Cardioprotective Strategy for Patients With Nonmetastatic Breast Cancer Who Are Receiving an Anthracycline-Based Chemotherapy: A Randomized Clinical Trial.

IMPORTANCE: Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients who are receiving cardiotoxic therapies. However, the optimal approach still represents a controversial issue. OBJECTIVE: To determine whether pharmacological cardioprevention could reduce subclinical heart damage in patients with breast cancer who are being treated with anthracycline-based chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: The SAFE trial was a 4-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study conducted at 8 oncology departments in Italy. It was a prespecified interim analysis on the first 174 patients who had completed cardiac assessment at 12 months. The study recruitment was conducted between July 2015 and June 2020. The interim analysis was performed in 2020. Patients were eligible for trial inclusion if they had indication to receive primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with a prior diagnosis of cardiovascular disease were excluded. INTERVENTIONS: Cardioprotective therapy (bisoprolol, ramipril, or both drugs compared with placebo) was administered for 1 year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of ERBB2-positive patients. Doses for all groups were systematically up-titrated up to the daily target dose of bisoprolol (5 mg, once daily), ramipril (5 mg, once daily), and placebo, if tolerated. MAIN OUTCOMES AND MEASURES: The primary end point was defined as detection of any subclinical impairment (worsening ≥10%) in myocardial function and deformation measured with standard and 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS). RESULTS: The analysis was performed on 174 women (median age, 48 years; range, 24-75 years) who had completed a cardiological assessment at 12 months and reached the end of treatment. At 12 months, 3D-LVEF worsened by 4.4% in placebo arm and 3.0%, 1.9%, 1.3% in the ramipril, bisoprolol, ramipril plus bisoprolol arms, respectively (P = .01). Global longitudinal strain worsened by 6.0% in placebo arm and 1.5% and 0.6% in the ramipril and bisoprolol arms, respectively, whereas it was unchanged (0.1% improvement) in the ramipril plus bisoprolol arm (P < .001). The number of patients showing a reduction of 10% or greater in 3D-LVEF was 8 (19%) in the placebo arm, 5 (11.5%) in the ramipril arm, 5 (11.4%) in the bisoprolol, arm and 3 (6.8%) in the ramipril plus bisoprolol arm; 15 patients (35.7%) who received placebo showed a 10% or greater worsening of GLS compared with 7 (15.9; ramipril), 6 (13.6%; bisoprolol), and 6 (13.6%; ramipril plus bisoprolol) (P = .03). CONCLUSIONS AND RELEVANCE: The interim analysis of this randomized clinical trials suggested that cardioprotective pharmacological strategies in patients who were affected by breast cancer and were receiving an anthracycline-based chemotherapy are well tolerated and seem to protect against cancer therapy-related LVEF decline and heart remodeling. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT2236806.

Surgical aortic valve replacement and left ventricular remodeling: Survival and sex-related differences.

OBJECTIVES: To analyze how left ventricular (LV) remodeling and hypertrophy geometry evolve after surgical aortic valve replacement (SAVR) in octogenarian patients, and identify potential sex-related differences and implications for long-term outcomes. METHODS: In 170 patients with aortic stenosis ([AS], age 80 ± 4 years, 59% women), hypertrophy geometry and remodeling (LV index) were reanalyzed one year post-SAVR. The six-year outcomes were evaluated. RESULTS: Pre-SAVR, 65% of the women and 38.6% of the men (P < .001) showed adaptive remodeling. Concentric hypertrophy was prevalent in adaptive remodeling, and mixed and dilated hypertrophy were more prevalent in maladaptive remodeling. At one year, the remodeling patterns and sex distribution were similar to those observed pre-SAVR, but the LV index decreased in women and increased in men (P < .0001). Women with adaptive remodeling had a higher incidence of persistent concentric hypertrophy with higher LV filling pressures. Long-term survival was better in women and worse in men with adaptive remodeling (P = .039). Men with adaptive remodeling and men with concentric hypertrophy had the highest risk of cardiac death. This risk was similar between sexes for patients with maladaptive remodeling and dilated hypertrophy. Women with LV ejection fraction >55% had a lower risk of cardiac death than men. CONCLUSIONS: The long-term outcomes of SAVR differ between sexes in older patients with AS and adaptive LV remodeling. The LV index facilitates studying the pathways of adaptation to AS. The follow-up shifts help explain the sex differences in long-term outcomes post-SAVR. Concentric hypertrophy is associated with the highest risk of cardiac death in men.

