Surgical therapy for major lung parenchymal damage from late coronavirus disease complication: case report and literature review.

Background: Coronavirus disease [severe acute respiratory syndrome coronavirus disease 19 (SARS COVID-19)] has emerged as one of the most challenging diseases of recent decades. After the pandemic outbreak, our knowledge of the virus has expanded and developed, but we face a new wave of atypical complications that require special attention. In addition to the acute complications of COVID-19 infection, late complications of the disease are taking an increasingly important part in the management of affected patients, which are grouped under the collective term "Long COVID". In this work, we present our therapy strategy in three cases of pulmonary cavity as a late complication after COVID-19, as well as perform a literature review of published articles in this matter. Case Description: This study includes 3 cases of pulmonary cavities as a late COVID complication. Among them only one patient was vaccinated. The mean duration between the occurrence of Long COVID and SARS COVID-19 disease was 4 weeks in our patients. All patients underwent adequate medical therapy after Long COVID. However, due to the disease progression and significant elevated infections parameters, all patients underwent surgical therapy. One patient underwent uniportal video-assisted thoracoscopic surgery (VATS) lobectomy and decortication of the empyema, whereas we performed thoracotomy for other patients. All patients treated successfully and discharged shortly after the operation. Our literature review provides a total of 12 publications with only 50 patients. No patients received vaccination. The mean interval time between acute infection and the appearance of pulmonary cavities was about 4 weeks. The results showed that most patients were treated with conservative therapies. Only two patients were treated using invasive therapies. Both patients were successfully treated and recovered from the procedures. Conclusions: This group of late complications COVID patients requires individualized treatment strategy. In the case of an underlying pulmonary cavities, depending on the findings, despite increased perioperative risks, very good results can be achieved by presentation to a specialized and experienced thoracic surgery center.

[Update on PCSK9 inhibition]. / PCSK9-Hemmung ­ ein Update.

Lowering of low-density lipoprotein (LDL) cholesterol represents one of the most effective interventions in cardiovascular prevention. Besides the oral treatment with statins, ezetimibe and bempedoic acid, subcutaneously administered inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) have been established as further cornerstones of lipid-lowering treatment. The antibodies evolocumab and alirocumab are administered subcutaneously every 2-4 weeks and lower LDL cholesterol by around 60%, independent of pre-treatment with very good tolerability. Both drugs successfully reduced cardiovascular endpoints in large outcome trials. A novel principle of PCSK9 inhibition is RNA interference, which is exploited by the novel compound inclisiran. Inclisiran is a double-stranded modified RNA molecule, which neutralizes the mRNA of PCSK9 and thus inhibits PCSK9 protein synthesis intracellularly. Inclisiran only needs to be administered every 6 months. The cardiovascular outcome trial ORION­4 is currently ongoing. In Germany, prescription of PCSK9 inhibitors is regulated by the decision of the Federal Joint Committee. Novel strategies to inhibit PCSK9 function are under development and include orally available drugs and animal experiment concepts on gene editing, which are in different states of evaluation.

Spontaneously reported persistent symptoms related to coronavirus disease 2019 one year after hospital discharge : A retrospective cohort single-center study.

BACKGROUND: There are no outcome studies for coronavirus disease 2019 (COVID-19) survivors one year after hospital discharge in Germany. METHODS: This retrospective cohort study included all patients with polymerase chain reaction (PCR)-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hospitalized in the departments of internal medicine of the Klinikum Saarbrücken, a tertiary care hospital, between March 15 and December 31, 2020. A telephone interview with survivors was conducted at least 12 months after discharge. The interview was initiated with an open-ended question whether the patient had fully recovered from the disease. In the event of a subjective incomplete recovery, the patient was prompted to report any continuous or frequent symptoms that had not occurred prior to COVID-19. Finally, independent of the open-ended question response, all patients were asked closed questions which addressed new symptom onset of persistent fatigue, cognitive dysfunction, headache, muscle and joint pain following COVID-19. RESULTS: In all, 235 survivors were contacted and 162 could be included in the analysis. In 55 of 162 interviews (34.0%) at least one persistent COVID-19 symptom (PCS) was spontaneously reported. Four of 55 survivors with PCS reported five additional symptoms on the closed questions. One survivor, who responded positively to the open-ended question, reported new onset PCS in response to the closed questions. Physical fatigue (24.7%), cognitive dysfunction (14.8%), shortness of breath (8.6%), muscle and joint pain (6.8%) and headache (6.2%) were the most frequently reported PCS. CONCLUSIONS: Despite an interview technique aimed to reduce attribution bias by patients, one third of COVID-19 inpatient survivors report PCS one year after hospitalization. The complete article is written in English.

