Efficacy of PCSK9 inhibitors in the treatment of heterozygous familial hypercholesterolemia: A clinical practice experience.

BACKGROUND: PCSK9 inhibitors are a treatment option for patients with familial hypercholesterolemia not on low-density lipoprotein cholesterol goals despite the use of maximally tolerated high intensity-statins dose. OBJECTIVE: To evaluate the efficacy of alirocumab and evolocumab in LDL-C reduction and targets attainment in patients with heterozygous familial hypercholesterolemia in clinical practice setting. METHODS: SAFEHEART is an open, long-term prospective study of a cohort of subjects with molecular diagnosis of familial hypercholesterolemia. This study analyze subjects ≥ 20 years of age on stable lipid-lowering therapy, who received PCSK9 inhibitors during the period 2016 to January 2020. RESULTS: 433 patients (mean age 55 years, 53% male, 39% with cardiovascular disease) were included and followed-up for a median of 2.5 years (IQR 1.6-3.0). Median LDL-C level prior to PCSK9 inhibitors was 145 mg/dL (IQR 125-173). The addition of PCSK9 inhibitors (211 alirocumab, 222 evolocumab) reduced LDL-C by 58% (IQR 41-70) p<0.001, in men and women, achieving a median LDL-C level of 62 mg/dL (IQR 44-87) without differences between both PCSK9 inhibitors. Out of them 67% with and 80% without cardiovascular disease reached 2016 ESC/EAS LDL-C targets, and 46% very high risk and 50% high risk patients achieved 2019 ESC/EAS LDL-C goals. Independent predictor factors for attainment of 2019 ESC/EAS LDL-C goals were to be male, smoking and the use of statins with ezetimibe. Both inhibitors were well tolerated. CONCLUSIONS: PCSK9 inhibitors on top of maximum lipid-lowering treatment significantly reduced LDL-C levels in patients with familial hypercholesterolemia and improved the achievement of LDL-C targets.

Minimizing cardiotoxicity while optimizing treatment efficacy with trastuzumab: review and expert recommendations.

Numerous clinical studies have demonstrated the therapeutic benefit of trastuzumab in women with breast cancer. However, a small but not insignificant proportion of patients have experienced trastuzumab-associated cardiotoxicity during these trials. This phenomenon is generally characterized by an asymptomatic reduction in left ventricular ejection fraction (LVEF) or, less often, congestive heart failure (CHF). Concomitant anthracycline therapy significantly increases the risk for cardiotoxicity during trastuzumab treatment, and such regimens are therefore not recommended. The cardiac dysfunction associated with trastuzumab is most often reversible upon discontinuation of treatment and initiation of standard medical therapy for CHF. Prior to treatment initiation, a risk-benefit analysis should be performed for each individual patient, including a thorough assessment of potential risk factors and cardiac function. Cardiac monitoring should be continued throughout trastuzumab therapy and the follow-up period, because early recognition of trastuzumab-associated cardiac dysfunction can allow effective medical intervention. Following the occurrence of asymptomatic LVEF reduction or CHF and appropriate medical intervention, reintroduction of trastuzumab may be considered in patients following resolution of normal cardiac function, or in those for whom the benefit of antitumor therapy outweighs the risk for CHF.

Clinical and prognostic comparison between left ventricular transient dyskinesia and a first non-ST-segment elevation acute coronary syndrome.

