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Cardiovascular diseases (CVD) and mental health disorders (MHD; e.g. depression, anxiety and cognitive dysfunction) are highly prevalent and are associated with significant morbidity and mortality and impaired quality of life. Currently, possible interactions between pathophysiological mechanisms in MHD and CVD are rarely considered during the diagnostic work-up, prognostic assessment and treatment planning in patients with CVD, and research addressing bidirectional disease mechanisms in a systematic fashion is scarce. Besides some overarching pathogenetic principles shared by CVD and MHD, there are specific syndromes in which pre-existing neurological or psychiatric illness predisposes and contributes to CVD development (as in Takotsubo syndrome), or in which the distorted interplay between innate immune and central nervous systems and/or pre-existing CVD leads to secondary MHD and brain damage (as in peripartum cardiomyopathy or atrial fibrillation). Clinical manifestations and phenotypes of cardio-psycho-neurological diseases depend on the individual somatic, psychosocial, and genetic risk profile as well as on personal resilience, and differ in many respects between men and women. In this article, we provide arguments on why, in such conditions, multidisciplinary collaborations should be established to allow for more comprehensive understanding of the pathophysiology as well as appropriate and targeted diagnosis and treatment. In addition, we summarize current knowledge on the complex interactions between the cardiovascular and central nervous systems in Takotsubo syndrome and peripartum cardiomyopathy, and on the neurological and psychiatric complications of atrial fibrillation.

Heart failure is a systemic disease. As populations are aging worldwide, the prevalence and importance of comorbidities as major determinants of heart failure symptoms, disease progression and prognosis are increasing. Since the last version of the European Society of Cardiology guidelines for the diagnosis and treatment of heart failure was published in 2016, promising novel pharmacotherapies for chronic heart failure and its comorbidities and new device-based treatment and monitoring options have become available; however, the broad range of therapeutic options as well as the diagnostic and therapeutic implications of comorbidities render the treatment of heart failure increasingly more complex. This review aims to provide practical guidance for a rational up-to-date approach to the evidence-based management of heart failure.

Heart failure remains a frequent cause of death and is the leading reason for hospitalization in Germany although therapeutic options have significantly increased over the past years particularly in heart failure with reduced ejection fraction. Clinical symptoms are usually preceded by cardiac remodeling, which was originally defined only by left ventricular dilatation and depressed function but is also associated with typical cellular and molecular processes. Healing after acute myocardial infarction is characterized by inflammation, cellular migration and scar formation. Cardiac remodeling is accompanied by adaptive changes of the peripheral cardiovascular system. Since prevention is the primary goal, rapid diagnosis and treatment of myocardial infarction are mandatory. Early reperfusion therapy limits infarct size and enables the best possible preservation of left ventricular function. Standard pharmacotherapy includes angiotensin-converting enzyme inhibitors, angiotensin-1-receptor blockers and beta blockers. In addition, mineralocorticoid receptor antagonists have proven beneficial. Compounds specifically targeting infarct healing processes are currently under development.

Heart failure and depression are widespread diseases and of particular clinical and economic relevance. Compared with the general population depression is up to 5‑times more common in patients with heart failure, with adverse effects on morbidity, mortality, quality of life and treatment costs. Depressive symptoms overlap with those of heart failure which renders diagnosis difficult. Simple screening tools, e. g. the two-item patient health questionnaire, help to recognize depression in the clinical routine. To date, there is no evidence that antidepressant pharmacotherapy improves mood and clinical outcomes in patients with heart failure and comorbid depression and antidepressant pharmacotherapy remains to be decided on a case by case basis; however, physical training, cognitive behavioral therapy and multidisciplinary comprehensive disease management improved symptoms and/or prognosis in a limited number of randomized studies.

Heart failure (HF) is highly prevalent and associated with adverse outcomes and high costs. Compared with the general population, depression is up to five times more common in HF patients. Comorbid depression increases morbidity and mortality risk and health-care expenditures even further and decreases quality of life. Possible, often interrelated, mediators of these effects include biological, behavioral, and psychosocial factors. Screening instruments such as the self-administered PHQ-2 facilitate detection of patients at risk. Although antidepressants may improve psychological well-being, no positive effects on hard clinical endpoints have been demonstrated to date.

The management of heart failure patients (diagnosis, treatment monitoring, assessment of prognosis) crucially depends on the accuracy of the tools used for patient evaluation. While the diagnostic accuracy of anamnesis, clinical signs and symptoms is poor, "classic" tools like chest X-ray or electrocardiogram show reasonable specificity but poor sensitivity. Transthoracic echocardiography is well suited for the diagnosis of heart failure, but is relatively costly and depends on availability and the skills of the investigator. Over the last 2 decades, numerous biomarkers have emerged that potentially might aid in the complex decisionmaking processes for diagnosis, treatment and monitoring of heart failure. The ideal biomarker would possess a favorable diagnostic test profile and deliver pivotal information. In this respect, the currently best evidence base has been accumulated for the natriuretic peptide family. A large array of other heart failure biomarkers (i.e., markers of inflammation, extracellular matrix remodeling, and myocyte damage and stress) are still in earlier phases of testing. This short review will provide a balanced comparison of those "classic tools" and natriuretic peptides focusing on their diagnostic capacity in various clinical settings, factors influencing test values, cutoff values and their interpretation, and the capacity of these biomarkers to guide the diagnostic and therapeutic decision-making processes in patients with suspected and established heart failure.

