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Background The sodium-glucose co-transporter 2 inhibitor empagliflozin improves cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM) and heart failure. Experimental studies suggest a direct cardiac effect of empagliflozin associated with an improvement in left ventricular diastolic function. Methods In the randomized, double-blind, two-armed, placebo-controlled, parallel group trial EmDia, patients with T2DM and elevated left ventricular E/E´ ratio were enrolled and randomized 1:1 to receive empagliflozin 10 mg/day versus placebo. The primary endpoint was the change of left ventricular E/E´ ratio after 12 weeks of intervention. Results A total of 144 patients with T2DM and an elevated left ventricular E/e´ ratio (age 68.9 ± 7.7 years; 14.1% women; E/e´ ratio 9.61[8.24/11.14], left ventricular ejection fraction 58.9% ± 5.6%). After 12 weeks of intervention, empagliflozin resulted in a significant higher decrease in the primary endpoint E/e´ ratio by − 1.18 ([95% confidence interval (CI) − 1.72/− 0.65]; P n = 30). Additional effects of empagliflozin on body weight, HbA1c, uric acid, red blood cell count, hemoglobin, mean corpuscular hemoglobin, and hematocrit were detected (all P E/e´ by empagliflozin could be explained by the variables examined. Conclusions Empagliflozin improves diastolic function in patients with T2DM and elevated end-diastolic pressure. Since the positive effects were consistent in patients with and without heart failure with preserved ejection fraction, the data add a mechanistic insight for the beneficial cardiovascular effect of empagliflozin. Trial registration Clinicaltrials.gov, unique identifier: NCT02932436. Graphical abstract

Aims To assess the prevalence of type 2 diabetes mellitus (T2DM) and prediabetes in the general population and to investigate the associated cardiovascular burden and clinical outcome. Methods and Results The study sample comprised 15,010 individuals aged 35–74 years of the population-based Gutenberg Health Study. Subjects were classified into euglycaemia, prediabetes and T2DM according to clinical and metabolic (HbA1c) information. The prevalence of prediabetes was 9.5% (n = 1415) and of T2DM 8.9% (n = 1316). Prediabetes and T2DM showed a significantly increased prevalence ratio (PR) for age, obesity, active smoking, dyslipidemia, and arterial hypertension compared to euglycaemia (for all, P prediabetes 1.20, 95% CI 1.07–1.35, P = 0.002) and represented as a risk factor for asymptomatic cardiovascular organ damage independent of traditional risk factors (PR 1.04, 95% CI 1.01–1.08, P = 0.025). Prediabetes was associated with a 1.5-fold increased 10-year risk for cardiovascular disease compared to euglycaemia. In Cox regression analysis, prediabetes (HR 2.10, 95% CI 1.76–2.51, P P P Conclusion Besides T2DM, also prediabetes inherits a significant cardiovascular burden, which translates into poor clinical outcome and indicates the need for new concepts regarding the prevention of cardiometabolic disorders.

Background Concomitant tricuspid regurgitation (TR) is a common finding in mitral regurgitation (MR). Transcatheter repair (TMVR) is a favorable treatment option in patients at elevated surgical risk. To date, evidence on long-term prognosis and the prognostic impact of TR after TMVR is limited. Methods Long-term survival data of patients undergoing isolated edge-to-edge repair from June 2010 to March 2018 (combinations with other forms of TMVR or tricuspid valve therapy excluded) were analyzed in a retrospective monocentric study. TR severity was categorized and the impact of TR on survival was analysed. Results Overall, 606 patients [46.5% female, 56.4% functional MR (FMR)] were enrolled in this study. TR at baseline was categorized severe/medium/mild/no or trace in 23.2/34.3/36.3/6.3% of the cases. At 30-day follow-up, improvement of at least one TR-grade was documented in 34.9%. Severe TR at baseline was identified as predictor of 1-year survival [65.2% vs. 77.0%, p = 0.030; HR for death 1.68 (95% CI 1.12–2.54), p = 0.013] and in FMR-patients also regarding long-term prognosis [adjusted HR for long-term mortality 1.57 (95% CI 1.00–2.45), p = 0.049]. Missing post-interventional reduction of TR severity was predictive for poor prognosis, especially in the FMR-subgroup [1-year survival: 92.9% vs. 78.3%, p = 0.025; HR for death at 1-year follow-up 3.31 (95% CI 1.15–9.58), p = 0.027]. While BNP levels decreased in both subgroups, TR reduction was associated with improved symptomatic benefit (NYHA-class-reduction 78.6 vs. 65.9%, p = 0.021). Conclusion In this large study, both, severe TR at baseline as well as missing secondary reduction were predictive for impaired long-term prognosis, especially in patients with FMR etiology. TR reduction was associated with increased symptomatic benefit. Graphic abstract