OBJECTIVES: Apical ballooning shares features with acute coronary syndromes. Recently, atypical forms have been reported without apical involvement. Usually, the prognostic reports have compared them with ST-segment elevation infarction. Left ventricular transient dyskinesias (LVTD), however, frequently occur without ST-segment elevation and when present, these patients always have open arteries. Our aim was to assess the baseline features, clinical presentation, natural history and compare long-term prognosis in an LVTD-cohort with a first non-ST-segment elevation acute coronary syndrome (NSTEMI) group. METHODS: We performed a prospective observational study including consecutive patients in two groups: (i) LVTD group: 62 patients with this syndrome between 2003 and 2007. Inclusion criteria were LV segmental transient motion abnormalities; ECG new alterations and elevated troponin; absence of recent significant head trauma or obstructive coronary artery lesions. (ii) CONTROL GROUP: 169 patients admitted for a first NSTEMI in 2004. RESULTS: Median follow-up was 35 months. Mean age was 65 years. LVTD group included 83.9% females. NSTEMI group was predominantly males. Eleven in-hospital deaths happened in NSTEMI cohort and none in LVTD. Four patients in the LVTD group required readmission and two patients died. In the NSTEMI group, heart failure, unstable angina, myocardial infarction (P<0.001) and death (P=0.11) were more frequent. Cox regression showed that diabetes mellitus, significant onset mitral regurgitation and NSTEMI versus LVTD were found as event-independent predictors. CONCLUSION: LVTD diagnosis represents a decreased risk of events when compared with classic non-ST-segment acute coronary syndrome, pointing out a different pathophysiologic mechanism.

Predictors of lack of response to resynchronization therapy.

About 30% of patients treated with cardiac resynchronization therapy (CRT) do not respond to treatment. The aim of this study was to identify clinical predictors of lack of improvement in patients receiving CRT. From 197 consecutive patients scheduled to receive CRT, 143 fulfilled the inclusion criteria. Mean age was 68 +/- 7 years and 79% were men. Heart failure was due to ischemic heart disease in 49 patients (34%). Mean QRS duration was 165 +/- 26 ms, and left ventricular ejection fraction was 27 +/- 7%. Nonresponder patients were defined as those who died of heart failure, underwent heart transplantation, or did not increase the distance walked in 6 minutes >10%. At 6-month follow-up, there were 28 nonresponders (20%). Among nonresponders, 2 patients received a heart transplantation and 9 patients died of heart failure. In logistic regression analysis, independent predictors of lack of response to CRT were ischemic heart disease (odds ratio [OR] 2.9, 95% confidence interval [CI] 1.2 to 7; p = 0.023), severe mitral regurgitation (OR 3.5, 95% CI 1.3 to 9; p = 0.014), and left ventricular end-diastolic diameter > or =75 mm (OR 3.1, 95% CI 1.1 to 8; p = 0.026). Patients with these 3 predictors had a probability response of 27%.

Two-dimensional echocardiographic features of the inferior right atrial isthmus: the role of vestibular thickness in catheter ablation of atrial flutter.

OBJECTIVES: The aim of this study was to examine the feasibility of transthoracic two-dimensional (2D)-echocardiography in defining the cavo-tricuspid isthmus (CTI) anatomy and its value concerning the ease of catheter ablation of isthmic atrial flutter (AF). METHODS: CTI analysis was accomplished in 39 cases: 16 necropsy specimens and 23 patients. Sixteen were patients with isthmus-dependent AF and seven controls with other supraventricular re-entrant tachycardias. Two-dimensional transthoracic echocardiography and a right atrium angiogram were performed before radiofrequency catheter ablation (RFCA). RESULTS: The measurements of the CTI with angiography were compared with those taken with echocardiography and correlation was excellent (r= 0.91; P < 0.0001). In normal patients, the dimension of the vestibular thickness was successfully compared and validated with the histological examination of the necropsy specimens: histology median 6.8 mm, range 4.4-10.5 vs. echo median 6.2 mm, range 5.4-8.7; P: NS. Vestibular thickness was greater in complex than in simple RFCA (13.6 ± 1.9 mm vs. 10.0 ± 2.3 mm; P = 0.01). When vestibular thickness ≥11.5 mm, the ablation prone to be complex (sensitivity 83.3%, specificity 80%, positive predictive value 71.4%, and negative predictive value 88.9%). CONCLUSIONS: Two-dimensional transthoracic echocardiography clearly depicts the inferior isthmus and, displaying the thickness of the tricuspid vestibule, it was related with complexity of the ablation procedure in isthmus-dependent AF.

Ergonovine stress echocardiography: Recent experience and safety in our centre.

