Endomyocardial biopsy: safety and prognostic utility in paediatric and adult myocarditis in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis Long-Term Registry.

BACKGROUND AND AIMS: Contemporary multicentre data on clinical and diagnostic spectrum and outcome in myocarditis are limited. Study aims were to describe baseline features, 1-year follow-up, and baseline predictors of outcome in clinically suspected or biopsy-proven myocarditis (2013 European Society of Cardiology criteria) in adult and paediatric patients from the EURObservational Research Programme Cardiomyopathy and Myocarditis Long-Term Registry. METHODS: Five hundred eighty-one (68.0% male) patients, 493 adults, median age 38 (27-52) years, and 88 children, aged 8 (3-13) years, were divided into 3 groups: Group 1 (n = 233), clinically suspected myocarditis with abnormal cardiac magnetic resonance; Group 2 (n = 222), biopsy-proven myocarditis; and Group 3 (n = 126) clinically suspected myocarditis with normal or inconclusive or no cardiac magnetic resonance. Baseline features were analysed overall, in adults vs. children, and among groups. One-year outcome events included death/heart transplantation, ventricular assist device (VAD) or implantable cardioverter defibrillator (ICD) implantation, and hospitalization for cardiac causes. RESULTS: Endomyocardial biopsy, mainly right ventricular, had a similarly low complication rate in children and adults (4.7% vs. 4.9%, P = NS), with no procedure-related death. A classical myocarditis pattern on cardiac magnetic resonance was found in 31.3% of children and in 57.9% of adults with biopsy-proven myocarditis (P < .001). At 1-year follow-up, 11/410 patients (2.7%) died, 7 (1.7%) received a heart transplant, 3 underwent VAD (0.7%), and 16 (3.9%) underwent ICD implantation. Independent predictors at diagnosis of death or heart transplantation or hospitalization or VAD implantation or ICD implantation at 1-year follow-up were lower left ventricular ejection fraction and the need for immunosuppressants for new myocarditis diagnosis refractory to non-aetiology-driven therapy. CONCLUSIONS: Endomyocardial biopsy was safe, and cardiac magnetic resonance using Lake Louise criteria was less sensitive, particularly in children. Virus-negative lymphocytic myocarditis was predominant both in children and adults, and use of immunosuppressive treatments was low. Lower left ventricular ejection fraction and the need for immunosuppressants at diagnosis were independent predictors of unfavourable outcome events at 1 year.

Sacubitril/valsartan in heart failure: efficacy and safety in and outside clinical trials.

Heart failure (HF) treatment has changed substantially over the last 30 years, leading to significant reductions in mortality and hospital admissions in patients with HF with reduced ejection fraction (HFrEF). Currently, the optimization of guideline-directed chronic HF therapy remains the mainstay to further improve quality of life, mortality, and HF hospitalizations for patients with HFrEF. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (S/V) has an important role in the treatment of patients with HFrEF. The PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) randomized controlled trial has established solid evidence for the treatment of HFrEF in various subgroups. Apart from HFrEF, several studies have been conducted using S/V in various indications: patients hospitalized with acute decompensated HF, HF with preserved ejection fraction, acute myocardial infarction with reduced ejection fraction, uncontrolled and resistant hypertension, and chronic kidney disease. Data from the German Institute for Drug Use Evaluation reveal that implementation of S/V has increased steadily over time and, by the end of 2021, an estimated 266 000 patients were treated with S/V in Germany. The estimated cumulative real-world patient exposure is >5.5 million patient-treatment years worldwide. The number of patients treated with S/V largely exceeds the number of patients treated in clinical trials, and the current indication for S/V is larger than the strict inclusion/exclusion criteria of the randomized trials. Especially elderly patients, women, and patients with more and more severe comorbidities are underrepresented in the clinical trials. We therefore aimed to summarize the importance of S/V in HF in terms of efficacy and safety in clinical trials and daily clinical practice.

Heart-Focused Anxiety, General Anxiety, Depression and Health-Related Quality of Life in Patients with Atrial Fibrillation Undergoing Pulmonary Vein Isolation.