Background Environmental noise exposure has been associated with increased cardiovascular morbidity and mortality. Recently, noise annoyance was shown to induce atrial fibrillation, which was accompanied by significantly increased levels of midregional pro atrial natriuretic peptide (MR-proANP). Therefore, the aim of the present study was to analyze the association between noise annoyance, MR-proANP, incident cardiovascular events, and all-cause mortality. Methods Levels of MR-proANP were measured in the first 5000 participants of the population-based Gutenberg Health Study. Annoyance was assessed separately for aircraft, road traffic, railway, neighborhood, and industrial/construction noise during the day and sleep. Results In cross-sectional analyses, aircraft noise annoyance during day and sleep, industrial/construction noise annoyance during day, and railway noise annoyance during sleep were independently associated with increased levels of MR-proANP after multivariable adjustment. After a 5-year follow-up period, there were 43 cases of incident atrial fibrillation and 103 of incident cardiovascular disease (comprising atrial fibrillation, coronary artery disease, myocardial infarction, heart failure, or stroke). Moreover, there were 301 deaths after a mean follow-up of 7.42 ± 1.66 years. An odds ratio (OR) of 2.82 ([95% confidence interval (CI) 1.86; 4.35], p p = 0.0046) for incident cardiovascular disease per 1-standard deviation (SD) increase in MR-proANP levels were found. A 36% (hazard ratio: 1.36 [95% CI 1.19; 1.55], p Conclusions Noise annoyance may contribute to cardiovascular morbidity and mortality and is characterized by increased levels of MR-proANP. Graphic abstract

Background Iron deficiency is now accepted as an independent entity beyond anemia. Recently, a new functional definition of iron deficiency was proposed and proved strong efficacy in randomized cardiovascular clinical trials of intravenous iron supplementation. Here, we characterize the impact of iron deficiency on all-cause mortality in the non-anemic general population based on two distinct definitions. Methods The Gutenberg Health Study is a population-based, prospective, single-center cohort study. The 5000 individuals between 35 and 74 years underwent baseline and a planned follow-up visit at year 5. Tested definitions of iron deficiency were (1) functional iron deficiency—ferritin levels below 100 µg/l, or ferritin levels between 100 and 299 µg/l and transferrin saturation below 20%, and (2) absolute iron deficiency—ferritin below 30 µg/l. Results At baseline, a total of 54.5% of participants showed functional iron deficiency at a mean hemoglobin of 14.3 g/dl; while, the rate of absolute iron deficiency was 11.8%, at a mean hemoglobin level of 13.4 g/dl. At year 5, proportion of newly diagnosed subjects was 18.5% and 4.8%, respectively. Rate of all-cause mortality was 7.2% (n = 361); while, median follow-up was 10.1 years. After adjustment for hemoglobin and major cardiovascular risk factors, the hazard ratio with 95% confidence interval of the association of iron deficiency with mortality was 1.3 (1.0–1.6; p = 0.023) for the functional definition, and 1.9 (1.3–2.8; p = 0.002) for absolute iron deficiency. Conclusions Iron deficiency is very common in the apparently healthy general population and independently associated with all-cause mortality in the mid to long term. Graphic abstract

Experimental data indicate that direct acting oral anticoagulants (DOAC) and vitamin K antagonists (VKA) may exert differential effects on cardiovascular disease. Data from the prospective, observational, single-center MyoVasc Study were used to examine associations of DOAC as compared to VKA with subclinical markers of cardiovascular disease, cardiac function, and humoral biomarkers in heart failure (HF). Multivariable analysis adjusted for age, sex, traditional cardiovascular risk factors, comorbidities, and medications with correction for multiple testing demonstrated that DOAC therapy was among all investigated parameters an independent significant predictor of better diastolic function (E/E′: β − 0.24 [− 0.36/− 0.12]; P

