Management of cancer patients at high and very-high risk of cardiotoxicity: Main questions and answers.

In recent years, important advances have been made in the field of Cardio-Oncology. The 2022 ESC Guidelines on Cardio-Oncology proposed a baseline cardiovascular risk stratification for cancer patients and preventive strategies in patients at high and very-high risk of cardiotoxicity. Cardiovascular toxic effects of anti-cancer drugs are being extensively studied; surveillance programs have been proposed, based on the baseline cardiovascular risk. On the other hand, there is little data on Cardio-Oncological management of patients at high and very-high cardiovascular risk with previous cardiovascular diseases. For example, little is known about management of cancer patients with heart failure with reduced ejection fraction (HFrEF), patients with a recent myocardial infarction or other cardiovascular diseases; when to resume anti-cancer drugs after a cardiovascular toxic event. Collaboration between Cardiologists and Oncologists and multidisciplinary team evaluations are certainly essential to decide the best therapeutic strategy for cancer patients, to treat cancer while saving the heart. Therefore, in the present review, we attempt to provide a useful guide to clinicians in treating patients with high and very-high risk of cardiotoxicity by enucleating main questions and answering them based on the evidence available as well as expert opinion and our clinical experience.

Echocardiographic Patterns of Abnormal Septal Motion: Beyond Myocardial Ischemia.

Abnormal septal motion (ASM), which often is associated with myocardial ischemia, is also observed in other diseases. Owing to the position of the interventricular septum (IVS) in the heart, its movement not only relies on contractile properties but is also affected by the pressure gradient between the 2 ventricles and by the mode of electrical activation. Echocardiography allows the operator to focus on the motion of the IVS, analyzing its characteristics and thereby gaining information about the possible underlying pathophysiological mechanism. In this review, we focused on the main echocardiographic patterns of ASM that are not related to a failure of contractile properties of the septum (i.e., acute coronary syndrome and cardiomyopathies), showing their pathophysiological mechanisms and underlining their diagnostic usefulness in clinical practice.

Cardiotoxicity Induced by Immune Checkpoint Inhibitors: What a Cardio-Oncology Team Should Know and Do.

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic scenario for several malignancies. However, they can be responsible for immune-related adverse events (irAEs), involving several organs, with a pooled incidence ranging between 54% and 76%. The frequency of cardiovascular system involvement is <1%. Among the cardiovascular irAEs, myocarditis is the most common and the most dangerous but other, less common manifestations of ICI-related cardiotoxicity include pericardial disease, arrhythmias, Takotsubo-like syndrome, and acute myocardial infarction, all of which remain poorly explored. Both oncologists and cardiologists, as well as the patients, should be aware of the possible occurrence of one or more of these complications, which in some cases are fatal, in order to implement effective strategies of cardiac surveillance. In this review, we summarize the latest studies and recommendations on the pathogenesis, clinical manifestation, diagnosis, and management of ICI-related cardiotoxicity in order to realize a complete and updated overview on the main aspects of ICI-related cardiotoxicity, from surveillance to diagnosis to management, useful for both oncologists and cardiologists in their clinical practice. In particular, in the first part of the review, we realize a description of the pathogenetic mechanisms and risk factors of the main cardiovascular irAEs. Then, we focus on the management of ICI-related cardiotoxicity by analyzing five main points: (1) identifying and evaluating the type and severity of the cardiotoxicity; (2) deciding whether to withhold ICI therapy; (3) initiating steroid and immunosuppressive therapy; (4) starting conventional cardiac treatment; and (5) restarting ICI therapy. Finally, we discuss the existing evidence on surveillance for ICI-related cardiotoxicity and propose a surveillance strategy for both short- and long-term cardiotoxicity, according to the most recent guidelines.

Lipomatous Hypertrophy of the Interatrial Septum: A Case Report and Insights from the Literature.

Lipomatous hypertrophy of the interatrial septum (LHIS) is a histologically benign cardiac lesion that is defined by excessive fat accumulation in the area of the interatrial septum (IAS) that does not include the fossa ovalis. Another unusual illness is lipomatosis, which is defined as a broad overgrowth of mature adipose tissue that involves a large portion of an extremity or trunk. We describe a rare case with significant LHIS accompanied by subcutaneous lipomatosis. Echocardiography revealed a mass in the right atrium in this patient. Magnetic resonance imaging revealed that this mass was composed of the adipose tissue and was an extension of a huge thickened IAS. Furthermore, this significant hypertrophy of the IAS was in direct continuation with the excessive mediastinal and epicardial fat.