Real-world experience with the wearable cardioverter defibrillator: clinical effectiveness and wear-time adherence in patients at high risk for sudden cardiac death.

BACKGROUND: Previous studies established a role for the wearable cardioverter defibrillator (WCD) to effectively and safely bridge temporary risk for sudden cardiac death (SCD) in patients with advanced heart failure. The prognostic relevance of the WCD remains controversial. OBJECTIVES: The authors investigated adherence to, as well as the safety and effectiveness of, WCD use in a real-world cohort of patients at high risk for SCD. MATERIAL AND METHODS: All consecutive patients (n = 83) receiving a WCD at a German tertiary care hospital between April 2012 and December 2019 were retrospectively included in this analysis. Patient characteristics were collected at the time of the index hospitalization. Using the Zoll® lifeVest® (ZOLL Medical Corporation, Chelmsford, MA, USA) network database, two separate investigators evaluated adherence to the WCD as well as arrhythmic events during WCD wear time. RESULTS: During 3680 wearing days (mean WCD wear time, 44 days) with a median daily wear time of 23.1 h, three arrhythmic events of relevance (sustained ventricular tachycardia, VT) occurred, one of which was sufficiently terminated by WCD shock. Another patient died from sudden cardiac death while pausing his WCD. Right bundle branch block correlated significantly with sustained VT occurrence (r = 0.3315; 95% CI -0.1265 to 0.3014; p = 0.0022). In 30 patients (36.1%) a cardioverter/defibrillator was implanted. CONCLUSION: In a real-life clinical setting, the use of WCD in patients at high risk for sudden cardiac death is effective and safe and adherence to the device is high. The event rate for VA was lower than in comparable patient cohorts. Adherence remains a crucial issue as one patient in the present series died while not wearing the device.

Gender aspects in cardiooncology.

BACKGROUND: Cardiooncology is a relatively new subspeciality, investigating the side effects of cytoreductive therapies on the cardiovascular (CV) system. Gender differences are well known in oncological and CV diseases, but are less elucidated in cardiooncological collectives. METHODS: Five hundred and fifty-one patients (278 male, 273 female) with diagnosed cancer who underwent regular cardiological surveillance were enrolled in the 'MAnnheim Registry for CardioOncology' and followed over a median of 41 (95% confidence interval: 40-43) months. RESULTS: Female patients were younger at the time of first cancer diagnosis [median 60 (range 50-70) vs. 66 (55-75), P = 0.0004], while the most common tumour was breast cancer (49.8%). Hyperlipidaemia was more often present in female patients (37% vs. 25%, P = 0.001). Male patients had a higher cancer susceptibility than female patients. They suffered more often from hypertension (51% vs. 67%, P = 0.0002) or diabetes (14% vs. 21%, P = 0.02) and revealed more often vitamin D deficiency [(U/l) median 26.0 (range 17-38) vs. 16 (9-25), P = 0.002] and anaemia [(g/dl) median 11.8 (range 10.4-12.9) vs. 11.7 (9.6-13.6), P = 0.51]. During follow-up, 140 patients died (male 77, female 63; P = 0.21). An increased mortality rate was observed in male patients (11.4% vs. 14%, P = 0.89), with even higher mortality rates of up to 18.9% vs. 7.7% (P = 0.02) considering tumours that can affect both sexes compared. CONCLUSIONS: Although female patients were younger at the time of first cancer diagnosis, male patients had both higher cancer susceptibility and an increased mortality risk. Concomitant CV diseases were more common in male patients.

