Clonal hematopoiesis of indeterminate potential: implications for the cardiologists.

Myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and myelofibrosis, are characterized by somatic gene mutations in bone marrow stem cells, which trigger an inflammatory response influencing the development of associated cardiovascular complications. In recent years, the same mutations were found in individuals with cardiovascular diseases even in the absence of hematological alterations. These genetic events allow the identification of a new entity called 'clonal hematopoiesis of indeterminate potential' (CHIP), as it was uncertain whether it could evolve toward hematological malignancies. CHIP is age-related and, remarkably, myocardial infarction, stroke, and heart failure were frequently reported in these individuals and attributed to systemic chronic inflammation driven by the genetic mutation. We reviewed the connection between clonal hematopoiesis, inflammation, and cardiovascular diseases, with a practical approach to improve clinical practice and highlight the current unmet needs in this area of knowledge.

Acute Myocarditis Associated With Desmosomal Gene Variants.

BACKGROUND: The risk of adverse cardiovascular events in patients with acute myocarditis (AM) and desmosomal gene variants (DGV) remains unknown. OBJECTIVES: The purpose of this study was to ascertain the risk of death, ventricular arrhythmias, recurrent myocarditis, and heart failure (main endpoint) in patients with AM and pathogenic or likely pathogenetic DGV. METHODS: In a retrospective international study from 23 hospitals, 97 patients were included: 36 with AM and DGV (DGV[+]), 25 with AM and negative gene testing (DGV[-]), and 36 with AM without genetics testing. All patients had troponin elevation plus findings consistent with AM on histology or at cardiac magnetic resonance (CMR). In 86 patients, CMR changes in function and structure were re-assessed at follow-up. RESULTS: In the DGV(+) AM group (88.9% DSP variants), median age was 24 years, 91.7% presented with chest pain, and median left ventricular ejection fraction (LVEF) was 56% on CMR (P = NS vs the other 2 groups). Kaplan-Meier curves demonstrated a higher risk of the main endpoint in DGV(+) AM compared with DGV(-) and without genetics testing patients (62.3% vs 17.5% vs 5.3% at 5 years, respectively; P < 0.0001), driven by myocarditis recurrence and ventricular arrhythmias. At follow-up CMR, a higher number of late gadolinium enhanced segments was found in DGV(+) AM. CONCLUSIONS: Patients with AM and evidence of DGV have a higher incidence of adverse cardiovascular events compared with patients with AM without DGV. Further prospective studies are needed to ascertain if genetic testing might improve risk stratification of patients with AM who are considered at low risk.

Prevalence, Characteristics, and Outcomes of COVID-19-Associated Acute Myocarditis.

BACKGROUND: Acute myocarditis (AM) is thought to be a rare cardiovascular complication of COVID-19, although minimal data are available beyond case reports. We aim to report the prevalence, baseline characteristics, in-hospital management, and outcomes for patients with COVID-19-associated AM on the basis of a retrospective cohort from 23 hospitals in the United States and Europe. METHODS: A total of 112 patients with suspected AM from 56 963 hospitalized patients with COVID-19 were evaluated between February 1, 2020, and April 30, 2021. Inclusion criteria were hospitalization for COVID-19 and a diagnosis of AM on the basis of endomyocardial biopsy or increased troponin level plus typical signs of AM on cardiac magnetic resonance imaging. We identified 97 patients with possible AM, and among them, 54 patients with definite/probable AM supported by endomyocardial biopsy in 17 (31.5%) patients or magnetic resonance imaging in 50 (92.6%). We analyzed patient characteristics, treatments, and outcomes among all COVID-19-associated AM. RESULTS: AM prevalence among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations considering definite/probable and 4.1 per 1000 considering also possible AM. The median age of definite/probable cases was 38 years, and 38.9% were female. On admission, chest pain and dyspnea were the most frequent symptoms (55.5% and 53.7%, respectively). Thirty-one cases (57.4%) occurred in the absence of COVID-19-associated pneumonia. Twenty-one (38.9%) had a fulminant presentation requiring inotropic support or temporary mechanical circulatory support. The composite of in-hospital mortality or temporary mechanical circulatory support occurred in 20.4%. At 120 days, estimated mortality was 6.6%, 15.1% in patients with associated pneumonia versus 0% in patients without pneumonia (P=0.044). During hospitalization, left ventricular ejection fraction, assessed by echocardiography, improved from a median of 40% on admission to 55% at discharge (n=47; P<0.0001) similarly in patients with or without pneumonia. Corticosteroids were frequently administered (55.5%). CONCLUSIONS: AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.