The purpose of this study was to compare the clinical outcomes of patients treated with bioresorbable scaffold (BRS) for off-label versus approved indications. The BRS promised some advantages in terms of complete biodegradation within 2–4 years, restored vascular physiology, and absence of potential stent-related long-term complications. However, the implication of BRS for off-label indications and further long-term follow-up of this particular patient group is not well described. The short- and long-term outcome after implantation of an everolimus-eluting, poly-l-lactic acid-based bioresorbable scaffold system (ABSORB, Abbott Vascular, Santa Clara, CA, USA) was evaluated in the prospective, non-interventional, multicenter real-world German–Austrian ABSORB RegIstRy (GABI-R). A total of 3188 patients were enrolled. Patients were divided into two groups: on-label BRS use (33.0%) and off-label use (66.9%) if at least one off-label use criteria was met. The incidence of scaffold thrombosis in confirmed cases was significantly higher in off-label group (1.3% versus 0.5%, p = 0.04; OR 2.41 (95% CI 1.00–5.82) with also a trend toward higher myocardial infarction rate (2.3% versus 1.4%, p = 0.077; OR 1.70 (95% CI 0.95–3.03) and cardiovascular death (1.2% versus 1.1%, p = 0.76, OR 1.11 (95% CI 0.56–2.21) at 6-month follow-up. In a real-world setting, the majority patients were treated with BRS for off-label indications. The off-label use of BRS compared to confirmed indications appears to be associated with a higher rate of clinical endpoints considering more complex lesions and higher morbidity in this patients’ group. Comparison between treatment of “established” versus complex “off-label” coronary lesions with Absorb® bioresorbable scaffold implantation: results from the GABI-R® registry.

Choroidal thickness is associated with several cardiovascular parameters in case–control studies including patients with manifest disease. So far, it was unclear whether underlying cardiovascular risk factors or the continuum of heart failure may lead to alterations of the choroid. Therefore, our hypothesis was to test in a population-based study, whether choroidal thickness is associated with cardiovascular risk factors and heart disease. A population-based cross-sectional study was carried out in Germany. A comprehensive medical examination including assessment of cardiovascular risk factors, echocardiography and ophthalmological examinations with spectral-domain optical coherence tomography of the choroid was performed. Subfoveal choroidal thickness as well as left ventricular ejection fraction (LVEF) and a surrogate marker for left ventricular end-diastolic pressure (E/e’) were measured. Linear regression analyses were carried out to determine the relationship between subfoveal choroidal thickness and age, sex, body mass index, systolic blood pressure, dyslipidemia, HbA1c level, hematocrit, estimated glomerular filtration rate (eGFR), LVEF, E/e’ and left ventricular mass index adjusted for ocular parameters. 1.742 subjects (48% females) with a mean age 59.3 ± 10.6 years were included in this study. Mean subfoveal thickness was 252 ± 77 µm (right eyes) and 255 ± 77 µm (left eyes). Unadjusted linear regression analysis revealed that subfoveal choroidal thickness is associated with sex, age, systolic blood pressure, hematocrit, eGFR, left ventricular end-diastolic pressure, left ventricular mass index (all p

Background Higher, but also lower resting heart rate (HR), has been associated with increased cardiovascular events and mortality. Little is known about the interplay between HR, cardiovascular risk factors, concomitant diseases, vascular (endothelial) function, neurohormonal biomarkers, and all-cause mortality in the general population. Thus, we aimed to investigate these relationships in a population-based cohort. Methods 15,010 individuals (aged 35–74 at enrolment in 2007–2012) from the Gutenberg Health Study were analyzed. Multivariable regression modeling was used to assess the relation between the variables and conditional density plots were generated for cardiovascular risk factors, diseases, and mortality to show their dependence on HR. Results There were 714 deaths in the total sample at 7.67 ± 1.68 years of follow-up. The prevalence of diabetes mellitus, arterial hypertension, coronary and peripheral artery disease, chronic heart failure, and previous myocardial infarction exhibited a J-shaped association with HR. Mortality showed a similar relation with a nadir of 64 beats per minute (bpm) in the total sample. Each 10 bpm HR reduction in HR 64 subjects (Hazard Ratio 1.29; 95% confidence interval 1.19–1.41 per 10 bpm increase in HR). Results found for vascular and neurohormonal biomarkers exhibited a differential picture in subjects with a HR below and above the nadir. Discussion These results indicate that in addition to a higher HR, a lower HR is associated with increased mortality. Electronic supplementary material The online version of this article (10.1007/s00392-019-01466-2) contains supplementary material, which is available to authorized users.