Nonbacterial Thrombotic Endocarditis with Atypical Presentation as Overt Congestive Heart Failure.

Nonbacterial thrombotic endocarditis (NBTE) is a form of endocarditis associated with malignancy or autoimmune disorders. Diagnosis remains a challenge as patients are often asymptomatic up to embolic events or rarely, valve dysfunction. We report a case of NBTE with uncommon clinical presentation and identified with multimodal echocardiography. An 82-year-old man presented to our outpatient clinic reporting dyspnea. Past medical history included hypertension, diabetes, kidney disease, and unprovoked deep-vein thrombosis. On physical examination, he was apyretic, mildly hypotensive, and hypoxemic, had a systolic murmur and lower limbs edema. Transthoracic echocardiography revealed severe mitral regurgitation due to verrucous thickening of the free margin of both leaflets, increased pulmonary pressure, and dilated inferior vena cava. Multiple blood cultures were negative. Transesophageal echocardiography confirmed "thrombotic" thickening of mitral leaflets. Nuclear investigations were highly suggestive of multi-metastatic pulmonary cancer. We did not further proceed with the diagnostic workup and prescribed palliative care. Lesions seen on echocardiography were suggestive of NBTE: they involved both sides of mitral leaflets, close to the edges, had irregular shape and echo density, a broad base, and no independent motion. Criteria for infective endocarditis were not met and the final diagnosis was paraneoplastic NBTE due to underlying lung cancer. We remark the lack of definitive recommendations about the treatment of NBTE and the only role of anticoagulation to prevent systemic embolism. We have reported a case of NBTE presenting with atypical symptoms and likely related to the prothrombotic state induced by underlying lung cancer. Provided the unconclusive microbiological tests, multimodal imaging has played a crucial role in the final diagnosis.

CMR predictors of secondary moderate to severe mitral regurgitation and its additive prognostic role in previous myocardial infarction.

BACKGROUND: We aimed to determine predictors and the additive prognostic role of moderate to severe (MS) ischemic mitral regurgitation (MR) in myocardial infarction (MI). METHODS: Four hundred twenty-two patients with previous MI underwent cardiac magnetic resonance (CMR) imaging for the assessment of left ventricular (LV) ejection fraction (EF), end-diastolic (EDV) and end-systolic volume (ESV), sphericity index, wall motion score index (WMSI), and late gadolinium enhancement (LGE). Echocardiography was performed to assess MR. RESULTS: Thirty-eight had from moderate to severe MR (MS-MR group) and 384 did not (No MS-MR group). The S-MR group had higher LV volumes, sphericity index, WMSI, and LGE extent, and lower LVEF. At univariate logistic regression analysis, dilated volumes, SI >0.43, dyskinesia of inferolateral wall, papillary muscle (PM)-LGE, and LGE extent >16% were associated with MS-MR. At multivariate analysis, only SI (OR=5.7) and PM-LGE (OR=3) were independently associated with MS-MR. Considering only patients without LV dilatation, only dyskinesia in the inferolateral wall was a predictor of MS-MR (OR 34.8). Thirty cardiac events (cardiac death, appropriate implantable cardioverter-defibrillator firing, and resuscitated cardiac arrest) occurred during a median follow-up of 1,276 days. After adjusting the prognostic variables at univariate analysis by age (>65 years) and selecting those that were significant (EDV > 95 ml/m2, ESV >53 ml/m2, EF <30%, WMSI >1.65, LGE >12%, S-MR), only WMSI >1.65 and MS-MR remained an independent predictor of cardiac events. CONCLUSIONS: Increased WMSI and PM-LGE in the overall population and inferolateral dyskinesia in patients without ESV dilatation are predictors of MS-MR; MS-MR and elevated WMSI have independent negative prognostic value.

Intracardiac thrombus in a patient with mitral bioprosthesis and atrial fibrillation treated with direct oral anticoaugulant: A case report.