A 57-year-old man with rapidly progressive pulmonary hypertension.

Pulmonary Tumor Thrombotic Microangiopathy (PTTM) is a rare condition associated with neoplastic disorders, predominantly gastric cancer, leading to pre-capillary Pulmonary Hypertension (PH). The pathologic mechanism involved is a fibrocellular intimal proliferation of small pulmonary vessels sustained by nests of carcinomatous cells lodged in pulmonary vasculature. Clinical presentation is nonspecific, including progressive dyspnea and dry cough. Diagnosis of PTTM is extremely challenging ante-mortem and prognosis is poor. Here we describe the case of a middle-aged man, without known previous cancer history. The clinical course was rapidly unfavorable, with progressive dyspnea and PH associated with hemodynamic instability, eventually culminating in patient's death. PTTM diagnosis was made post-mortem. PTTM should be considered in any patient presenting with unexplained PH, especially if it is rapidly progressive, poorly responsive to standard approaches or there is suspected history of malignancy. A prompt diagnosis of PTTM could help in bringing light into this still under-recognized condition.

Integrating natriuretic peptides and diastolic dysfunction to predict adverse events in high-risk asymptomatic subjects.

BACKGROUND: Natriuretic peptides and diastolic dysfunction have prognostic value in asymptomatic subjects at risk for heart failure. Their integration might further refine the risk stratification process in this setting. Aim of this paper was to explore the possibility to predict heart failure and death combining diastolic dysfunction and natriuretic peptides in an asymptomatic population at risk for heart failure. METHODS: Among 4047 subjects aged ≥55/≤80 years followed by 10 general practitioners in Italy, the DAVID-Berg study prospectively enrolled 623 asymptomatic outpatients at increased risk for heart failure. Baseline evaluation included electrocardiogram, echocardiogram, and natriuretic peptides collection. Based on diastolic dysfunction and natriuretic peptides, subjects were classified in four groups: control group (no diastolic dysfunction/normal natriuretic peptides, 57%), no diastolic dysfunction/high natriuretic peptides (9%), diastolic dysfunction/normal natriuretic peptides (24%), and diastolic dysfunction/high natriuretic peptides (11%). We applied Cox multivariable and Classification and Regression Tree analyses. RESULTS: The mean age of the population was 69 ± 7 years, 44% were women, mean left ventricular ejection fraction was 61%, and 35% had diastolic dysfunction. During a median follow-up of 5.7 years, 95 heart failure/death events occurred. Overall, diastolic dysfunction and natriuretic peptides were predictive of adverse events (respectively, hazard ratio 1.91, confidence interval 1.19-3.05, padjusted = 0.007, and hazard ratio 2.25, confidence interval 1.35-3.74, padjusted = 0.002) with Cox analysis. However, considering the four study subgroups, only the group with diastolic dysfunction/high natriuretic peptides had a significantly worse prognosis compared to the control group (hazard ratio 4.48, confidence interval 2.31-8.70, padjusted < 0.001). At Classification and Regression Tree analysis, diastolic dysfunction/high natriuretic peptides was the strongest prognostic factor (risk range 24-58%). CONCLUSIONS: The DAVID-Berg data suggest that we look for the quite common combination of diastolic dysfunction/high natriuretic peptides to correctly identify asymptomatic subjects at greater risk for incident heart failure/death, thus more suitable for preventive interventions.