Cardiovascular disease is the most frequent non-malignant cause of morbidity and mortality in adult survivors of childhood or adolescent cancer. Thrombin generation (TG) analysis gives insight in hypercoagulability as an important mechanism linked to cardiovascular risk factors (CVRFs). In 200 individuals, from the cardiac and vascular late sequelae in long-term survivors of childhood cancer study, TG in platelet-rich plasma (PRP) and platelet-free plasma (PFP) at 1pM tissue factor was investigated. Endogenous thrombin potential (ETP) and peak height were the analysed parameters of a TG curve. Sex-specific multivariable linear regression analysis adjusted for age and CVRFs was used to assess the clinical determinants of TG. Females presented with higher ETP and peak height compared to males, both in PRP and PFP. Hypertension (beta estimate, ss: 184.8 [90.7; 278.8]), obesity (ss: 161.9 [63.9; 259.5]), and HbA1c (ss: 715.6 [97.4; 1333.8]) were associated with higher ETP in PRP only. ETP in PRP was positively associated with obesity and HbA1c in both males and females and with dyslipidemia (ss: 253.07 [72.92; 433.22]) and systolic hypertension (ss: 436.7 [119.02; 754.39]) in females only. CVRFs showed no association with TG variables in PFP. In conclusion, this study presents an important relation between traditional CVRFs and TG in the presence of platelets only. Sex-specific differences in TG with females presenting with higher TG, particularly those with dyslipidemia and systolic hypertension, were demonstrated. These results highlight the potential of the platelet-coagulant function in identifying cancer survivors at higher risk for adverse cardiovascular events.

The electrocardiographic pattern of early repolarization (ER) is related to increased cardiac mortality in the general population. The pathophysiological basis of ER is largely unknown. We investigated the association of echocardiographic structural and functional parameters of the left ventricle with the presence of ER in the community. The presence of ER (ER+) was assessed in 13,878 participants (mean age 54.6 years, 51.1% women) of the Gutenberg Health Study and related to left ventricular structure and function derived from standard echocardiography. The prevalence of ER was 5.0% (694/13,878), with higher prevalence in men than women (6.6% vs. 3.5%, p

Obesity is a risk factor for heart failure (HF) and identification of symptomatic, and obese HF patients are challenging, because obesity can mimic HF symptoms. We aimed to evaluate novel biomarkers for HF in obese subjects of the general population. Midregional proadrenomedullin (MR-proADM), growth differentiation factor-15 (GDF-15), midregional pro-atrial natriuretic peptide (MR-proANP), and NT-proBNP were measured in 5000 individuals of the population-based Gutenberg Health Study (GHS), including 1204 obese individuals (BMI ≥ 30 kg/m2) and 107 individuals with HF. NT-proBNP and MR-proANP were lower in obese vs. non-obese HF individuals (p = 0.013 and p = 0.01, respectively), whereas GDF-15 was similar and MR-proADM was higher in obese vs. non-obese HF individuals. All biomarkers increased the odds ratio (OR) for prevalent HF. For NT-proBNP and MR-proANP, this increase was lower in obese vs. non-obese individuals, whereas it was comparable for MR-proADM and GDF-15. All biomarkers were associated with increased all-cause mortality (median follow-up 7.3 years, 211 events). Results were validated in 8373 individuals (n = 1734 with BMI ≥ 30 kg/m2) of the FINRISK study with a median follow-up of 13.8 years (1030 events). Using a dichotomized biomarker cutoff for HF, the best predictor for all-cause mortality in obese subjects was GDF-15 (p

Since 2008, the German Cardiac Society (DGK) has been establishing a network of certified chest pain units (CPUs). The goal of CPUs was and is to carry out differential diagnostics of acute or newly occurring chest pain of undetermined origin in a rapid and goal-oriented manner and to take immediate therapeutic measures. The basis for the previous certification process was criteria that have been established and published by the task force on CPUs. These criteria regulate the spatial and technical requirements and determine diagnostic and therapeutic strategies in patients with chest pain. Furthermore, the requirements for the organization of CPUs and the training requirements for the staff of a CPU are defined. The certification process is carried out by the DGK; currently, 225 CPUs are certified and 139 CPUs have been recertified after running for a period of 3 years. The certification criteria have now been revised and updated according to new guidelines.