Cardiac Metastasis of Sacral Chordoma.

Chordoma is a rare tumor, usually diagnosed when the disease is advanced. Despite its slow growth, it is locally aggressive and has a poor long-term prognosis. Surgery is the mainstay treatment. Although cardiac metastases are very rare, the heart is frequently involved in systemic neoplastic diseases. This report describes a typical case of metastatic chordoma: the age at first diagnosis, the site of the primary tumor, and the slow growth of the cardiac metastasis were all typical features. Surgical excision of the mass from the right ventricular outflow tract is described together with echocardiographic, radiologic, and histopathologic characteristics of the metastatic chordoma.

Results of comprehensive cardiovascular diagnostic work-up in HIV positive patients.

Cardiovascular disease (CVD) in the HIV population accounts for a large proportion of morbidity and mortality and, with the increased life expectancy, the burden of CVD is expected to rise. Inflammation, immune dysfunction, side effects of HIV medications, high prevalence of other risk factors are the likely pathogenic mechanisms for accelerated atherosclerosis. We aimed to evaluate the diagnostic yield of a cardiovascular multimodality diagnostic work-up in a contemporary cohort of HIV-infected patients. From November 2017 to October 2019, HIV infected patients were screened in a cardiovascular diagnostic work-up program including clinical history, physical examination, arterial blood pressure measurement, 12-lead ECG, and Transthoracic Echocardiogram (TTE). Advanced non-invasive cardiovascular imaging tests, like Coronary Computed Tomography Angiography (CCTA), stress-echocardiography, Cardiac Magnetic Resonance (CMR), were performed in patients with suspicion of chronic coronary syndrome (CCS) or non-ischemic heart disease (NIHD). 117 HIV-infected consecutive patients underwent this cardiovascular diagnostic work-up and were included in our study. Fifty-two patients (45%) had evidence of CVD. Of them, 22 presented Coronary Artery Disease (CAD), whereas 47 cases showed NIHD. In 17 cases both conditions were present. Among patients with CAD, 8 showed critical coronary stenosis; among them, 5 were treated with percutaneous coronary intervention, 2 with Aorto-Coronary By-Pass Grafting (CABG), and one with medical therapy. Hypertension and diabetes were significantly associated with the development of CVD (respectively p<0.001 and p< 0.05), while current smoking (p<0.02) and hypertension (p<0.007) were positively associated to CAD. A comprehensive cardiovascular diagnostic work-up including advanced multimodality diagnostic imaging modalities led to early detection of CVD in nearly half of an HIV population with immediate interventions required in 6.8% of them, and aggressive prevention treatment started in the remaining HIV patients.

Papillary fibroelastoma of the right atrial appendage: Is it that rare?

Papillary fibroelastoma (PF) of the right atrium accounts for 2% of nonvalvular cases, and right appendage (RAA) PF was described only once in literature. We present three cases of RAA PF in patients with unrelated symptoms undergoing 3-dimensional transesophageal echocardiographic examination (3D-TEE) scheduled for conventional indications. Key to diagnosis in routine practice resides in systematic examination of the right atrium and RAA in live 3D-TEE imaging with backward and forward navigation of the real-time pyramidal data. A review of literature is provided. Our experience demonstrates that systematic imaging of all cardiac structures with 3D-TEE allows refining PF nosology.

Left ventricular mass regression after aortic valve replacement: Sex differences or effect of different methods of indexation?