The importance of sex- and gender-related features of various diseases regarding the impact of different risk factors on the natural course of disease, the response to therapy and outcome have only more recently been appreciated. Studies investigating sex- and gender-related aspects in rheumatoid arthritis (RA) are scarce. Unambiguous classification of factors of potential pathogenetic relevance or with the capacity to influence clinical course and disease management into sex- or gender- related aspects is difficult (Figure 1). The majority of RA patients is female. As illustrated by Figure 2, available evidence indicates a progressive decline in the incidence of this disease over the past 40 years in both men and women. There appears to be a cyclical pattern in the annual incidence rates with peaks and troughs occurring for both sexes, but at different times, which suggests the changing exposure to environmental factors which may promote or decrease RA. Current knowledge suggests that RA is characterized by chronic local and systemic inflammation which may trigger accelerated atherogenesis. Sex hormones may also play a pathogenetic role. Androgens and estrogens may stimulate the production of inflammatory cytokines in the synovial fluid. These cytokines then may influence sex hormone metabolism thus modifying sex hormone levels (Figure 3). Compared to the general population (Figures 4 and 5), the risk of cardiovascular morbidity and mortality is significantly increased in patients with rheumatic diseases and in particular in RA. This is evidenced by a higher incidence of congestive heart failure (Figure 6), coronary artery disease and (frequently silent) myocardial infarction, as well as sudden cardiac death. Several studies have demonstrated a significantly increased standardized mortality ratio in RA and identified cardiovascular events as the most frequent cause. Compared with expected mortality rates in the normal population, women with RA have a significantly more compromised life expectancy than men (Table 1). Amongst factors with uneven distribution between sexes are traditional cardiovascular risk factors (Table 2), but also more recently recognized potential risk indicators or risk modifiers such as inflammatory markers and sex hormones. Drugs directed against RA may influence the natural course of cardiovascular disease, as, e. g., indicated by the increased rates of cardiac events and stroke associated with cyclooxygenase-(COX-)2 inhibitor treatment. In contrast, the effect of pharmacotherapy for cardiovascular diseases on the course of RA is unexplored. Prospective cohort studies aiming at early detection of cardiovascular morbidity and precise and detailed characterization of disease manifestations will be required in order to more thoroughly understand the interplay of factors and conditions determining an individuals' risk for developing cardiovascular comorbidity in autoimmune diseases. This article summarizes the available evidence for sex- and gender-related differences in the disease manifestation of rheumatic disorders as well as in cardiovascular risk factors with an emphasis on the cardiovascular comorbidity observed in RA.

In patients with heart failure, increased wall stretch due to volume and pressure overload leads to an increase in circulating natriuretic peptides (ANP and BNP and their N-terminal fragments NT-proANP and NT-proBNP). Plasma BNP levels commonly considered normal (< 20 pg/ml) are influenced by age, sex, and also by genetic factors. ANP and BNP are synthesized and released by atrial and ventricular myocytes (Figure 1). In subjects with acute dyspnea, a BNP plasma concentration of 100 pg/ml has been established as a cutoff value for the diagnosis of heart failure yielding a very high negative predictive value coupled with an acceptable positive predictive value (Figure 3). However, recent evidence suggests that much more subtle elevations of plasma BNP may also indicate an increased long-term risk of cardiovascular events and death (Figure 2). In acute heart failure, natriuretic peptides correlate with ventricular pressure and volume overload, as well as with NYHA functional class. They can, however, not reliably discriminate between heart failure due to reduced ejection fraction and heart failure with preserved systolic function (Figure 4). Thus, elevated BNP or NT-proBNP levels always demand further clarification of heart failure etiology using echocardiography as the method of choice. As indicated by the algorithm for a BNP-based differential diagnosis of acute heart failure symptoms (Figure 5), a variety of noncardiac causes may also lead to moderate elevations of the markers (BNP plasma concentrations of 100-400 pg/ml). In addition, normal marker levels may be observed in > 20% of patients with long-term stable heart failure. Thus, increased plasma concentrations of natriuretic peptides are not strictly specific for heart diseases and also lack sensitivity in the chronic compensated state. Diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, and spironolactone have been shown to decrease BNP and NT-proBNP in parallel with clinical and hemodynamic improvement. In patients hospitalized for decompensated heart failure, predischarge plasma BNP levels reflect the risk of future death and rehospitalization (Figure 6). Although adjusting heart failure treatment to reduce plasma NT-proBNP levels may improve outcome, a general recommendation for monitoring drug therapy using this marker should not be derived from this observation. General practitioners may, in the future, use BNP or NT-proBNP as a rule-out test for heart failure and preselect patients for further diagnostic work-up on the basis of an elevated plasma level. Within the framework of the German network for heart failure the multicentric "Handheld-BNP Study" will clarify, whether echocardiography using low-price simple handcarried devices could be used as an alternative or, more likely, as a complementary diagnostic tool to further improve heart failure diagnosis in primary care.