(1) Background: Atrial fibrillation (AF) is associated with anxiety, depression, and chronic stress, and vice versa. The purpose of this study was to evaluate potential effects of pulmonary vein isolation (PVI) on psychological factors. (2) Methods: Psychological assessment was performed before PVI as well as after six months. (3) Results: A total of 118 patients [age 64 ± 9 years, 69% male, left ventricular ejection fraction 57 ± 8%, 56% paroxysmal AF] undergoing PVI were included. After PVI, significant improvements were observed in the mean total heart-focused anxiety (HFA) score, as well as in the Cardiac Anxiety Questionnaire (CAQ) sub-scores: HFA attention, HFA fear, and HFA avoidance scores. Subgroup analyses showed an association of improvement with freedom of documented AF recurrence. Mean scores of general anxiety and depression evaluated by the Hospital Anxiety and Depression Scale (HADS) decreased significantly after PVI in all subgroups regardless of AF recurrence. Further, both physical and mental composite scores of the Short Form Health Survey (SF-12) increased significantly from baseline. (4) Conclusions: PVI results in a significant reduction in HFA. Improvements in general anxiety and depressive symptoms did not seem to be related only to rhythm control per se. Therefore, CAQ may represent a more specific evaluation tool as HADS in patients with AF.

'Time is prognosis' in heart failure: time-to-treatment initiation as a modifiable risk factor.

In heart failure (HF), acute decompensation can occur quickly and unexpectedly because of worsening of chronic HF or to new-onset HF diagnosed for the first time ('de novo'). Patients presenting with acute HF (AHF) have a poor prognosis comparable with those with acute myocardial infarction, and any delay of treatment initiation is associated with worse outcomes. Recent HF guidelines and recommendations have highlighted the importance of a timely diagnosis and immediate treatment for patients presenting with AHF to decrease disease progression and improve prognosis. However, based on the available data, there is still uncertainty regarding the optimal 'time-to-treatment' effect in AHF. Furthermore, the immediate post-worsening HF period plays an important role in clinical outcomes in HF patients after hospitalization and is known as the 'vulnerable phase' characterized by high risk of readmission and early death. Early and intensive treatment for HF patients in the 'vulnerable phase' might be associated with lower rates of early readmission and mortality. Additionally, in the chronic stable HF outpatient, treatments are often delayed or not initiated when symptoms are stable, ignoring the risk for adverse outcomes such as sudden death. Consequently, there is a dire need to better identify HF patients during hospitalization and after discharge and treating them adequately to improve their prognosis. HF is an urgent clinical scenario along all its stages and disease conditions. Therefore, time plays a significant role throughout the entire patient's journey. Therapy should be optimized as soon as possible, because this is beneficial regardless of severity or duration of HF. Time lavished before treatment initiation is recognized as important modifiable risk factor in HF.

Myopathic Cardiac Genotypes Increase Risk for Myocarditis.

Impairments in certain cardiac genes confer risk for myocarditis in children. To determine the extent of this association, we performed genomic sequencing in predominantly adult patients with acute myocarditis and matched control subjects. Putatively deleterious variants in a broad set of cardiac genes were found in 19 of 117 acute myocarditis cases vs 34 of 468 control subjects (P = 0.003). Thirteen genes classically associated with cardiomyopathy or neuromuscular disorders with cardiac involvement were implicated, including >1 associated damaging variant in DYSF, DSP, and TTN. Phenotypes of subjects who have acute myocarditis with or without deleterious variants were similar, indicating that genetic testing is necessary to differentiate them.

Timely and individualized heart failure management: need for implementation into the new guidelines.