Distinct Patterns of Blood Cytokines Beyond a Cytokine Storm Predict Mortality in COVID-19.

BACKGROUND: COVID-19 comprises several severity stages ranging from oligosymptomatic disease to multi-organ failure and fatal outcomes. The mechanisms why COVID-19 is a mild disease in some patients and progresses to a severe multi-organ and often fatal disease with respiratory failure are not known. Biomarkers that predict the course of disease are urgently needed. The aim of this study was to evaluate a large spectrum of established laboratory measurements. PATIENTS AND METHODS: Patients from the prospective PULMPOHOM and CORSAAR studies were recruited and comprised 35 patients with COVID-19, 23 with conventional pneumonia, and 28 control patients undergoing elective non-pulmonary surgery. Venous blood was used to measure the serum concentrations of 79 proteins by Luminex multiplex immunoassay technology. Distribution of biomarkers between groups and association with disease severity and outcomes were analyzed. RESULTS: The biomarker profiles between the three groups differed significantly with elevation of specific proteins specific for the respective conditions. Several biomarkers correlated significantly with disease severity and death. Uniform manifold approximation and projection (UMAP) analysis revealed a significant separation of the three disease groups and separated between survivors and deceased patients. Different models were developed to predict mortality based on the baseline measurements of several protein markers. A score combining IL-1ra, IL-8, IL-10, MCP-1, SCF and CA-9 was associated with significantly higher mortality (AUC 0.929). DISCUSSION: Several newly identified blood markers were significantly increased in patients with severe COVID-19 (AAT, EN-RAGE, myoglobin, SAP, TIMP-1, vWF, decorin) or in patients that died (IL-1ra, IL-8, IL-10, MCP-1, SCF, CA-9). The use of established assay technologies allows for rapid translation into clinical practice.

Effects of selective heart rate reduction with ivabradine on LV function and central hemodynamics in patients with chronic coronary syndrome.

OBJECTIVES: We assessed left ventricular (LV) function and central hemodynamic effects in patients with a heart rate (HR) at rest of ≥70 beats per minute (bpm) and chronic coronary syndrome (CCS) after long-term treatment with ivabradine compared to placebo by cardiac magnetic resonance (CMR) imaging. METHODS AND RESULTS: In a randomized, double-blinded, prospective cross-over design, 23 patients (18 male, 5 female) were treated with ivabradine (7.5 mg bid) or placebo for 6 months. CMR imaging was performed at baseline and after 6 and 12 months to determine LV functional parameters.Mean resting HR on treatment with ivabradine was 58 ± 8.2 bpm and 70.2 ± 8.3 bpm during placebo (p < 0.0001).There was no difference in systolic LV ejection fraction (ivabradine 57.4 ± 11.2% vs placebo 53.0 ± 10.9%, p = 0.18), indexed end-diastolic (EDVi) or end-systolic volumes (ESVi). Indexed stroke volume (SVi) (ml/m2) remained unchanged after treatment with ivabradine. Volume time curve parameters reflecting systolic LV function (peak ejection rate and time) were unaffected by ivabradine, while both peak filling rate (PFR) and PFR/EDV were significantly increased. Mean aortic velocity (cm/s) was significantly reduced during treatment with ivabradine (ivabradine 6.7 ± 2.7 vs placebo 9.0 ± 3.4, p = 0.01). Aortic flow parameters were correlated to parameters of vascular stiffness. The strongest correlation was revealed for mean aortic velocity with aortic distensibility (AD) (r = -0.86 [-0.90 to -0.85], p < 0.0001). CONCLUSION: Long-term reduction of HR with ivabradine in patients with CCS improved diastolic function and reduced mean aortic flow velocity.

Arterial Stiffness Is Associated With Increased Symptom Burden in Patients With Atrial Fibrillation.