Dabigatran etexilate, a direct thrombin inhibitor and non-vitamin K antagonist oral anticoagulant (NOAC), has been shown to effectively prevent thromboembolic events in patients with non-valvular atrial fibrillation (AF). However, there is a paucity of data on the antithrombotic efficacy and safety of dabigatran in the resolution of left atrial appendage (LAA) thrombi in AF patients. The primary objective of the RE-LATED AF trial is to assess whether dabigatran results in a faster complete LAA thrombus resolution as compared to vitamin K antagonist phenprocoumon. Secondary objectives are to assess the impact of dabigatran on complete LAA thrombus resolution rate within 6 weeks of treatment and change in LAA thrombus volume under treatment. Furthermore, this study aims to assess and compare safety and tolerability of dabigatran vs. phenprocoumon. The study is designed as a prospective, randomized, open-label, controlled, explorative, blinded endpoint (PROBE) trial. Patients with AF and left atrial appendage thrombus confirmed by transoesophageal echocardiography (TEE) will be randomized to receive either dabigatran (150 mg bid) or phenprocoumon (INR 2–3) for the resolution of LAA thrombus formation for at least 21 days. Thrombus resolution will be determined by TEE 3 weeks after treatment initiation and subsequently at weeks 4 and 6, if the LAA thrombus has not been resolved before. A total of 110 patients are planned to be randomized. This is the first prospective, multicentre, randomized controlled clinical trial investigating safety and efficacy of a NOAC for the resolution of LAA thrombi in patients with non-valvular AF.

In the Gutenberg Health Study, a random sample of the population was scanned with vascular ultrasound for early atherosclerosis. A continuous classical risk marker model (waist circumference, HbA1c, LDL/HDL ratio, pack years and pulse pressure) was compared to a model of modern biomarkers (C-reactive protein, troponin I, N-terminal pro B-type natriuretic peptide, copeptin, mid-regional pro-adrenomedullin, and asymmetric dimethylarginine) with regard to the ability of ruling out abnormal intima-media thickness (IMT), respectively, carotid plaques.Data of the first consecutive 5,000 participants (aged 35-74 years; 2,540 men, 2,460 women) were analyzed. IMT was measured at both common carotid arteries using an edge detection system. Plaques were defined as protrusion of ≥1.5 mm in common, internal and external carotid artery.For classical risk factors, in comparison to a model of six modern biomarkers, regarding the variable (a) IMT0.85 mm negative and positive predictive value (NPV and PPV) were 0.98 and 0.16 for both the classical risk factor model and the biomarker model. The second variable (b) presence of plaque could be ruled out with an NPV of 0.84 and identified with a PPV of 0.61 for classical risk factors, and 0.84 and 0.58 for biomarkers, respectively. Values were calculated using logistic regression analysis.Classical risk factors allow ruling out pathologic IMT and presence of carotid plaques in a population of primary prevention in a reliable way. Modern biomarkers performed almost equally well but did not provide further information.

Aim of the study was to analyze the correlation of high-sensitivity assayed troponin I with cardiac and vascular structure and function in a large population-based cohort. In a sample of 4,139 subjects (2,099 men, 2,040 women, age 35–74 years) from the population-based Gutenberg Health Study, troponin I was measured with a high-sensitivity assay that had a limit of detection of 1.9 pg/mL. In the study cohort, 3,405 subjects had detectable troponin I concentrations [82.3 % overall, 89.9 % men (N = 1,888), 74.4 % women (N = 1,517)]. All analyses were adjusted for age. The strongest correlate between detectable troponin I and measures of cardiac phenotypes was observed for left ventricular mass (p

The aim of this analysis was to compare troponin-positive patients presenting to a chest pain unit (CPU) and undergoing coronary angiography with or without subsequent revascularization. Leading diagnosis, disease distribution, and short-term outcomes were evaluated. Chest pain units are increasingly implemented to promptly clarify acute chest pain of uncertain origin, including patients with suspected acute coronary syndrome (ACS). A total of 11,753 patients were prospectively enrolled into the German CPU-Registry of the German Cardiac Society between December 2008 and April 2011. All patients with elevated troponin undergoing a coronary angiography were selected. Three months after discharge a follow-up was performed. A total of 2,218 patients were included. 1,613 troponin-positive patients (72.7 %) underwent a coronary angiography with subsequent PCI or CABG and had an ACS in 96.0 %. In contrast, 605 patients (27.3 %) underwent a coronary angiography without revascularization and had an ACS in 79.8 %. The most frequent non-coronary diagnoses in non-revascularized patients were acute arrhythmias (13.4 %), pericarditis/myocarditis (4.5 %), decompensated congestive heart failure (3.7 %), Takotsubo cardiomyopathy (2.7 %), hypertensive crisis (2.4 %), and pulmonary embolism (0.3 %). During the 3-month follow-up, patients without revascularization had a higher mortality (12.1 vs. 4.5 %, p