An unexpected case of recurrence of pulmonary embolism in a patient recovered from COVID19 in full regimen dose of direct oral anticoagulant drug.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is a pandemic affecting all countries in the world. Italy has been particularly afflicted by the health emergency, and since the peak phase has passed, major concern regarding medium to long term complications due to COVID-19 is arising. Little is known in literature regarding thromboembolic complications once healed after COVID-19. CASE PRESENTATION: A 51-year-old patient recovered from COVID-19 pneumonia complicated by pulmonary embolism (PE) came to the hospital for palpitations and chest pain. Although he was on treatment dose of direct oral anticoagulation (DOAC), massive recurrent PE was diagnosed. CONCLUSION: In the early post COVID-19 era, the question remains regarding the efficacy of DOACs in COVID-19 patients.

Association between sleep disordered breathing, neurocognitive impairment and diastolic function in acute heart failure patients: an insight after the vulnerable phase of the hospitalization.

Sleep disordered breathing (SDB) and neurocognitive impairment (NI) are a typical feature of HF (heart failure), especially with preserved ejection fraction (HFpEF). So far, very few data exist regarding changes in the severity of SDB, the degree of NI, and the diastolic function in acute HF (AHF) patients and during follow up. In a population of 24 AHF patients (12 with reduced ejection fraction-HFrEF- and 12 HFpEF) with SDB a complete echocardiogram, a set of NI tests, and a polysomnography were performed in the acute phase and after 90 days. A control group of 12 non-HF patients hospitalized for other cardiovascular causes was considered. At baseline, SDB were present both in HFpEF and HFrEF, and a consistent reduction of apneic events was observed at follow up. Improvements in diastolic and right ventricular function were documented at three months compared to baseline, both in HFpEF and in HFrEF. Compared to HFrEF patients and controls, HFpEF patients showed lower NI scores at baseline tests, but a more significant improvement at three months follow-up. In AHF patients with SDB the achievement of a better compensation could lead to important beneficial effect not only on echocardiographic variables and nocturnal respiratory profile, but also on NI, especially in HFpEF.

[Grey zones on diabetes in cardiovascular disease. Expert opinion]. / Grey zones sul diabete mellito in ambito cardiologico. Opinioni degli esperti.

Clinical guidelines, while representing an objective reference to perform correct therapeutic choices, contain grey zones, where recommendations are not supported by solid evidence. In a conference held in Bergamo in October 2018, an attempt was made to highlight some of the main grey zones in Cardiology and, through a comparison between experts, to draw shared conclusions that can illuminate our clinical practice. This manuscript contains the statements of the symposium concerning the controversies in diabetes mellitus and cardiovascular disease. The first topic concerns the appropriateness of second level cardiovascular screening of the entire population of diabetic patients. The second gap in evidence concerns the validity of a target of glycated hemoglobin considering the last trials. The work has also been implemented with the evidences deriving from important randomized studies published after the date of the Conference.

An unexpected recovery of patients with pulmonary arterial hypertension and SARS-CoV-2 pneumonia: a case series.

Since the beginning of the SARS-CoV-2 outbreak, few cases of COVID-19 pneumonia in patients with pulmonary arterial hypertension have been reported. We present four patients with known history of PAH admitted to our hospital with SARS-CoV-2 pneumonia to analyze the impact of this disease on their clinical outcome.

QRS fragmentation as a possible electrocardiographic diagnostic marker in patients with acute myocarditis: preliminary histopathological validation.