BACKGROUND: Increased arterial stiffness (AS) has been described as a predictor of atrial fibrillation (AF). This study was performed to assess whether increased AS leads to a higher symptom burden in patients with AF. METHODS: One hundred sixty-two consecutive patients (104 male, 58 female) with diagnosed AF (paroxysmal or persistent) were enrolled. Symptoms most likely attributable to AF were quantified according to the Canadian Cardiovascular Society Severity of Atrial Fibrillation (SAF) scale. AS indices (aortic distensibility, cyclic circumferential strain, and aortic compliance) were characterized using transoesophageal echocardiography. RESULTS: The cohort was divided into asymptomatic to oligosymptomatic (SAF scale 0-1, n = 78 [48.1%]) and symptomatic (SAF scale ≥ 2, n = 84 [51.9%]) patients. Symptomatic patients tended to be younger (median, 75 [interquartile range (IQR) 67-80] vs 71 [65-79]; P = 0.047) and were more likely to be female (22 [28.2%] vs 36 [42.9%]; P = 0.052). Hypertension was more frequent in symptomatic patients. Aortic compliance indices each were reduced in symptomatic patients, most pronounced for aortic compliance (median, 0.05 [IQR 0.03-0.06] vs 0.04 [0.03-0.05] cm/mm Hg; P = 0.01) followed by cyclic circumferential strain (median, 0.09 [IQR 0.07-0.11] vs 0.07 [0.04-0.10]; P = 0.02) and aortic distensibility (10-3 mm Hg-1, median, 1.74 [IQR 1.34-2.24] vs 1.54 [1.12-2.08]; P = 0.03). Multivariable analysis revealed aortic compliance as an independent predictor for symptoms in patients with AF with an odds ratio of 2.6 (95% confidence interval, 1.2-3.4; P = 0.003). CONCLUSIONS: AS contributes to a high symptom burden in patients with AF, emphasizing the prognostic role of AS in the early detection and prevention in patients with AF.

Effects of edoxaban and warfarin on vascular remodeling: Atherosclerotic plaque progression and collateral artery growth.

BACKGROUND AND PURPOSE: Oral anticoagulation prevents thromboembolism in atrial fibrillation. Factor Xa inhibitors, like edoxaban, are known to reduce inflammation and proliferation of smooth muscle cells, while vitamin K antagonism can cause vascular calcific damage. The influence of edoxaban compared to warfarin on vascular remodeling, atherosclerosis and arteriogenesis is unknown. EXPERIMENTAL APPROACH: Apolipoprotein E knockout (ApoE -/-) mice were fed cholesterol-rich diet alone (control, co), with warfarin+vitamin K1 (warf) or with edoxaban (Edo) for 8 weeks. After 6 weeks, femoral artery ligation was performed. KEY RESULTS: There was no difference in hind-limb perfusion restoration between the three groups after 14 days (Co 0.36 ± 0.05 vs. Warf 0.39 ± 0.09 (p = .39), Co vs. Edo 0.51 ± 0.06 (p = .089), Warf vs. Edo (p = .83)) after ligation. Immuno-histologically, there was no difference in smooth muscle cell count in both hindlimbs between the three groups or in the amount of perivascular macrophages in collateral-bearing hindlimb tissue. Edoxaban showed the lowest amount of plaque tissue in the aortic sinus tissue (Co 74 ± 11% vs. Edo 62 ± 12% (p = .024), Co vs. Warf 69 ± 14% (p = .30), Edo vs. Warf (p = .14)) as well as the least amount of fibrosis (Co 3.1 ± 0.9% vs. Edo 1.7 ± 0.6% (p = .027), Co vs. Warf 4.1 ± 0.7% (p = .081), Edo vs. Warf (p < .001)). No difference in mRNA content of inflammatory cytokines in muscle tissue or spleen was detected between the three groups. CONCLUSION AND IMPLICATIONS: These data suggest that treatment with edoxaban unlike warfarin prevents vascular maladaptive remodeling, which may be clinically important.

Effects of heart rate reduction with ivabradine on vascular stiffness and endothelial function in chronic stable coronary artery disease.