RATIONALE: Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased morbidity, especially stroke and heart failure. There is also increasing awareness that atrial fibrillation is a major cause of embolic events which in 75% of cases are complicated by cerebrovascular accidents. PATIENT CONCERNS: A 50-year-old woman with mitral bioprosthesis under warfarin for nonvalvular atrial fibrillation was referred to our Coronary Intensive Care Unit due to acute myocardial infarction without evidence of significant coronary artery stenosis. DIAGNOSES: Cardiovascular examination showed an irregular pulse and a grade II diastolic murmur was audible at the apical area. The patient underwent coronary angiography showing absence of obstructive coronary artery disease. We decided to replace Warfarin with direct oral anticoagulants as anticoagulant therapy. INTERVENTIONS: Transoesophageal echocardiography revealed a thrombus in left atrial appendage that was treated by replacing warfarin with an oral direct thrombin inhibitor. OUTCOMES: At 2-month follow-up, the therapy showed to be effective for thrombus resolution. LESSONS: Our case demonstrated how AF has high risk of thromboembolic complications, not only in terms of stroke but also of myocardial infarction and death.The use of direct oral anticoagulants in AF patients with bioprosthetic heart valves is still debated due to an unclear definition of "nonvalvular" AF.

Arterial Stiffness: Effects of Anticancer Drugs Used for Breast Cancer Women.

Purpose: It is well known that anticancer drugs used for treating breast cancer can cause cardiac toxicity, and less is known about vascular toxicity. The aim of this study was to assess subclinical vascular effects of anthracyclines and trastuzumab (TRZ) in women treated for breast cancer. Methods: We enrolled 133 female patients with breast cancer undergoing adjuvant treatment with anthracycline-containing chemotherapy (CT) followed by taxane (paclitaxel/docetaxel) + TRZ. Patients underwent a standard echocardiography including measurement of left ventricular ejection fraction and global longitudinal strain at baseline and at follow-up. Vascular toxicity was evaluated by measuring brachial blood pressure (BP) and arterial stiffness indices (pulse wave velocity and Beta stiffness index) at T0 (baseline), T1 (3 months), T2 (6 months), and T3 (12 months). Results: Arterial stiffness indices were significantly increased at T1 in patients treated with anthracycline-containing CT (PWV 5.5 m/s IQR 5.15-6.4 at T0 vs. PWV 6.7 m/s IQR 5.6-7.2 at T1, p < 0.05; Beta index PWV 6.7 IQR 5.25-6.65 at T0, PWV 8.35 IQR 6.5-10.15 at T1, p < 0.05) but not at T2 and T3, when treatment with anthracyclines was stopped and patients were under treatment with taxane and TRZ. Blood pressure values did not significantly change during follow-up. Conclusion: Changes in arterial stiffness parameters occur early after starting treatment with anthracyclines, and they seem to be reversible if anthracycline treatment is stopped. These changes are not influenced by blood pressure values modifications. Therefore, in breast cancer women, anthracyclines seem to cause early reversible subclinical vascular injury.

Asymptomatic Left Ventricular Dysfunction: Is There a Role for Screening in General Population?

Stage A and B heart failure (HF) include asymptomatic patients without and with structural cardiac disorder, respectively. Asymptomatic left ventricular (LV) dysfunction represents an early stage of HF that should be recognized to prevent overt HF development. Echocardiography plays a pivotal role in assessment of cardiac structure and function and represents the ideal imaging technique for screening in the general population, thanks to its availability, feasibility, and low cost. Traditional echocardiography, with LV systolic and diastolic function and cardiac remodeling assessment, is usually performed. Development of new technologies may offer additional information and insights in detection of early LV dysfunction.

Anthracyclines and regional myocardial damage in breast cancer patients. A multicentre study from the Working Group on Drug Cardiotoxicity and Cardioprotection, Italian Society of Cardiology (SIC).