Aims Chest pain units (CPUs) have been established to optimize treatment of patients with acute coronary syndrome (ACS) and to early and accurately discharge patients with noncoronary chest pain. The aim of this analysis was to elucidate whether treatment of ACS patients in the CPU versus emergency department (ED) has prognostic implications. Methods and results Patients presenting with suspected ACS to either the ED between August 2004 and June 2005 or the CPU between July 2005 and May 2006 were retrospectively analyzed. Of 1,796 included patients, 483 had the discharge diagnosis ACS. When compared to patients with exclusion of ACS they had more cardiovascular risk factors and higher troponin, creatinine and C-reactive protein levels (P \ 0.001) at admission. Within 1 year, 37 patients of the ACS group suffered an event. Treatment in the ED compared with the CPU showed a significant increase in hazard ratio of 2.1 ( P= 0.034) for the combined endpoint death, myocardial infarction and stroke, remaining unchanged after adjusting for confounders. Event-free 1-year survival was higher in CPU patients for the combined endpoint (Plogrank = 0.02). Conclusion These results demonstrate a better 1-year prognosis for ACS patients treated in the CPU instead of the ED, therefore, supporting the idea to establish CPUs in Europe.

Heart-rate reduction is a major goal in treatment of patients with coronary artery disease (CAD) and chronic congestive heart failure [1, 2], and an elevated resting pulse robustly correlates with decreased survival in these patients [3]. Therefore, heart rate reduction down to 55–60 bpm is recommended in the current guidelines for the treatment of CAD of the American Heart Association [4] and of the European Society of Cardiology [5] alike. The selective If-channel inhibitor ivabradine represents a novel pharmaceutical to achieve this goal [6]. In an experimental trial in a rodent model of heart failure, ivabradine was demonstrated to increase stroke volume, improve LV-function, and beneficially influence myocardial remodeling [7]. Whether the use of this drug is beneficial in patients with established systolic chronic heart failure, is currently under investigation in the SHIFT trial [8]. The treatment of restrictive cardiomyopathy, e.g., due to cardiac amyloidosis, however, differs substantially from that of patients with systolic heart failure due to ischemic heart disease or idopathic dilated cardiomyopathy. Special attention must be payed to fluid balance, and blood pressure lowering drugs must be administered carefully due to the development of profound hypotension; in addition, the usefulness of betablockers in patients with sinus rhythm has not been tested in cardiac amyloidosis [9]. So far, there are also no data about the effects of ivabradine in patients with cardiac amyloidosis, and data are lacking, if a heart rate reduction per se can improve hemodynamics, outcomes, or quality-of-life in patients with restrictive cardiomyopathy. We here report on a 78-year old male who was admitted to our emergency room with symptoms of decompensated congestive heart failure (pulmonary congestion, massive peripheral edema, pleural effusion), hypotension, and acute on chronic renal failure (creatinine 2.08 mg/dl, urea-N 83 mg/dl). Brain natriuretic peptide levels exceeded 5,000 pg/ml. The initial ECG showed a left axis, sinus rhythm, tachycardia of 110 bpm, and a Sokolow-LyonIndex of 3.5 mV. It is noteworthy that the patient had no history of arterial hypertension. A therapy with furosemide i.v. was initiated to recompensate the patient. This kind of therapy was not successful and the patient could not get rid of the massive peripheral edema, and we could not reduce the body weight. Echocardiography revealed the picture of a restrictive cardiomyopathy (see Fig. 1). Cardiac MRI showed diffuse hyperenhancement typical for amyloidois. Cardiac catheterization revealed a cardiac index (CI) of 1.2 l/min/m, a dip-plateau-phenomenon, and a tachycardia of 90–100 bpm. The coronary arteries were free of significant stenosis. Histological examination of a right-ventricular biopsy revealed a positive Kongo-red-staining proving the diagnosis cardiac amyloidosis, which was secondary to monoclonal gammopathy type lambda. Due to severe hypotension, diuretic resistance to high doses of furosemide and a marked tachycardia at rest was noted. Due to the low blood pressure, treatment with betablockers was not possible. The poor clinical state of the patient did not allow an aggressive treatment of the amyloidosis, e.g., using alkylating agents like melphalan. Slowing down the heart rate in patients with restrictive cardiomyopathy via use of digoxin and betareceptor P. Wenzel (&) N. Abegunewardene T. Munzel Universitatsmedizin der Johannes-Gutenberg-Universitat Mainz, II. Medizinische Klinik—Kardiologie, Angiologie und Internistische Intensivmedizin, Langenbeckstr. 1, 55131 Mainz, Germany e-mail: wenzelp@uni-mainz.de