INTRODUCTION: Epidemiological and clinical studies have shown a relevant association between heart rate and cardiovascular mortality. Experimental studies identified vascular effects of heart rate reduction with the If channel inhibitor ivabradine. Therefore, the effects of heart rate reduction on endothelial function and indices of arterial stiffness were examined in patients with stable coronary artery disease in a prospective, placebo-controlled clinical crossover study. METHODS AND RESULTS: Twenty-three patients (18 men and 5 women) with a resting heart rate (HR) of at least 70 beats per minute (bpm) and stable coronary artery disease were enrolled in this study. In a cross-over design, all patients were treated with ivabradine (Iva, 7.5 mg b.i.d.) and placebo for 6 months each. Iva reduced heart rate by 11.4 bpm (Iva 58.8 ±â€Š8.2 bpm vs. placebo 70.2 ±â€Š8.3 bpm, P < 0.0001). Augmentation index (AIx75), carotid-femoral pulse wave velocity (cfPWV) and central aortic blood pressure were measured using applanation tonometry (SphygmoCor). HRR by Iva increased AIx75 by 12.4% (Iva 24.3 ±â€Š10.5% vs. placebo 21.3 ±â€Š10.1%, P < 0.05) and reduced cfPWV by 14.1% (Iva 6.3 ±â€Š1.7 m/s vs. placebo 7.3 ±â€Š1.4 m/s, P < 0.01). Iva increased mean central blood pressure by 7.8% (Iva 107.5 ±â€Š15.4 mmHg vs. placebo 99.1 ±â€Š12.2 mmHg, P < 0.001). Endothelial function was determined measuring the flow-mediated vasodilation (FMD) of the brachial artery. HRR by Iva increased FMD by 18.5% (Iva 7.3 ±â€Š2.2% vs. placebo 6.0 ±â€Š2.0%, P < 0.001). Aortic distensibility was characterized by MRI. HRR by Iva increased aortic distensibility by 33.3% (Iva 0.003 ±â€Š0.001/mmHg vs. placebo 0.002 ±â€Š0.010/mmHg, P < 0.01) and circumferential cyclic strain by 37.1% (Iva 0.062 ±â€Š0.027 vs. placebo 0.039 ±â€Š0.018, P < 0.0001). CONCLUSION: Heart rate reduction with Iva increased endothelium-dependent vasodilation and reduced arterial stiffness in patients with stable CAD. These findings corroborate and expand the results collected in experimental studies and indicate the importance of heart rate as a determinant of vascular function.

Fleckenstein's hypothesis revisited: excessive myocardial calcification after prolonged high dose catecholamine treatment: a case report.

BACKGROUND: Myocardial calcification after prolonged highly dosed catecholamine treatment has been described experimentally. Here, we demonstrate myocardial calcifications by high-dose catecholamine treatment leading to chronic heart failure in patients. CASE SUMMARY: A 62-year-old Caucasian woman presented with central pulmonary embolism, developing acute heart failure, and cardiogenic shock. Twenty-six days of high-dose norepinephrine treatment had to be administered to maintain circulation. After 74 days of intensive care treatment, the patient fortunately recovered but was readmitted to emergency ward because of dyspnoea and congestion. Computed tomography pulmonary angiography ruled out recurrence of pulmonary embolism, but depicted massive intramural cardiac calcifications, which were not present before treatment. Coronary angiography showed normal coronary arteries, and myocardial biopsy excluded infectious myocarditis. There was no evidence for sarcoidosis, thyroid disease, tuberculosis, or hyperparathyroidism. Oral heart failure treatment was initiated and at the 7 week follow-up the patient remained symptomatic with New York Heart Association functional Class III, while right and left ventricular function had recovered. DISCUSSION: Prolonged activation of the heart by catecholamines leading to myocardial calcifications has first been examined experimentally by Fleckenstein et al. Herein, we are able to show, that this can occur in clinical situations. Careful dosing of catecholamines and early use of non-catecholamine-based haemodynamic support is recommended to avoid consecutive impairment of heart function and heart failure.

Medication knowledge of patients hospitalized for heart failure at admission and after discharge.