AIMS: In breast cancer (BC) patients treated with anthracyclines-based therapies, we aim at assessing whether adjuvant drugs impact cardiac function differently and whether their cardiotoxicity has a regional pattern. METHODS AND RESULTS: In a multicentre study, 146 BC patients (56 ± 11 years) were prospectively enrolled and divided into three groups according to the received treatments: AC/EC-Group (doxorubicin or epirubicin + cyclophosphamide), AC/EC/Tax-Group (AC/EC + taxanes), FEC/Tax-Group (fluorouracil + EC + taxanes). Fifty-six patients of the total cohort also received trastuzumab. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were calculated before starting chemotherapy (T0), at 3 months (T3), at 6 (T6), and 12 months (T12). A ≥10% drop of EF, while remaining within the normal range, was reached at T6 in 25.3% of patients from the whole cohort with an early decrease only in FEC/Tax-Group (P = 0.04). A ≥15% GLS reduction was observed in many more (61.6%) patients. GLS decreased early both in the whole population (P < 0.001) and in the subgroups. The FEC-Tax Group showed the worst GLS at T6. Trastuzumab further worsened GLS at T12 (P = 0.031). A significant reduction of GLS was observed in all LV segments and was more relevant in the anterior septum and apex. CONCLUSIONS: The decrease of GLS is more precocious and pronounced in BC patients who received FEC + taxanes. Cardiac function further worsens after 6 months of adjuvant trastuzumab. All LV segments are damaged, with the anterior septum and the apex showing the greatest impairments.

Assessment of Intra and Extra-Hospital Outcome after Takotsubo Syndrome in a Single-Center Population.

Objectives: To evaluate short- and long-term outcome in a single prospective cohort of Takotsubo syndrome (TTS) patients, trying to early identify those with better prognosis and to assess the prevalence of left ventricular ejection fraction (LVEF) recovery over time. Methods: Forty-nine patients prospectively enrolled underwent to assessment of demographic, clinical, and echocardiographic characteristics, and later were followed to identify the outcomes during a mean follow-up (FU) of 93 months. At the end of the FU phase, a subgroup of patients underwent to a clinical and echocardiographic re-evaluation. As major adverse cardiac events (MACE) were considered: Intra and extra-hospital death, re-hospitalizations for acute heart failure or atrial fibrillation (AF) or acute myocardial infarction (AMI) and TTS recurrence; minor events were considered minor symptoms of heart failure and angina not requiring hospitalization. Results: The prevalence of re-hospitalizations (MACE) over time was: 41% (n = 12) for HF; 6.8% (n = 2) for AMI; 3.4% (n = 1) for TTS relapse and 20% (n = 6) for AF. Minor events were the symptoms of chest pain and dyspnea not requiring hospitalization in 6 (20.7%) and 12 (34.4%) patients, respectively. LVEF at the time of admission was predictor for MACE. Stratifying patients on the LVEF admission median value (40%). Patients with LVEF <40% at admission had a significantly lower survival free from adverse cardiac events compared to patients with LVEF ≥40%. Twenty-seven (93%) patients underwent to a clinical reassessment with electrocardiogram and echocardiographic examination. LVEF value showed a statistically significant increase (P = 0.004) at the end of FU. Conclusions: At admission, "high-risk" patients (LVEF <40%) can be easily detected, allowing an appropriate pharmacological and/or mechanical support strategy and a more "careful" FU.

Redox Imbalances in Ageing and Metabolic Alterations: Implications in Cancer and Cardiac Diseases. An Overview from the Working Group of Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology (SIC).

Metabolic syndrome (MetS) is a well established risk factor for cardiovascular (CV) diseases. In addition, several studies indicate that MetS correlates with the increased risk of cancer in adults. The mechanisms linking MetS and cancer are not fully understood. Several risk factors involved in MetS are also cancer risk factors, such as the consumption of high calorie-food or high fat intake, low fibre intake, and sedentary lifestyle. Other common aspects of both cancer and MetS are oxidative stress and inflammation. In addition, some anticancer treatments can induce cardiotoxicity, including, for instance, left ventricular (LV) dysfunction and heart failure (HF), endothelial dysfunction and hypertension. In this review, we analyse several aspects of MetS, cancer and cardiotoxicity from anticancer drugs. In particular, we focus on oxidative stress in ageing, cancer and CV diseases, and we analyse the connections among CV risk factors, cancer and cardiotoxicity from anticancer drugs.

Peripheral Artery Disease and Stroke.