Due to remarkable improvements in heart failure (HF) management over the last 30 years, a significant reduction in mortality and hospitalization rates in HF patients with reduced ejection fraction (HFrEF) has been observed. Currently, the optimization of guideline-directed chronic HF therapy remains the mainstay to further improve outcomes for patients with HFrEF to reduce mortality and HF hospitalization. This includes established device therapies, such as implantable defibrillators and cardiac resynchronization therapies, which improved patients' symptoms and prognosis. Over the last 10 years, new HF drugs have merged targeting various pathways, such as those that simultaneously suppress the renin-angiotensin-aldosterone system and the breakdown of endogenous natriuretic peptides (e.g., sacubitril/valsartan), and those that inhibit the If channel and, thus, reduce heart rate (e.g., ivabradine). Furthermore, the treatment of patient comorbidities (e.g., iron deficiency) has shown to improve functional capacity and to reduce hospitalization rates, when added to standard therapy. More recently, other potential treatment mechanisms have been explored, such as the sodium/glucose co-transporter inhibitors, the guanylate cyclase stimulators and the cardiac myosin activators. In this review, we summarize the novel developments in HFrEF pharmacological and device therapy and discuss their implementation strategies into practice to further improve outcomes.

Changes in quality of life, depression, general anxiety, and heart-focused anxiety after defibrillator implantation.

AIMS: The Anxiety-CHF (Anxiety in patients with Chronic Heart Failure) study investigated heart-focused anxiety (HFA, with the dimensions fear, attention, and avoidance of physical activity), general anxiety, depression, and quality of life (QoL) in patients with heart failure. Psychological measures were assessed before and up to 2 years after the implantation of an implantable cardioverter defibrillator (ICD) with or without cardiac resynchronization therapy defibrillator (CRT-D). METHODS AND RESULTS: One hundred thirty-two patients were enrolled in this monocentric prospective study (44/88 CRT-D/ICD, mean age 61 ± 14 years, mean left ventricular ejection fraction 31 ± 9%, and 29% women). Psychological assessment was performed before device implantation as well as after 5, 12, and 24 months. After device implantation, mean total HFA, HFA-fear, HFA-attention, general anxiety, and QoL improved significantly. Depression and HFA-related avoidance of physical activity did not change. CRT-D patients compared with ICD recipients and women compared with men reported worse QoL at baseline. Younger patients (

Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Predictors of heart-focused anxiety in patients with stable heart failure.

BACKGROUND: It has been shown that heart-focused anxiety raises the risk of adverse outcomes in patients with heart disease. Yet, there is a lack of studies investigating this association. We aim at identifying predictors of heart-focused anxiety in patients with stable heart failure to facilitate the identification of individuals with increased risk for adverse outcomes. METHODS: We assessed heart-focused anxiety and a set of psychological, demographic/lifestyle, and medical/laboratory variables in a sample of 107 patients with stable chronic heart failure to identify predictors of heart-focused anxiety. RESULTS: Heart-focused anxiety was best predicted by self-reported anxiety and quality of life. Moreover, the personality dimension conscientiousness as well as physical activity, and the laboratory value of renal function, the estimated glomerular filtration rate (eGFR), had predictive validity for heart-focused anxiety. LIMITATIONS: The present findings should be replicated in a longitudinal design with a less selective sample including more women and participants with more divers ethnical backgrounds. CONCLUSION: Heart-focused anxiety is predictable by psychological and lifestyle variables. eGFR, as a laboratory marker for renal function, showed also predictive validity. The awareness of such predictors may help detecting comorbid underlying heart-focused anxiety and thus identify patients with an increased need for psychological care.

Management of hyperkalaemia in acute kidney injury in a heart failure patient with patiromer.

AIMS: One prevalent comorbidity of chronic heart failure (CHF) is chronic kidney disease(CKD). Hyperkalemia is associated with both CHF and CKD, which often leads to withdrawal of heart failure medications in clinical praxis. METHODS AND RESULTS: A patient is presented who suffered from acute kidney injury with pre-existing CKD as heart failure comorbidity and a history of hyperkalemia. CONCLUSIONS: This case shows that potassium levels remained stable in acute kidney injury under ongoing heart failure medications, including an MRA, with the use of the potassium binder patiromer.

ESC EORP Cardiomyopathy Registry: real-life practice of genetic counselling and testing in adult cardiomyopathy patients.