The negative impact of cigarette smoking on the cardiovascular system has been recognized for more than 50 years. Smoking is associated with increased heart rate and sympathetic outflow, inflammation, with accelerated progression of atherosclerosis, enhanced platelet aggregation, decreased fibrinolytic activity, endothelial dysfunction, worsening of renal function [1], and ultimately with increased hospitalizations for myocardial infarction, stroke and heart failure [2, 3]. Importantly, many of these effects are felt to be mediated, at least in part, by increased exposure to reactive oxygen species. This concept is supported by increased plasma markers of oxidative stress and by the observation that administration of antioxidants such as vitamin C reverses the vascular abnormalities associated with smoking [4]. The irrefutable evidence of higher ischemic rates in smokers stands in contrast with several large epidemiological studies demonstrating that, among patients who experience a myocardial infarction, those who smoke appear to have lower mortality and morbidity [5–7]. Some authors have argued that this observation is due to differences between the populations studied [6]; other studies found that in patients with infarction, smoking remains associated with reduced mortality even after controlling for age, infarct size, clinical presentation, blood pressure, cardiovascular risk factors and several other parameters [7, 8]. The complex mechanisms triggered by reactive oxygen species might contribute to explain this smoker’s paradox. While having a crucial role in the pathophysiology and progression of cardiovascular disease, reactive oxygen and nitrogen species are also involved in ischemic preconditioning, a protective phenomenon associated with a reduced susceptibility to ischemia and reperfusion damage [9]. We set out to investigate the impact of smokinginduced oxidative stress on the vascular-endothelial dysfunction induced by ischemia and reperfusion. Radial artery endothelium-dependent flow-mediated dilation (FMD) was measured before and after local ischemia/reperfusion (15 min ischemia by inflating a pneumatic cuff around the upper arm followed by 15 min reperfusion) in 10 healthy subjects (7 males, 25–28 years old) with no cardiac risk factors. These procedures were carried out twice, at 7-day intervals. Twenty-four hours before each visit, subjects underwent, under supervision and in randomized order, two protocols: in the first protocol, they smoked two cigarettes (nicotine content 1.2 mg, tar 16 mg, CO 14 mg) 15 min after receiving 2 g of intravenous vitamin C. In the second protocol, they smoked two cigarettes 15 min after receiving an intravenous placebo (10 ml of normal saline). Subjects were occasional smokers (0–2 cigarettes/month), and none of them had smoked in the previous 7 days. A separate group of 10 smokers (7 males, age 24–28 years, 3–10 cigarettes/day) underwent the same FMD-IR-FMD protocol after a 24-h non-smoking interval. The methods for the assessment of FMD in our laboratory have been previously described [9]. Briefly, the diameter of the radial artery is measured in M. Lisi S. Dragoni M. C. Leone Department of Internal, Cardiovascular and Geriatric Medicine, University of Siena, Siena, Italy

A 34-year-old Caucasian male physician was admitted in June 2008 to our emergency department with complaints of palpitations. The symptoms had appeared the day before. The patient had had an ECG recorded at a peripheral hospital, showing monomorphic ventricular extrasystole and trigeminism (Fig. 1a); markers of cardiac necrosis were negative. Episodes of mild cough, that lasted 4– 5 days, and sporadic palpitations, had been present in the last 3 weeks, although these symptoms did not limit normal life and physical activities. He had a history of mildly elevated liver enzymes, was a former smoker, and had a positive family history of cardiovascular disease. Physical examination was absolutely negative except for the presence of swollen lymph nodes in neck and inguinal region. Laboratory showed elevated markers of liver function (GPT-ALT:69U/l, GOT-AST:41U/l, gamma-GT:227U/l) and C-reactive-protein (7.8 mg/dl, reference \5 mg/dl). ECG showed negative T-waves in leads DII, DIII and aVF (Fig. 1b). Transthoracic echocardiography showed normal size and function of all heart chambers, no valvular disease, and no pericardial effusion. The patient was admitted for further workout. At cardiac magnetic resonance, after the administration of Gadolinium, a well-defined mid-myocardial and subepicardial area of contrast enhancement was detected in the inferior septum (Fig. 2a–c). The almost complete absence