Peripheral artery disease (PAD) and stroke can occur as vascular complication of anticancer treatment. Although the mechanisms, monitoring, and management of cardiotoxicities have received broad attention, vascular toxicities remain often underrecognized. In addition, the development of new chemotherapeutic drugs bears the risk of vasotoxicities that are yet to be identified and may not be realized with short-term follow-up periods. The propensity to develop PAD and/or stroke reflects the complex interplay between patient's baseline risk and preexisting vascular disease, particularly hypertension and diabetes, while evidence for genetic predisposition is increasing. Chemotherapeutic agents with a prominent vascular side effect profile have been identified. Interruption of vascular endothelial growth factor (VEGF) inhibitors (VEGFIs) signaling (i.e., bevacizumab) is associated with vascular toxicity and clinical sequelae such as hypertension, stroke, and thromboembolism beyond acute coronary syndromes. Cisplatin and 5-fluorouracil are the main drugs involved in the stroke risk. In addition, circulating concentrations of VEGF are reduced by cyclophosphamide administered at continuous low doses, which might underpin some of the observed vascular toxicity, such as stroke, as seen in patients treated with VEGF inhibitors. The risk of stroke is also increased after treatment with anthracyclines that can induce endothelial dysfunction and increase arterial stiffness. Proteasome inhibitors ( bortezomib and carfilzomib) and immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide), approved for use in multiple myeloma, carry a black box warning for an increased risk of stroke. Finally, head-and-neck radiotherapy is associated with a doubled risk of cerebrovascular ischemic event, especially if exposure occurs in childhood. The mechanisms involved in radiation vasculopathy are represented by endothelial dysfunction, medial necrosis, fibrosis, and accelerated atherosclerosis. However, BCR-ABL tyrosine kinase inhibitor (TKI), used for the treatment of chronic myeloid leukemia (CML), is the main antineoplastic drugs involved in the development of PAD. In particular, second- and third-generation TKIs, such as nilotinib and ponatinib, while emerging as a potent arm in contrasting CML, are associated with a higher risk of PAD development rather than traditional imatinib. Factors favoring vascular complication are the presence of traditional cardiovascular risk factors (CVRF) and predisposing genetic factors, high doses of BCR-ABL TKIs, longer time of drug exposure, and sequential use of potent TKIs. Therefore, accurate cardiovascular risk stratification is strongly recommended in patient candidate to anticancer treatment associated with higher risk of vascular complication, in order to reduce the incidence of PAD and stroke through CVRF correction and selection of appropriate tailored patient strategy of treatment. Then, a clinical follow-up, eventually associated with instrumental evaluation through vascular ultrasound, should be performed.

Echocardiographic reference ranges for normal left ventricular layer-specific strain: results from the EACVI NORRE study.

AIMS: To obtain the normal range for 2D echocardiographic (2DE) measurements of left ventricular (LV) layer-specific strain from a large group of healthy volunteers of both genders over a wide range of ages. METHODS AND RESULTS: A total of 287 (109 men, mean age: 46 ± 14 years) healthy subjects were enrolled at 22 collaborating institutions of the EACVI Normal Reference Ranges for Echocardiography (NORRE) study. Layer-specific strain was analysed from the apical two-, three-, and four-chamber views using 2DE software. The lowest values of layer-specific strain calculated as ±1.96 standard deviations from the mean were -15.0% in men and -15.6% in women for epicardial strain, -16.8% and -17.7% for mid-myocardial strain, and -18.7% and -19.9% for endocardial strain, respectively. Basal-epicardial and mid-myocardial strain decreased with age in women (epicardial; P = 0.008, mid-myocardial; P = 0.003) and correlated with age (epicardial; r = -0.20, P = 0.007, mid-myocardial; r = -0.21, P = 0.006, endocardial; r = -0.23, P = 0.002), whereas apical-epicardial, mid-myocardial strain increased with the age in women (epicardial; P = 0.006, mid-myocardial; P = 0.03) and correlated with age (epicardial; r = 0.16, P = 0.04). End/Epi ratio at the apex was higher than at the middle and basal levels of LV in men (apex; 1.6 ± 0.2, middle; 1.2 ± 0.1, base 1.1 ± 0.1) and women (apex; 1.6 ± 0.1, middle; 1.1 ± 0.1, base 1.2 ± 0.1). CONCLUSION: The NORRE study provides useful 2DE reference ranges for novel indices of layer-specific strain.

Impaired myocardial strain in early stage of Duchenne muscular dystrophy: its relation with age and motor performance.