AIMS: Cardiomyopathies comprise a heterogeneous group of diseases, often of genetic origin. We assessed the current practice of genetic counselling and testing in the prospective European Society of Cardiology EURObservational Research Programme Cardiomyopathy Registry. METHODS AND RESULTS: A total of 3208 adult patients from 69 centres in 18 countries were enrolled. Genetic counselling was performed in 60.8% of all patients [75.4% in hypertrophic cardiomyopathy (HCM), 39.2% in dilated cardiomyopathy (DCM), 70.8% in arrhythmogenic right ventricular cardiomyopathy (ARVC), and 49.2% in restrictive cardiomyopathy (RCM), P < 0.001]. Comparing European geographical areas, genetic counselling was performed from 42.4% to 83.3% (P < 0.001). It was provided by a cardiologist (85.3%), geneticist (15.1%), genetic counsellor (11.3%), or a nurse (7.5%) (P < 0.001). Genetic testing was performed in 37.3% of all patients (48.8% in HCM, 18.6% in DCM, 55.6% in ARVC, and 43.6% in RCM, P < 0.001). Index patients with genetic testing were younger at diagnosis and had more familial disease, family history of sudden cardiac death, or implanted cardioverter defibrillators but less co-morbidities than those not tested (P < 0.001 for each comparison). At least one disease-causing variant was found in 41.7% of index patients with genetic testing (43.3% in HCM, 33.3% in DCM, 51.4% in ARVC, and 42.9% in RCM, P = 0.13). CONCLUSIONS: This is the first detailed report on the real-life practice of genetic counselling and testing in cardiomyopathies in Europe. Genetic counselling and testing were performed in a substantial proportion of patients but less often than recommended by European guidelines and much less in DCM than in HCM and ARVC, despite evidence for genetic background.

Adherence to Antihypertensive Drugs Assessed by Hyphenated High-Resolution Mass Spectrometry Analysis of Oral Fluids.

Background It is currently unknown if antihypertensive drugs can be monitored in oral fluid (OF) using liquid chromatography coupled to high-resolution mass spectrometry. Methods and Results We assessed adherence using liquid chromatography coupled to high-resolution mass spectrometry in OF, plasma, and urine of 56 consecutive patients with hypertension referred to a tertiary hypertension unit. Of these patients, 59% were completely adherent (all drugs detectable in urine), whereas 29% and 13% were partially adherent (1 drug not detectable in urine) or nonadherent (>1 drug not detectable in urine), respectively. Adherent patients were on fewer antihypertensive drugs (P=0.001), had fewer daily drug doses (P=0.012), and had lower 24-hour ambulatory systolic (P=0.012) and diastolic (P=0.009) blood pressures than nonadherent or partially adherent patients. Most drugs were detected in urine compared with plasma and OF (181 versus 119 versus 88; P=0.001). Compared with urine and plasma, detection rates of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and diuretics were lower in OF. There was no difference in the frequency of detecting ß blockers (P=1.0) and calcium channel blockers (P=0.063) when comparing OF with urine. There was no difference in the number of calcium channel blockers (P=0.727), ß blockers (P=1.000), thiazide diuretics (P=0.125), and α-2 agonists (P=0.125) identified between OF and plasma. Conclusions This study shows the feasibility of drug adherence testing for several antihypertensive drugs, especially those without acidic components, in OF, with a similar recovery compared with plasma. Therefore, drug adherence testing in OF should be further explored as a noninvasive approach, which can easily be performed in an "out-of-office" setting.

COVID-19 pandemic and troponin: indirect myocardial injury, myocardial inflammation or myocarditis?

The initial mechanism for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is the binding of the virus to the membrane-bound form of ACE2, which is mainly expressed in the lung. Since the heart and the vessels also express ACE2, they both could become targets of the virus. However, at present the extent and importance of this potential involvement are unknown. Cardiac troponin levels are significantly higher in patients with more severe infections, patients admitted to intensive care units or in those who have died. In the setting of COVID-19, myocardial injury, defined by an increased troponin level, occurs especially due to non-ischaemic myocardial processes, including severe respiratory infection with hypoxia, sepsis, systemic inflammation, pulmonary thrombosis and embolism, cardiac adrenergic hyperstimulation during cytokine storm syndrome, and myocarditis. At present, there are limited reports on definite diagnosis of myocarditis caused by SARS-CoV-2 in humans and limited demonstration of the virus in the myocardium. In conclusion, although the heart and the vessels are potential targets in COVID-19, there is currently limited evidence on the direct infection of the myocardium by SARS-CoV-2. Additional pathological studies and autopsy series will be very helpful to clarify the potentiality of COVID-19 to directly infect the myocardium and cause myocarditis.

Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future.

In contrast to the wealth of proven therapies for heart failure with reduced ejection fraction (HFrEF), therapeutic efforts in the past have failed to improve outcomes in heart failure with preserved ejection fraction (HFpEF). Moreover, to this day, diagnosis of HFpEF remains controversial. However, there is growing appreciation that HFpEF represents a heterogeneous syndrome with various phenotypes and comorbidities which are hardly to differentiate solely by LVEF and might benefit from individually tailored approaches. These hypotheses are supported by the recently presented PARAGON-HF trial. Although treatment with LCZ696 did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among HFpEF patients, subanalyses suggest beneficial effects in female patients and those with an LVEF between 45 and 57%. In the future, prospective randomized trials should focus on dedicated, well-defined subgroups based on various information such as clinical characteristics, biomarker levels, and imaging modalities. These could clarify the role of LCZ696 in selected individuals. Furthermore, sodium-glucose cotransporter-2 inhibitors have just proven efficient in HFrEF patients and are currently also studied in large prospective clinical trials enrolling HFpEF patients. In addition, several novel disease-modifying drugs that pursue different strategies such as targeting cardiac inflammation and fibrosis have delivered preliminary optimistic results and are subject of further research. Moreover, innovative device therapies may enhance management of HFpEF, but need prospective adequately powered clinical trials to confirm safety and efficacy regarding clinical outcomes. This review highlights the past, present, and future therapeutic approaches in HFpEF.

Measuring Anxiety in Older Adults: Development, Diagnostic Accuracy, and Preliminary Validation of a Short-Form of the German Geriatric Anxiety Scale (GAS-G-SF).

Anxiety symptoms and anxiety disorders are highly prevalent among older adults, and are associated with considerable distress, functional impairment, and burden. Also, there is growing need for brief instruments to measure anxiety symptoms in primary care and geriatric medical settings. Therefore, the current study focuses on the development and psychometric evaluation of a short-form of the Geriatric Anxiety Scale (GAS-G), a well-established anxiety instrument for use with older adults. Study 1 draws on the original data from the GAS-G validation study (N = 242) to develop the short-form (GAS-G-SF) and determines whether the results replicate with the short-form. Study 2 extends the validation of the GAS-G-SF to a clinical sample (N = 156; 62 patients with heart disease, 94 patients with Parkinson's disease). Overall, the GAS-G-SF showed promising psychometric properties in terms of internal consistency and validity. Also, the GAS-G-SF showed good discriminatory power based on receiver operating characteristic curve analysis in both studies. These results support the utility of the GAS-G-SF as a brief assessment measure for anxiety.

Optimization of Heart Failure Treatment by Heart Rate Reduction.

Heart failure (HF) treatment should be optimized in addition to guideline-directed and recommended drugs to achieve an appropriate heart rate (i.e. 50-60 bpm) by ivabradine in patients with a heart rate >70 bpm in sinus rhythm and with an ejection fraction ≤35%. Heart rate reduction was to reduce cardiovascular death and HF hospitalization dependent on baseline resting heart rate. In particular in patients at a heart rate >75 bpm, a reduction in cardiovascular death, all-cause death, HF death, HF hospitalization and all-cause hospitalization has been observed. The optimal heart rate achieved appears to be between 50-60 bpm, if well tolerated as in these patients the lowest event rate is observed on treatment. Heart rate reduction is, therefore, a treatable risk factor in chronic HF. Observational studies support the concept that it is a risk indicator in other cardiovascular and non-cardiovascular conditions. Whether heart rate reduction is also modifying risk in other conditions than chronic HF should be explored in prospective clinical trials.