BACKGROUND: A substantial aspect of health literacy is the knowledge of prescribed medication. In chronic heart failure, incomplete intake of prescribed drugs (medication non-adherence) is inversely associated with clinical prognosis. Therefore, we assessed medication knowledge in a cohort of patients with decompensated heart failure at hospital admission and after discharge in a prospective, cross-sectional study. METHODS: One hundred and eleven patients presenting at the emergency department with acute decompensated heart failure were included (mean age 78.4±9.2, 59% men) in the study. Patients' medication knowledge was assessed during individual interviews at baseline, course of hospitalization, and 3 months after discharge. Individual responses were compared with the medical records of the referring general practitioner. RESULTS: Median N-terminal prohormone of brain natriuretic peptide plasma concentration in the overall population at baseline was 4,208 pg/mL (2,023-7,101 pg/mL [interquartile range]), 20 patients died between the second and third interview. The number of prescribed drugs increased from 8±3 at baseline to 9±3 after 3 months. The majority of patients did not know the correct number of their drugs. Medication knowledge decreased continuously from baseline to the third interview. At baseline, 37% (n=41) of patients stated the correct number of drugs to be taken, whereas only 18% (n=16) knew the correct number 3 months after discharge (P=0.008). Knowledge was inversely related to N-terminal prohormone of brain natriuretic peptide levels. CONCLUSION: Medication knowledge of patients with acute decompensated heart failure is poor. Despite care in a university hospital, patients' individual medication knowledge decreased after discharge. The study reveals an urgent need for better strategies to improve and promote the knowledge of prescribed medication in these very high-risk patients.

Resting heart rate is an independent predictor of all-cause mortality in the middle aged general population.

BACKGROUND: High resting heart rate (RHR) predicts cardiovascular outcomes in patients with vascular disease and heart failure. We evaluated the prognostic value of RHR in a large contemporary population-based, prospective cohort of individuals without known coronary artery disease. METHODS AND RESULTS: Resting heart rate (RHR) was determined in 4091 individuals (mean age 59.2 ± 7.7; 53 % women) from the Heinz Nixdorf RECALL study, of whom, 3348 were free of heart rate lowering medication. During 10.5 years of follow-up (median), 159 (3.9 %) individuals developed a coronary event and 398 (9.7 %) died of any cause. Persons without any event (n = 3603) had similar heart rates as persons with coronary events (69.5 ± 11 versus 69.9 ± 11 bpm, p = 0.51) but lower heart rates than persons who died (72.3 ± 13 bpm, p < 0.0001). In individuals without heart rate lowering medication, an increase in heart rate by 5 bpm was associated with an increased hazard ratio (HR) for all-cause mortality of 13 % in unadjusted analysis and also upon adjustment for traditional cardiovascular risk factors, including coronary artery calcification [full model: HR (95 % CI) 1.13 (1.07-1.20), p < 0.0001], but not for coronary events [HR 1.02 (0.94-1.11), p = 0.60]. In individuals without heart rate lowering medication, the HR (full model) for heart rate ≥70 versus <70 bpm with regard to all-cause mortality and coronary events was 1.68 (1.30-2.18), p < 0.0001, and 1.20 (0.82-1.77), p = 0.35. Analysis of the entire cohort revealed a continuous relationship of heart rate with all-cause mortality [HR for lowest to highest heart rate quartile 1.64 (1.22-2.22), p = 0.001, full model] but not with coronary events [HR 1.04 (0.65-1.66), p = 0.86]. CONCLUSIONS: In the general population without known coronary artery disease and heart rate lowering medication, elevated RHR is an independent risk marker for all-cause mortality but not for coronary events.

[LDL-Cholesterol--Is there an "LDL hypothesis"?]. / LDL-Cholesterin: Von der Hypothese zur Kausalität.

The term "LDL-Hypothesis" is frequently used to describe the association between LDL cholesterol (LDL-C) and cardiovascular outcomes. In the light of recent results of randomized trials the question arises whether the term hypothesis is still adequate. Considering the causal importance of LDL for the pathogenesis of atherosclerosis, epidemiological evidence and the clear genetic association of LDL-C with cardiovascular risk as well as the large statin trials and the reduction of events by a non-statin intervention in the IMPROVE-IT study, the term "hypothesis" appears to be outdated and should be replaced by "LDL-causality".