AIM: To study recent experience and safety of ergonovine stress echocardiography in our centre. METHODS: In this study we collected the clinical variables of patients referred since 2002 for ergonovine stress echocardiography, in addition to indications, the results of this test, complications, blood pressure and heart rate values during the test and the number and results of tests requested before this technique. RESULTS: We performed 40 tests in 38 patients, 2 tests were carried out to verify therapy efficacy. The prevalence of classic cardiovascular risk factors was low and the most frequent indication was chest pain (57.5%). Coronary angiography was performed in 32 patients, and showed normal coronary arteries in 27 patients and non-significant stenosis in 5 cases. In 16 patients, coronary angiography was carried out after a positive or inconclusive ischemia test. Another 6 patients had a normal stress test (5 exercise electrocardiography tests and 1 nuclear imaging test). Of the 40 ergonovine stress echocardiography tests, 6 were positive (4 in the right coronary artery territory and 2 in the circumflex coronary artery territory), all of them by echocardiographic criteria, and by electrocardiographic criteria in only 3 (50%). The presence of non-significant coronary artery stenosis was more frequent in patients with positive ergonovine stress echocardiography (50% vs 6%, P = 0.038), and were related to ischemic territory. During the maximum stress stage, there was a higher systolic (130.26 ± 19.17 mmHg vs 136.58 ± 27.27 mmHg, 95% CI: -12.77 to 0.14 mmHg, P = 0.055) and diastolic blood pressure (77.89 ± 13.49 mmHg vs 83.95 ± 15.73 mmHg, 95% CI: -10.41 to -1.69 mmHg, P = 0.008) than at the baseline stage, and the same was registered with heart rate (73 ± 10.96 beats/min vs 79.79 ± 11.72 beats/min, 95% CI: -9.46 to -4.11 beats/min, P < 0.01). Nevertheless, there were only 2 hypertensive reactions during the last stage, which did not force a premature end to the test, without sustained tachy or bradyarrhythmias, and the technique was well tolerated in 58% of cases. A unique complication (2.5%) of this test was a prolonged vasospasm with a slight increase in necrosis biomarkers, however, this was without repercussion. CONCLUSION: Ergonovine stress echocardiography can be performed with safety, is well tolerated in the majority of cases, and is useful for determining the ischemia mechanism in selected cases.

Clinical usefulness of tissue Doppler imaging in predicting preclinical Fabry cardiomyopathy.

UNLABELLED: Fabry cardiomyopathy (FC) is characterized by left ventricular hypertrophy (LVH). The aim of this study is to determine whether early changes revealed by tissue Doppler imaging (TDI) are useful for detecting preclinical cardiac abnormalities in patients with this X-linked genetic disorder. If so, this tool could help in deciding whether to begin enzymatic therapy earlier than otherwise. METHODS AND RESULTS: 59 consecutive patients with confirmed Fabry disease (FD) underwent conventional and TD echocardiography. FD patients with and without LVH had significantly lower early diastolic tissue Doppler velocities (Ea) compared with the control group (P<0.001); The isovolumic relaxation time (IVRT) was significantly longer in the FD group with LVH (P<0.001). Isovolumic contraction time (IVCT) was significantly shorter in the FD group without LVH compared with the control group (P<0.001). Additionally, peak systolic wall motion velocity (Sa) was significantly lower in patients with LVH, compared with those without LVH (P<0.001). The systolic myocardial velocity correlates inversely with septum and posterior wall thickness (r: -0.74 and r: -0.90; P<0.001 respectively). In respect of predicting preclinical cardiac impairment, the area under the ROC curve of 0.83 suggests an optimal IVRT cut-off point of 60 ms for separating early cardiac impairment from the established condition. This gives a 96.6% specificity rate for the early detection of cardiac involvement. The best parameter for detecting preclinical FC is the IVCT, with a cut-off point of 105 ms, which shows high sensitivity and specificity (100% and 91%, respectively; AUC: 0.97). CONCLUSIONS: Myocardial contraction and relaxation evaluation confirms that TDI is a reliable method for early identification of preclinical FC, even before FC patients develop LVH.