BACKGROUND: The influence of sex on regression of left ventricular (LV) hypertrophy (LVH) after aortic valve replacement (AVR) for aortic stenosis (AS) remains elusive. The lack of consensus on how to correct LV mass (LVM) for body size, and different normalcy values, contribute to inconclusive results. METHODS: In 164 consecutive patients (mean age 80 ± 4 years, 59% females) with AS, we analyzed LVM (Devereux formula) before and 1 year after AVR (St.Jude Trifecta bio-prosthesis). LVM was indexed to BSA (Du Bois and Gehan formulas), to height1.7 and height2.7 . Limits of normalcy were (women and men, respectively): <95 and <115 g/m², BSA-indexed LVM; <60 and <81 g/m, LVM/height1.7 ; <44 and <48 g/m, LVM/height2.7 . RESULTS: Women had smaller BSA, but not body mass index, than men. AS severity and incidence of hypertension did not differ. LVM indexed to height2.7 was greater in women. LVH incidence was similar in males and females. Independently of the indexation method, LVH reduced significantly (P < 0.0001). LVM reduction was greater in women (P < 0.05 for all methods). At follow-up, nearly half the patients, irrespective of sex, showed residual LVH, and diastolic dysfunction. CONCLUSIONS: We tested different methods of LVM indexation in AS patients. LVM was similar between men and women. Indexation to height2.7 gives higher LVM in women because of their shorter stature. LVH prevalence is independent of sex. Irrespective of the indexation method, LVM reduction is greater in females, whereas LVM normalization occurs in equal proportion. Persistent LVH and diastolic dysfunction suggest earlier AVR in elderly.

Left ventricular outflow tract shape after aortic valve replacement with St. Jude Trifecta prosthesis.

BACKGROUND: Aortic prosthesis area (EOA) is computed by continuity equation from left ventricular (LV) stroke volume (SV) derived from LV outflow tract diameter (LVOTD ) or, when unmeasurable, from LV volumes (SVV ). There is evidence to suggest LVOT ellipticity and recommend 3D LVOT area (LVOTCSA ) adoption in aortic stenosis. We sought to evaluate if the same concept applies to supra-annular aortic prosthesis comparing SV and EOA derived from LVOTD (EOAD ) and from LVOTCSA (EOACSA ). EOA computed from SVV (EAOV ) accuracy was evaluated in this setting. Patient-prosthesis mismatch (PPM) was compared among different EOA computations. METHODS: A consecutive series of 202 patients (aged 81 ± 4 years, 43% males) underwent St.Jude Trifecta aortic valve replacement (AVR) and were followed up with echocardiography at one-year (335 ± 31 days). All measurements followed the EACVI or ASE guidelines, 3D X-plane modality was used to compute SVv and measure LVOTCSA ; SV was calculated from LVOTD (SVD ) and LVOTCSA (SVCSA ). PPM was indexed EOA <0.65 cm²/m². RESULTS: LVOT showed a significant ellipticity index (1.17 ± .27), independent of prosthesis size. EOAD (1.70 ± 0.55 cm²) was less than EOACSA (1.95 ± 0.62 cm²) (P < .0001). SVV was significantly lower than SVD and SVCSA . Bland-Altman analysis showed a significant correlation between SVV and SVD or SVCSA although with large bias and imprecision. The correlations improved reducing bias and imprecision when LVOT time-velocity integral was <20 cm. PPM incidence was higher in EOAV (15.6%) compared to EOAD (P = .04) or EOACSA (P < .001). CONCLUSIONS: In supra-annular AVR, LVOT retains its elliptical shape and LVOTCSA yielded larger prosthesis EOA with lower PPM incidence. PPM may be overestimated by EOAV .

SAFE trial: an ongoing randomized clinical study to assess the role of cardiotoxicity prevention in breast cancer patients treated with anthracyclines with or without trastuzumab.

Over the years, thanks to the addition of new generation systemic agents, as well as the use of more advanced and precise radiotherapy techniques, it was able to obtain a high curability rate for breast cancer. Anthracyclines play a key role in the treatment of breast disease, with a well-known benefit on disease-free survival of patients with positive nodal status. Trastuzumab have shown a significant outcome advantage after 1-year administration in case of HER2-positive disease. Unfortunately, significant increase in cardiotoxicity has been observed after anthracyclines and trastuzumab therapies. Even though the cardiology and oncology community strongly recommend a cardiotoxicity prevention strategy for this subset of patients, there is still no consensus on the optimal patient's approach. We aimed to review the published and ongoing researches on cardioprevention strategies and to present the SAFE trial (CT registry ID: NCT2236806; EudraCT number: 2015-000914-23). It is a randomized phase 3, four-arm, single-blind, placebo-controlled study that aims to evaluate the effect of bisoprolol, ramipril or both drugs, compared to placebo, on subclinical heart damage evaluated by speckle tracking cardiac ultrasound in non-metastatic breast cancer patients.