Sirs, A 69-year-old caucasian man was admitted to the Emergency Department for worsening dyspnea (NYHA II–III) and paroxysmal nocturnal dyspnea. The symptoms had appeared in the last months and had progressively worsened through the last 6 weeks. He referred no angina or syncope. The patient’s clinical history was absolutely negative and he reported none of the major cardiovascular risk factors. A physical exam was essentially unremarkable except for the presence of bilateral basal crepitations and mild bilateral ankle edema. Blood pressure was 100/ 60 mmHg. An ECG showed atrial fibrillation with a ventricular rate of 130/min and no sign suggestive of acute ischemia. Blood analysis showed elevated creatinine (1.6 mg/dl) and BNP (750 pg/ml). All other parameters, including C-reactive protein, were normal. Therapy with loop diuretics, 100 mg aspirin and amiodarone was started. On the first day after admission, the patient was asymptomatic and his heart rate was 90/min, and ECG showed atypical atrial flutter with irregular AV conduction. Echocardiography showed a dilated left ventricle (end-diastolic volume 130 ml) with global hypokinesia and an ejection fraction of 25%. Both atria were dilated, and there was a mild to moderate (secondary) mitral insufficiency. On day 5 after admission, a cardiac magnetic resonance and a coronary angiography excluded the presence of coronary artery disease, prior myocardial infarction and of signs suggestive of myocarditis. Left and right heart catheterization showed data compatible with heart failure (Table 1), and moderate to severe mitral regurgitation. The patient was discharged with a diagnosis of dilated cardiomyopathy and was prescribed amiodarone, spironolactone (25 mg o.d.), low-dose b-blockers (carvedilol 6.25 mg b.i.d), angiotensin converting enzyme (ACE)-inhibitors (ramipril 2.5 mg o.d.), low-molecular weight heparin (followed by oral anticoagulants). An electrophysiology examination was scheduled for the next 6 weeks. Further, since the patient appeared to be hemodynamically stable after initiating therapy with the above drugs, hydralazine (25 mg b.i.d.) and the oral organic nitrate pentaerythrityl tetranitrate (PETN, 50 mg t.i.d) were also added. Six weeks later, the patient was admitted again for the scheduled electrophysiology examination and follow-up right heart catheterization. He had scrupulously followed the therapy prescribed and had been essentially asymptomatic since discharge, and his mean heart rate was 80/ min. At this time, echocardiography, as well as left and right heart catheterization showed a marked improvement in the parameters of left ventricular performance (Table 1; Fig. 1). The mitral regurgitation was only mid-grade. The patient underwent the electrophysiology examination and successful cavotricuspid isthmus ablation. We describe a case of dilated cardiomyopathy in which medical treatment with a combination of antineurohormonal drugs and nitrate/hydralazine led to a dramatic improvement in symptoms and hemodynamic variables. Organic nitrates are widely used in the therapy of patients with chronic congestive heart failure, especially in North America [1], and the coadministration with the vasodilator and antioxidant [2] hydralazine has been associated with improvements in exercise tolerance, left ventricular size, systolic function, ischemia, cardiac remodeling [3] and, ultimately, mortality in African Americans [4]. Of note, this benefit appears to be T. Gori (&) T. Munzel 2. Medizinische Klinik, Universitatsmedizin der Johannes Gutenberg-Universitat Mainz, Mainz, Germany e-mail: tommaso.gori@ukmainz.de; tomgori@hotmail.com

Aims Epidemiological studies suggest the existence of a relationship between aircraft noise exposure and increased risk for myocardial infarction and stroke. Patients with established coronary artery disease and endothelial dysfunction are known to have more future cardiovascular events. We therefore tested the effects of nocturnal aircraft noise on endothelial function in patients with or at high risk for coronary artery disease. Methods 60 Patients (50p 1–3 vessels disease; 10p with a high Framingham Score of 23 %) were exposed in random and blinded order to aircraft noise and no noise conditions. Noise was simulated in the patients’ bedroom and consisted of 60 events during one night. Polygraphy was recorded during study nights, endothelial function (flow-mediated dilation of the brachial artery), questionnaires and blood sampling were performed on the morning after each study night. Results The mean sound pressure levels Leq(3) measured were 46.9 ± 2.0 dB(A) in the Noise 60 nights and 39.2 ± 3.1 dB(A) in the control nights. Subjective sleep quality was markedly reduced by noise from 5.8 ± 2.0 to 3.7 ± 2.2 (p