Systolic blood pressure variation and mean heart rate is associated with cognitive dysfunction in patients with high cardiovascular risk.

UNLABELLED: Elevated systolic blood pressure (SBP) correlates to cognitive decline and incident dementia. The effects of heart rate (HR), visit to visit HR variation, and visit to visit SBP variation are less well established. Patients without preexisting cognitive dysfunction (N=24 593) were evaluated according to mean SBP, SBP visit to visit variation (coefficient of variation [standard deviation/mean×100%], CV), mean HR, and visit to visit HR variation (HR-CV) in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease. Cognitive function was assessed with mini mental state examination. Cognitive dysfunction (fall in mini mental state examination ≤24 points), important cognitive decline (drop of ≥5 points), and cognitive deterioration (drop of >1 point per year or decline to <24 points) were assessed. SBP and HR were measured over 10.7±2.2 (mean±SD) visits. Mean SBP, mean HR, and SBP-CV were associated with cognitive decline, dysfunction, and deterioration (all P<0.01, unadjusted). After adjustment, only SBP-CV (P=0.0030) and mean HR (P=0.0008) remained predictors for cognitive dysfunction (odds ratios [95% confidence intervals], 1.32 [1.10-1.58] for 5th versus 1st quintile of SBP-CV and 1.40 [1.18-1.66] for 5th versus 1st quintile of mean HR). Similar effects were observed for cognitive decline and deterioration. SBP-CV and mean HR showed additive effects. In conclusion, SBP-CV and mean HR are independent predictors of cognitive decline and cognitive dysfunction in patients at high CV risk. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00153101.

Heart rate is associated with increased risk of major cardiovascular events, cardiovascular and all-cause death in patients with stable chronic cardiovascular disease: an analysis of ONTARGET/TRANSCEND.

AIMS: Heart rate was proposed as an emergent cardiovascular (CV) risk factor. Previous studies have shown associations between increased heart rate and CV risk in various populations. We aimed to evaluate the prognostic relevance of heart rate in a large contemporaneous medically optimized cohort of patients with stable chronic CV disease. METHODS AND RESULTS: In a post hoc analysis of the ONTARGET/TRANSCEND trials, we evaluated associations between baseline and average heart rate in trial with CV risk in 31, 531 patients followed for a median of 5 years. The primary outcome, major vascular events (MVE), was a composite of CV death, myocardial infarction (MI), stroke, and congestive heart failure (CHF). Pre-specified secondary outcomes included all-cause death and the individual components of the primary outcome. Associations between heart rate and outcomes were computed with heart rate as a continuous variable, baseline heart rate >70 vs ≤ 70 bpm, and across heart rate quintiles, adjusting for other markers of risk, beta-blocker and non-dihydropyridine calcium channel blocker use. For each 10 bpm increase in baseline and average heart rate, we observed a significant increase in risk of MVE, CV death, CHF and all-cause death. There was a continuous relationship between MVE and baseline and, more importantly, average in-trial heart rate, with no observed threshold. MVE, CV death, stroke, CHF, and all-cause death increased across heart rate quintiles. There was no association between MI and HR. Results were consistent in clinically relevant subgroups. There were modest but significant improvements in C-statistic and in statistical measures of model calibration for models that included heart rate for MVE, CV death, CHF and all-cause death. CONCLUSIONS: This large study examined and quantitated associations between heart rate and CV events in a contemporary medically optimized population with stable CV disease. Resting and, in particular, in-trial average heart rate are independently associated with significant increases in CV events and all-cause death.

Heart rate: a global target for cardiovascular disease and therapy along the cardiovascular disease continuum.