Duchenne muscular dystrophy (DMD) is complicated by an early and progressive left ventricular (LV) dysfunction. Despite the reduction of ejection fraction (EF) usually manifests in the second decade, subtle alterations in LV mechanics can be detected earlier. Longitudinal and circumferential LV deformation, evaluated by speckle tracking echocardiography (STE), are considered sensitive markers of early dysfunction. We retrospectively examined clinical and echocardiographic data of 32 DMD children with preserved LV function. According to the median age, patients were then divided into younger and older than 9 years, and compared to 24 age-matched healthy subjects. Six-minute-walk test (6MWT), North Star Ambulatory Assessment (NSAA), and a comprehensive cardiac evaluation were performed. Although EF was within the normal range, DMD patients had significantly lower values than healthy controls, and the same occurred for the remaining conventional systolic and diastolic indices. Global longitudinal strain (GLS) was reduced in all patients (older and younger, both p < 0.001). Global circumferential strain (GCS) was reduced only in older patients (< 0.001). Both GLS and GCS worsened with age in DMD patients (GLS p = 0.005; GCS p = 0.024). GLS was significantly worse in the apical segments and in the postero-lateral wall. GCS in the antero-septal, anterior and antero-lateral segments was significantly reduced in older patients, with a prevalent involvement of the sole septal wall in the younger boys. 6MWT appeared to be correlated inversely to GLS and directly to EF. A longitudinal evaluation should be scheduled in DMD boys to assess the global cardiac performance over time and to evaluate the impact of therapies.

Correlation between non-invasive myocardial work indices and main parameters of systolic and diastolic function: results from the EACVI NORRE study.

AIMS: The present study sought to evaluate the correlation between indices of non-invasive myocardial work (MW) and left ventricle (LV) size, traditional and advanced parameters of LV systolic and diastolic function by 2D echocardiography (2DE). METHODS AND RESULTS: A total of 226 (85 men, mean age: 45 ± 13 years) healthy subjects were enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. Global work index (GWI), global constructive work (GCW), global work waste (GWW), and global work efficiency (GWE) were estimated from LV pressure-strain loops using custom software. Peak LV pressure was estimated non-invasively from brachial artery cuff pressure. LV size, parameters of systolic and diastolic function and ventricular-arterial coupling were measured by echocardiography. As advanced indices of myocardial performance, global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) were obtained. On multivariable analysis, GWI was significantly correlated with GLS (standardized beta-coefficient = -0.23, P < 0.001), ejection fraction (EF) (standardized beta-coefficient = 0.15, P = 0.02), systolic blood pressure (SBP) (standardized beta-coefficient = 0.56, P < 0.001) and GRS (standardized beta-coefficient = 0.19, P = 0.004), while GCW was correlated with GLS (standardized beta-coefficient = -0.55, P < 0.001), SBP (standardized beta-coefficient = 0.71, P < 0.001), GRS (standardized beta-coefficient = 0.11, P = 0.02), and GCS (standardized beta-coefficient = -0.10, P = 0.01). GWE was directly correlated with EF and inversely correlated with Tei index (standardized beta-coefficient = 0.18, P = 0.009 and standardized beta-coefficient = -0.20, P = 0.004, respectively), the opposite occurred for GWW (standardized beta-coefficient =--0.14, P = 0.03 and standardized beta-coefficient = 0.17, P = 0.01, respectively). CONCLUSION: The non-invasive MW indices show a good correlation with traditional 2DE parameters of myocardial systolic function and myocardial strain.

Impact of aortic stenosis on layer-specific longitudinal strain: relationship with symptoms and outcome.