AIMS: We aim to assess the reproducibility of QRS fragmentation (fQRS) on a multi-centre dataset of patients with acute myocarditis (AM), including a histopathological validation in a subgroup with biopsy-proven disease. Electrocardiogram (ECG) in patients with myocarditis is usually considered aspecific. ST changes and conduction anomalies have been commonly reported so far. We have previously described fQRS in patients with AM. METHODS AND RESULTS: Patients admitted between 2008 and 2019 in two centres with a diagnosis of AM were included. Standard ECG, echocardiography, and cardiac magnetic resonance (CMR) findings were recorded at baseline and at follow-up (FU). Eighty patients were analysed, 66 men (82%), with median age of 34 (26-43) years. Twenty-two patients had biopsy-proven AM. At presentation, 61 patients (76%) displayed fQRS. Median ejection fraction (EF) was 55% (43-60). Seventy-two patients (90%) underwent CMR and displayed late gadolinium enhancement (LGE). ECG leads showed that fQRS correlated with distribution of LGE. In patients with positive biopsy, fQRS was present in 18 (81%). Median FU was 419 days (224-956). Complete FU was available for 64 patients (80%), and 33 patients (52%) displayed persistence of fQRS. Median EF was 60% (57-64). Eleven patients underwent a repeated biopsy at FU, eight of whom had persistent inflammation and fQRS. Fifteen patients (23%) had ventricular tachycardia, 14 of whom still showed fQRS. CONCLUSIONS: In this cohort fQRS was confirmed as an additional useful ECG sign. Persistence of fQRS was associated with ongoing inflammation and with a poorer outcome in terms of ventricular function and occurrence of arrhythmias.

Risk stratifying asymptomatic left ventricular systolic dysfunction in the community: beyond left ventricular ejection fraction.

AIMS: Midwall fractional shortening (MWFS) is a measure of left ventricular (LV) systolic function that is more reliable in case of concentric LV geometry compared to LV ejection fraction (LVEF). We hypothesized that MWFS might predict heart failure (HF) and death in a high-risk asymptomatic population, beyond other echocardiographic parameters. METHODS AND RESULTS: Among 4047 subjects aged ≥55/≤80 years followed by 10 general practitioners in northern Italy, the DAVID-Berg study prospectively enrolled 623 asymptomatic outpatients at increased risk for HF. Baseline evaluation included clinical visit, electrocardiogram, N-terminal pro-brain natriuretic peptide (NT-proBNP), and echocardiogram. Mean age of the population was 69 ± 7 years, 56% were men, 88% had hypertension, mean LVEF was 61 ± 9%, and mean MWFS 16.2 ± 3.3. During a median follow-up of 5.7 years, 95 subjects experienced HF/death events. At Cox analysis, lower MWFS was the only echocardiographic parameter, among structural/functional ones, associated with higher risk of HF/death [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.84-0.95, Padjusted < 0.001]. The risk of HF/death related to clinical data and NT-proBNP (baseline model) was reclassified by echocardiography only when MWFS was included into the model (baseline C-statistics 0.761; adding conventional structural/functional echocardiographic data 0.776, P = 0.09; adding MWFS 0.791, P = 0.007). Compared to subjects with normal LVEF and MWFS, only subjects with combined systolic dysfunction (11% of the population) were at higher risk (P = 0.001 for both abnormal; P > 0.24 for either LVEF or MWFS abnormal). CONCLUSION: DAVID-Berg data suggest to include MWFS assessment in clinical practice, a simple and reliable echocardiographic parameter able to improve risk stratification in subjects at high risk for HF.

Is mild asymptomatic left ventricular systolic dysfunction always predictive of adverse events in high-risk populations? Insights from the DAVID-Berg study.