Paradoxical embolization in TIPS: take a closer look to the heart.

No definitive indications are provided in the literature for pre-TIPS patient workup, which is often limited to prevent the incidence of refractory hepatic encephalopathy or unacceptable deterioration of liver function. Concerning cardiologic workup, efforts are generally limited at excluding ventricular failure or porto pulmonary hypertension. The cases presented herein focus the attention of the readers on the possible occurrence of post-TIPS paradoxical embolization in the presence of a patent foramen ovale, frequently recognized in adult population. In conclusion, although this complication has been already reported in literature, in the present manuscript we concentrate on possible additional risk factors which may allow to identify a subset of patients with a higher likelihood to experience paradoxical embolization following TIPS. Another important line of information presented herein is the feasibility of percutaneous closure of a patent foramen ovale before TIPS deployment in the presence of portal vein thrombosis and possibly with additional risk factors.

Myocardial perfusion echocardiography and coronary microvascular dysfunction.

Our understanding of coronary syndromes has evolved in the last two decades out of the obstructive atherosclerosis of epicardial coronary arteries paradigm to include anatomo-functional abnormalities of coronary microcirculation. No current diagnostic technique allows direct visualization of coronary microcirculation, but functional assessments of this circulation are possible. This represents a challenge in cardiology. Myocardial contrast echocardiography (MCE) was a breakthrough in echocardiography several years ago that claimed the capability to detect myocardial perfusion abnormalities and quantify coronary blood flow. Research demonstrated that the integration of quantitative MCE and fractional flow reserve improved the definition of ischemic burden and the relative contribution of collaterals in non-critical coronary stenosis. MCE identified no-reflow and low-flow within and around myocardial infarction, respectively, and predicted the potential functional recovery of stunned myocardium using appropriate interventions. MCE exhibited diagnostic performances that were comparable to positron emission tomography in microvascular reserve and microvascular dysfunction in angina patients. Overall, MCE improved echocardiographic evaluations of ischemic heart disease in daily clinical practice, but the approval of regulatory authorities is lacking.

Analysis of left ventricular volumes and function: a multicenter comparison of cardiac magnetic resonance imaging, cine ventriculography, and unenhanced and contrast-enhanced two-dimensional and three-dimensional echocardiography.

BACKGROUND: Contrast echocardiography improves accuracy and reduces interreader variability on left ventricular (LV) functional analyses in the setting of two-dimensional (2D) echocardiography. The need for contrast imaging using three-dimensional (3D) echocardiography is less defined. The aim of this multicenter study was to define the accuracy and interreader agreement of unenhanced and contrast-enhanced 2D and 3D echocardiography for the assessment of LV volumes and ejection fraction (EF). METHODS: A multicenter, open-label study was conducted including 63 patients, using intrasubject comparisons to assess the agreement of unenhanced and contrast-enhanced 2D and 3D echocardiography as well as calibrated biplane cine ventriculography with cardiac magnetic resonance for the determination of LV volumes and EF. Each of the imaging techniques used to define LV function was assessed by two independent, off-site readers unaware of the results of the other imaging techniques. RESULTS: LV end-systolic and end-diastolic volumes were underestimated by 2D and 3D unenhanced echocardiography compared with cardiac magnetic resonance. Contrast enhancement resulted in similar significant increases in LV volumes on 2D and 3D echocardiography. The mean percentage of interreader variability for LV EF was reduced from 14.3% (95% confidence interval [CI], 11.7%-16.8%) for unenhanced 2D echocardiography and 14.3% (95% CI, 9.7%-18.9%) for unenhanced 3D echocardiography to 8.0% (95% CI, 6.3%-9.7%; P < .001) for contrast-enhanced 2D echocardiography and 7.4% (95% CI, 5.7%-9.1%; P < .01) for contrast-enhanced 3D echocardiography and thus to a similar level as for cardiac magnetic resonance (7.9%; 95% CI, 5.4%-10.5%). A similar effect was observed for interreader variability for LV volumes. CONCLUSIONS: Contrast administration on 3D echocardiography results in improved determination of LV volumes and reduced interreader variability. The use of 3D echocardiography requires contrast application as much as 2D echocardiography to reduce interreader variability for volumes and EF.

