year. Preoperative depression predicted worse physical HRQoL in all outcomes, except general health perception 1 year after surgery. After adjusting for depression, gender lost its predictive power with respect to physical functioning. However, compared with women, men still reported a better role functioning. Conclusion: Our data suggest that gender is a marker for role functioning, independent of the clinical health status and depression. Rehabilitation measures designed for the specific needs of women might help to improve their HRQoL. CABG = coronary artery bypass graft; PF = physical functioning; RP = role functioning; BP = bodily pain; GH = general health; SF-36 = Medical Outcomes Study 36-Item Short Form Health Survey.