BACKGROUND: Mild asymptomatic left ventricular systolic dysfunction (ALVSD) may be associated with incident heart failure (HF). However, this gray zone group needs incremental risk refinement. We hypothesized that diastolic dysfunction (DD) may refine HF and death risk prediction in mild ALVSD. METHODS AND RESULTS: Among 4047 subjects aged ≥55/≤80 years followed by 10 general practitioners in northern Italy, the DAVID-Berg study prospectively enrolled 623 asymptomatic outpatients at increased risk for HF. Baseline evaluation included clinical visit, N-terminal pro B-type natriuretic peptide, and echocardiogram. Based on left ventricular ejection fraction (LVEF) and DD, subjects were classified as: control group (normal LVEF, n = 459, 76%), mild ALVSD (LVEF ≥40%/<53%) without DD (n = 89, 15%) and with DD (n = 54, 9%). Subjects with LVEF <40% or without full echocardiographic data were excluded from the analysis (n = 21). Mean age of the population was 69 ±7 years, 56% were men, mostly hypertensive, mean LVEF was 61%. During a median follow-up of 5.7 years, 88 subjects (15%) experienced HF/death events (59 HF events and 29 deaths). Compared to the control group, mild ALVSD was associated with a higher risk of incident HF/death (hazard ratio 1.80, 95% confidence interval 1.10-2.93, adjusted P = 0.019) according to the Cox proportional hazards model. However, this higher risk was present only in subjects with combined DD (P = 0.005) and not in those without it (P = 0.30). Results were consistent even considering the individual components of the primary outcome. CONCLUSION: In a high-risk population, an echocardiographic exam is normally performed to assess systolic dysfunction. Our data underline the importance of also relying on DD to risk stratify mild ALVSD. Mild ALVSD might be a predictor of adverse events mainly in subjects with combined DD, though further studies are needed to confirm these results.

Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis: Multicenter Lombardy Registry.

BACKGROUND: There is controversy about the outcome of patients with acute myocarditis (AM), and data are lacking on how patients admitted with suspected AM are managed. We report characteristics, in-hospital management, and long-term outcome of patients with AM based on a retrospective multicenter registry from 19 Italian hospitals. METHODS: A total of 684 patients with suspected AM and recent onset of symptoms (<30 days) were screened between May 2001 and February 2017. Patients >70 years of age and those >50 years of age without coronary angiography were excluded. The final study population comprised 443 patients (median age, 34 years; 19.4% female) with AM diagnosed by either endomyocardial biopsy or increased troponin plus edema and late gadolinium enhancement at cardiac magnetic resonance. RESULTS: At presentation, 118 patients (26.6%) had left ventricular ejection fraction <50%, sustained ventricular arrhythmias, or a low cardiac output syndrome, whereas 325 (73.4%) had no such complications. Endomyocardial biopsy was performed in 56 of 443 (12.6%), and a baseline cardiac magnetic resonance was performed in 415 of 443 (93.7%). Cardiac mortality plus heart transplantation rates at 1 and 5 years were 3.0% and 4.1%. Cardiac mortality plus heart transplantation rates were 11.3% and 14.7% in patients with complicated presentation and 0% in uncomplicated cases (log-rank P<0.0001). Major AM-related cardiac events after the acute phase (postdischarge death and heart transplantation, sustained ventricular arrhythmias treated with electric shock or ablation, symptomatic heart failure needing device implantation) occurred in 2.8% at the 5-year follow-up, with a higher incidence in patients with complicated forms (10.8% versus 0% in uncomplicated AM; log-rank P<0.0001). ß-Adrenoceptor blockers were the most frequently used medications both in complicated (61.9%) and in uncomplicated forms (53.8%; P=0.18). After a median time of 196 days, 200 patients had follow-up cardiac magnetic resonance, and 8 of 55 (14.5%) with complications at presentation had left ventricular ejection fraction <50% compared with 1 of 145 (0.7%) of those with uncomplicated presentation. CONCLUSIONS: In this contemporary study, overall serious adverse events after AM were lower than previously reported. However, patients with left ventricular ejection fraction <50%, ventricular arrhythmias, or low cardiac output syndrome at presentation were at higher risk compared with uncomplicated cases that had a benign prognosis and low risk of subsequent left ventricular systolic dysfunction.

Strategy to identify subjects with diabetes mellitus more suitable for selective echocardiographic screening: The DAVID-Berg study.