Comparison of two- and three-dimensional unenhanced and contrast-enhanced echocardiographies versus cineventriculography versus cardiac magnetic resonance for determination of left ventricular function.

Contrast enhancement has been shown to improve detection of regional wall motion abnormalities (RWMA) in 2-dimensional (2D) echocardiography. This study determined the use of contrast enhancement in the setting of 3-dimensional (3D) echocardiography for definition of left ventricular RWMA compared with 2D echocardiography, cineventriculography, and cardiac magnetic resonance (CMR). In 63 patients, unenhanced and contrast-enhanced (SonoVue; Bracco Imaging S.p.A., Milan, Italy) 2D and 3D echocardiographies, CMR, and cineventriculography were performed. Hypokinesia in ≥1 segment defined the presence of RWMA. Interreader agreement (IRA) between 2 blinded off-site readers on presence of RWMA was determined within each imaging technique. Intermethod agreement among imaging techniques was analyzed. A standard of truth for the presence of RWMA was obtained by an independent expert panel decision. IRA on presence of RWMA expressed as Cohen's κ coefficient was 0.27 for unenhanced 3D echocardiography, 0.40 for unenhanced 2D echocardiography, 0.57 for CMR, and 0.51 for cineventriculography. The use of contrast increased IRA on RWMA to 0.42 for 3D echocardiography and to 0.56 for 2D echocardiography. Agreement with CMR on RWMA increased for 3D echocardiography when contrast enhancement was used (κ 0.40 vs 0.22 for unenhanced 3D echocardiography). Similarly, agreement of 2D echocardiography with CMR on RWMA increased with contrast enhancement (κ 0.50 vs 0.32). Accuracy to detect expert panel-defined RWMA was highest for CMR (84%) followed by 2D contrast echocardiography (78%) and 3D contrast echocardiography (76%). It was lesser for 2D and 3D unenhanced echocardiographies. In conclusion, analysis of RWMA is characterized by considerable interreader variability even using high-quality imaging techniques. IRA on RWMA is lower with 3D echocardiography compared with 2D echocardiography. IRA on RWMA and accuracy to detect panel-defined RWMA improve with contrast enhancement irrespective of the 2D or 3D echocardiography use.

Characterization of Löeffler eosinophilic myocarditis by means of real time three-dimensional contrast-enhanced echocardiography.

Löeffler endocarditis is a rare myocardial disease often due to eosinophil leukemia or idiopathic hypereosinophilic syndrome. Degranulation of eosinophils within the eosinophil infiltrated myocardium is associated with myocardial necrosis due to the release of toxic cationic proteins, and with mural thrombi formation, which can occur anywhere in the ventricles. Thrombus formed on denuded myocardium is replaced by fibrosis as the final pathological stage of the disease, eventually leading to restrictive cardiomyopathy. We describe a multimodality imaging approach to the diagnosis and follow-up evaluation of Löeffler disease complicated by thrombus formation and neoangiogenesis of LV apex.

The challenge of integrated echocardiographic approach in percutaneous closure of paravalvular leak.

Paravalvular leak after prosthetic mitral valve surgery may lead to symptomatic mitral regurgitation and hemolytic anemia requiring reoperation. Percutaneous closure of paravalvular leaks is a relatively recent technique still considered a challenging procedure burdened by possible complications, to be offered only to poor redo surgical candidate patients. Multimodality imaging is advocated to plan and guide the procedure, to minimize the risk of complications. We report on a case of dehisced prosthetic mitral valve in which transthoracic real time three-dimensional echocardiography was used to locate the dehiscence area and characterize mitral paraprosthesis leak, whereas intracardiac echocardiography was used to guide and monitor the percutaneous closure procedure.

Effects of dipyridamole on cardiac and systemic haemodynamics: real-time three-dimensional stress echo beyond regional wall motion.