Heart rate is a predictor of cardiovascular and all-cause mortality in the general population and in patients with cardiovascular disease. Increased resting heart rate multiplies risk and interferes at all stages of the cardiovascular disease continuum initiating from endothelial dysfunction and continuing via atherosclerotic lesion formation and plaque rupture to end-stage cardiovascular disease. As a therapeutic target, heart rate is accessible via numerous pharmacological interventions. The concept of selective heart rate reduction by the I(f) current inhibitor ivabradine provides an option to intervene effectively along the chain of events and to define the specific and prognostic role of heart rate for patients with coronary artery disease and heart failure. Future interventional studies will further clarify the significance of heart rate and targeted heart rate reduction for primary and secondary prevention in cardiovascular and cerebrovascular events.

Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction.

AIMS: In diabetes mellitus, heart failure with preserved ejection fraction (HFPEF) is a significant comorbidity. No therapy is available that improves cardiovascular outcomes. The aim of this study was to characterize myocardial function and ventricular-arterial coupling in a mouse model of diabetes and to analyse the effect of selective heart rate (HR) reduction by If-inhibition in this HFPEF-model. METHODS AND RESULTS: Control mice, diabetic mice (db/db), and db/db mice treated for 4 weeks with the If-inhibitor ivabradine (db/db-Iva) were compared. Aortic distensibility was measured by magnetic resonance imaging. Left ventricular (LV) pressure-volume analysis was performed in isolated working hearts, with biochemical and histological characterization of the cardiac and aortic phenotype. In db/db aortic stiffness and fibrosis were significantly enhanced compared with controls and were prevented by HR reduction in db/db-Iva. Left ventricular end-systolic elastance (Ees) was increased in db/db compared with controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/µL, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered Ees (4.0 ± 1.1 mmHg/µL, P < 0.01), and improved the other contractility parameters. In db/db active relaxation was prolonged and end-diastolic capacitance was lower compared with controls (28 ± 3 vs. 48 ± 8 µL, P < 0.01). These parameters were ameliorated by HR reduction. Neither myocardial fibrosis nor hypertrophy were detected in db/db, whereas titin N2B expression was increased and phosphorylation of phospholamban was reduced both being prevented by HR reduction in db/db-Iva. CONCLUSION: In db/db, a model of HFPEF, selective HR reduction by If-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, If-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans.

Effects of omega-3 fatty acids on postprandial triglycerides and monocyte activation.

OBJECTIVE: Epidemiologic studies suggest that elevated postprandial triglycerides (ppTG) are associated with future cardiovascular events. Monocyte activation plays an important role in vascular diseases. Omega-3 fatty acids (n3-FA) lower fasting TG levels. The effects of n3-FA on ppTG and the role of ppTG for monocyte activation are insufficiently understood. METHODS AND RESULTS: 23 healthy volunteers and 30 non-diabetic patients with documented coronary artery disease were subjected to an oral TG tolerance test (OTTT) consisting of 80 g cream fat or to water as control (H(2)O). Patients were treated with 4 g n3-FA/day or placebo for 3 weeks in a randomized, placebo-controlled, double-blind, crossover study. Relative postprandial TG increase reached its maximum 4 h after fat intake (185.1 ± 10.9% of baseline). n3-FA reduced fasting TG from 137.1 ± 12.9 to 112.2 ± 8.6 mg/dl (p < 0.05), and maximum ppTG concentrations from 243.6 ± 24.6 to 205.8 ± 17.1 mg/dl (p < 0.05), while relative TG increase (192.8 ± 12.7%) was comparable to placebo. Relative monocytopenia and neutrophilia were detected following fat intake, which was unaffected by n3-FA and also detectable in the H(2)O group. Serum chemotactic cytokine (MCP1 and fractalkine) concentrations and monocyte migration were not affected by fat intake or n3-FA. Monocyte activation markers CD11b and CD14, monocyte subpopulations CD16(+)CD14(high) and CD16(+)CD14(low), sICAM serum levels and markers of oxidative stress remained unchanged by fat intake or n3-FA. CONCLUSION: The postprandial TG increase does not stimulate monocytes beyond their circadian activation patterns. n3-FA reduce fasting TG and the postprandial TG increase. n3-FA may therefore allow to prospectively study whether selected patients benefit from TG-lowering independent of LDL- and HDL-cholesterol.