AIMS: The present study sought to assess the impact of aortic stenosis (AS) on myocardial function as assessed by layer-specific longitudinal strain (LS) and its relationship with symptoms and outcome. METHODS AND RESULTS: We compared 211 patients (56% males, mean age 73 ± 12 years) with severe AS and left ventricular ejection fraction (LVEF) ≥50% (114 symptomatic, 97 asymptomatic) with 50 controls matched for age and sex. LS was assessed from endocardium, mid-myocardium, and epicardium by 2D speckle-tracking echocardiography. Despite similar LVEF, multilayer strain values were significantly lower in symptomatic patients, compared to asymptomatic and controls [global LS: 17.9 ± 3.4 vs. 19.1 ± 3.1 vs. 20.7 ± 2.1%; endocardial LS: 20.1 ± 4.9 vs. 21.7 ± 4.2 vs. 23.4 ± 2.5%; epicardial LS: 15.8 ± 3.1 vs. 16.8 ± 2.8 vs. 18.3 ± 1.8%; P < 0.001 for all]. On multivariable logistic regression analysis, endocardial LS was independently associated to symptoms (P = 0.012), together with indexed left atrial volume (P = 0.006) and LV concentric remodelling (P = 0.044). During a mean follow-up of 22 months, 33 patients died of a cardiovascular event. On multivariable Cox-regression analysis, age (P = 0.029), brain natriuretic peptide values (P = 0.003), LV mass index (P = 0.0065), LV end-systolic volume (P = 0.012), and endocardial LS (P = 0.0057) emerged as independently associated with cardiovascular death. The best endocardial LS values associated with outcome was 20.6% (sensitivity 70%, specificity 52%, area under the curve = 0.626, P = 0.022). Endocardial LS (19.1 ± 3.3 vs. 20.7 ± 3.3, P = 0.02) but not epicardial LS (15.2 ± 2.8 vs. 15.9 ± 2.5, P = 0.104) also predicted the outcome in patients who were initially asymptomatic. CONCLUSION: In patients with severe AS, LS impairment involves all myocardial layers and is more prominent in the advanced phases of the disease, when the symptoms occur. In this setting, the endocardial LS is independently associated with symptoms and patient outcome.

Echocardiographic reference ranges for normal non-invasive myocardial work indices: results from the EACVI NORRE study.

AIMS: To obtain the normal ranges for 2D echocardiographic (2DE) indices of myocardial work (MW) from a large group of healthy volunteers over a wide range of ages and gender. METHODS AND RESULTS: A total of 226 (85 men, mean age: 45 ± 13 years) healthy subjects were enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. Global work index (GWI), global constructive work (GCW), global work waste (GWW), and global work efficiency (GWE) were estimated from left ventricle (LV) pressure-strain loops. Peak LV systolic pressure was non-invasively derived from brachial artery cuff pressure. The lowest values of MW indices in men and women were 1270 mmHg% and 1310 mmHg% for GWI, 1650 mmHg% and 1544 mmHg% for GCW, and 90% and 91% for GWE, respectively. The highest value for GWW was 238 mmHg% in men and 239 mmHg% in women. Men had significant lower values of GWE and higher values of GWW. GWI and GCW significantly increased with age in women. CONCLUSION: The NORRE study provides useful 2DE reference ranges for novel indices of non-invasive MW.

Arterial stiffness and mitral regurgitation in arterial hypertension: an intriguing pathophysiological link.

BACKGROUND: We examined the relative impact of arterial stiffness on the presence and/or severity of chronic mitral regurgitation (MR) in hypertensive patients. METHODS: We prospectively enrolled 141 untreated hypertensive patients (mean age 56.6 ±â€¯11.5 years): 94 with MR, 47 without MR. As a measure of arterial stiffness, pulse wave velocity (PWV) was assessed by applanation tonometry. Assessment of MR severity was obtained through calculation of effective regurgitant orifice area (EROA) and vena contracta by standard two-dimensional transthoracic echocardiography. RESULTS: PWV appears to progressively increase according to the presence and severity of MR (no MR = 7.3 ±â€¯1.1 m/s, mild MR = 7.9 ±â€¯1.3 m/s, moderate MR = 9.0 ±â€¯1.7 m/s, severe MR = 13.3 ±â€¯4.1 m/s; P < 0.001 for all comparisons). EROA was positively correlated with age (P = 0.011), left atrial volume index (P = 0.023), PWV (P < 0.001) and augmentation index (P < 0.001), and negatively correlated with left ventricular ejection fraction (P = 0.002) and heart rate (HR) (P = 0.018). On stepwise multivariate logistic regression analysis, only PWV (OR = 2.87, 95% CI 1.750-4.738, P < 0.001) and HR (OR = 0.94, 95% CI 0.895-0.994, P = 0.02) appeared to be independent predictors of severe MR. Receiver operating characteristic curves showed that a cutoff of 9 m/s for PWV provided the best sensitivity/specificity for predicting both the presence of any degree of MR (sensitivity 73%, specificity 87%, AUC = 0.863; P < 0.001) and MR severity (sensitivity 100%, specificity 81%, AUC = 0.954; P < 0.001). CONCLUSION: Reduced arterial elasticity because of increased stiffness may be an important marker for the presence and severity of MR in hypertensive patients.