AIMS: Coronary vasodilation and coronary steal are the basis for routine use of dipyridamole in stress echocardiography for non-invasive assessment of coronary artery disease (CAD). This study investigates dipyridamole effects on cardiac (regional function, synchronicity and contractility) and systemic (ventricular arterial coupling) haemodynamics during real-time three-dimensional (RT3D) stress echocardiography in very low CAD risk patients. METHODS: From our RT3D stress echocardiography database, we identified 132 subjects (75 men, aged 68 ± 10 years) referred to stress echocardiography because of risk factors and/or atypical chest pain, who had normal baseline echocardiography, negative dipyridamole stress echocardiography and uneventful 2-year follow-up. All participants had good-quality RT3D datasets acquired during dipyridamole stress echocardiography (0.84 mg/kg in 10 min). From full volume datasets, ventricular volumes, regional subvolume curves and dyssynchrony index (SDI) were obtained; ventricular arterial coupling was calculated as stroke volume/end-systolic volume. RESULTS: In all participants, ventricular arterial coupling increased, whereas SDI decreased. End-systolic volume decreased and stroke index increased independently of pressure drop; the relationship between heart rate and arterial pressure changes was non-linear (quadratic regression, r = 0.368, P < 0.0001). The decrease in systemic resistance showed a curvilinear behaviour with respect to the ventricular arterial coupling increase. CONCLUSION: In a large population of normal individuals, dipyridamole administration improved ventricular energetics and better synchronization of regional contraction may be one of the mechanisms. The relationship between blood pressure and heart rate response suggests that heart rate response is of little help in identifying the systemic haemodynamic response to dipyridamole.

Elevated plasma levels of urotensin II do not correlate with systemic haemodynamics in patients with cirrhosis.

BACKGROUND: The hyperdynamic circulation of hepatic cirrhosis is related to decreased systemic vascular resistance due to arterial vasodilation. Urotensin II plasma levels are increased in cirrhotic patients, and have been suggested to play a role in the pathogenesis of systemic haemodynamic alterations. AIM: To evaluate the relationships between systemic haemodynamics and urotensin II plasma levels. METHODS: Thirty-six consecutive in-patients with cirrhosis and no alteration of plasma creatinine, and 20 age- and gender-matched healthy volunteers underwent noninvasive assessment of systemic haemodynamics and measurement of urotensin II plasma levels. RESULTS: In comparison to healthy controls, cirrhotic patients had signs of hyperdynamic circulation and higher plasma urotensin II levels. Plasma urotensin II was neither significantly different amongst patients with different severity of cirrhosis nor between patients with or without ascites. Both in controls and cirrhotic patients no significant correlations were found between parameters of systemic haemodynamics and plasma urotensin II levels. CONCLUSIONS: In patients with cirrhosis and hyperdynamic circulation, but with normal serum creatinine, urotensin II is higher than in healthy subjects. However, no correlation with cardiac index or other haemodynamic parameters was observed, indicating that other mechanisms prevail.

Second-opinion stress tele-echocardiography for the Adonhers (Aged donor heart rescue by stress echo) project.

BACKGROUND: To resolve the current shortage of donor hearts, we established the Adonhers protocol. An upward shift of the donor age cut-off limit (from the present 55 to 65 years) is acceptable if a stress echo screening on the candidate donor heart is normal. This study aimed to verify feasibility of a "second opinion" of digitally transferred images of stress echo results to minimize technical variability in selection of aged donor hearts for heart transplant. METHODS: The informatics infrastructure was created for a core lab reading with a second opinion from the Pisa stress echo lab. To test the system, simulation standard stress echo cineloops were sent digitally from 5 peripheral labs to the central core lab.Starting January 2009, real marginal donor stress echos were sent via internet to the central core echo lab, Pisa, for a second opinion before heart transplant. RESULTS: In the simulation protocol, 30 dipyridamole stress echocardiograms were sent from the five peripheral echo labs to the central core lab in Pisa. Both the echo images and reports were correctly uploaded in the web system and sent to the core echo lab; the second opinion evaluation was obtained in all cases (100% feasibility). In the transplant protocol, eight donor cases were sent to the Pisa core lab for the second opinion protocol, and six of them were transplanted in marginal recipients. CONCLUSIONS: Second-Opinion Stress Tele-Echocardiography can effectively be performed in a network aimed to safely expand the heart donor pool for heart transplant.