BACKGROUND: Despite the burden of pre-clinical heart failure (HF) among diabetes mellitus (DM) patients, routine screening echocardiography is not currently recommended. We prospectively assessed risk prediction for HF/death of a screening strategy combining clinical data, electrocardiogram, NTproBNP, and echocardiogram, aiming to identify DM patients more suitable for selective echocardiography. METHODS: Among 4047 screened subjects aged≥55/≤80years, the DAVID-Berg Study prospectively enrolled 623 outpatients with DM, or hypertension, or known cardiovascular disease but with no HF history/symptoms. The present analysis focuses on data obtained during a longitudinal follow-up of the 219 patients with DM. RESULTS: Mean age was 68years, 61% were men, and median DM duration was 4.9years. During a median follow-up of 5.2years, 50 subjects developed HF or died. A predictive model using clinical data demonstrated moderate predictive power, which significantly improved by adding electrocardiogram (C-statistic 0.75 versus 0.70; p<0.05), but not NTproBNP (C-statistic 0.72, p=0.20). Subjects with normal clinical variables or abnormal clinical variables but normal electrocardiogram had low events rate (1.3 versus 2.4events/100-person-years, p=NS). Conversely, subjects with both clinical and electrocardiogram abnormalities (47%) carried higher risk (9.0events/100-person-years, p<0.001). The predictive power for mortality/HF development increased when echocardiography was added (13.6events/100-person-years, C-statistic 0.80, p<0.05). CONCLUSIONS: Our prospective study found that a selective echocardiographic screening strategy guided by abnormal clinical/electrocardiogram data can reliably identify DM subjects at higher risk for incident HF and death. This screening approach may hold promise in guiding HF prevention efforts among DM patients.

[Screening of asymptomatic left ventricular systolic dysfunction in a population sample at high cardiovascular risk in Lombardy (Italy): the DAVID-Berg study]. / Lo screening della disfunzione ventricolare sinistra sistolica asintomatica in un campione di popolazione ad alto rischio cardiovascolare in Lombardia: lo studio DAVID-Berg.

BACKGROUND: Prevalence of asymptomatic left ventricular systolic dysfunction (ALVSD) increases with age and cardiovascular (CV) risk exposure. Early diagnosis and treatment allow reducing heart failure and fatal and non-fatal event rates. Data on ALVSD prevalence in Italy are still scarce and ALVSD remains commonly under-diagnosed in primary care, where diagnostic facilities are limited. Among subjects at high CV risk in primary care, we assessed the prevalence of ALVSD and the relative predictive value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and the Framingham Heart Failure Risk Score (FHFRS). METHODS: Records of 4047 subjects aged 55-80 years, without history, symptoms or signs of heart failure, registered at three primary care practices in Lombardy, Northern Italy, were reviewed; 623 subjects at high CV risk underwent visit, ECG, echocardiography, NT-proBNP and FHFRS calculation. RESULTS: ALVSD, defined as left ventricular ejection fraction <50%, was detected in 33 subjects (5.3%) who showed higher NT-proBNP (p<0.001) and FHFRS (p=0.013) than those without ALVSD. NT-proBNP levels beyond normal age and gender-specific 95th percentile had a 97.7% negative predictive value for ALVSD and were associated with a 6-fold increase in ALVSD risk. Adding NT-proBNP to FHFRS significantly improved prediction (C-statistic 0.76, 95% confidence interval [CI] 0.67-0.84 vs 0.63, 95% CI 0.53-0.73, p=0.04; net reclassification improvement 38.4%). The combination of FHFRS and major ECG abnormalities was not superior to stand alone NT-proBNP (C-statistic 0.71, 95% CI 0.63-0.80 vs 0.74, 95% CI 0.64-0.83, p=0.61). CONCLUSIONS: In subjects at high CV risk in primary care, prevalence of ALVSD is 5.3%; for diagnosis NT-proBNP adds predictive value to the FHFRS and is equivalent to the combination of FHFRS and ECG. Because of its practical advantages, NT-proBNP might be routinely used for ALVSD screening in primary care.