Cardiac toxicity of chemotherapy for breast cancer: do angiotensin-converting enzyme inhibitors and beta blockers protect?

Cardiotoxicity is a relatively frequent and potentially serious side effect of anticancer treatments, particularly anthracyclines and trastuzumab, widely used in the treatment of breast cancer. The increase in cancer survivors has generated a growing interest in the prevention of cardiotoxicity. Although early studies suggested an overall benefit on cardiac function with the use of ACE inhibitors (ACEIs) and beta blockers (BBs), more recent randomized trials have demonstrated little or no effect of pharmacological interventions. Even the various meta-analyses conducted in this area have provided weak results in favour of cardioprotective therapies for which the benefit would not always justify the risk of developing side effects. Given the incompleteness of the evidence, there is no clear consensus on which patients should initiate cardioprotective therapy. As recommended in the new guidelines of the European Society of Cardiology, risk stratification before treatment is crucial to identify high-risk patients who would benefit most from the use of cardioprotective therapy. Randomized trials are currently underway to evaluate other therapeutic strategies such as sacubitril/valsartan, and the possibility of using gliflozins in the future cannot be excluded. However, rigorous control and treatment of risk factors remain the primary focus in the management of these patients.

Prevention of chemotherapy-induced left ventricular dysfunction.

Prevention of left ventricular dysfunction predominantly induced by anthracyclines and/or trastuzumab still represents a challenge for cardio-oncology today. Indeed, this complication threatens to limit the significant gain in cancer survival achieved to date. Oncology strategies with cumulative dose limitation, continuous infusion, dexrazoxane, and liposomal formulations have been shown to decrease the risk of anthracycline cardiotoxicity. The preventive use of ace inhibitors, sartans, and/or beta-blockers has not yet provided convincing evidence and the positive effect on left ventricular ejection fraction decline appears poor without a clear clinical relevance. Assessment of the cardiovascular risk profile is a key aspect of the baseline evaluation of any patient scheduled for cancer therapy. Control and/or correction of modifiable cardiovascular risk factors is the first form of primary prevention of cardiotoxicity. It will be necessary to select populations at higher risk of developing cardiac dysfunction, identify patients genetically predisposed to develop cardiotoxicity in order to build the most appropriate strategies to correctly and timely target cardioprotective therapies.

Ventricular dyssynchrony: 12-month evaluation in ischemic versus nonischemic CRT patients.

OBJECTIVE: Few data exist about the potential differences in the dyssynchrony status of cardiac resynchronization therapy (CRT) candidates stratified by etiology of heart failure, and about the evolution of dyssynchrony at long-term follow-up. We provided a description of intra-ventricular dyssynchrony at baseline, 6 months and 12 months in ischemic and nonischemic CRT patients. METHODS: Tissue Doppler Imaging was performed in 35 CRT candidates (18 ischemic, 17 nonischemic) at baseline, and at 6-month and 12-month follow-up. A group of 11 healthy subjects was considered for comparison. RESULTS: At baseline, the standard deviation and the maximum activation delay between any 2 segments were significantly greater in ischemic (38+/-33ms, 94+/-76ms) and nonischemic (38+/-24ms, 96+/-62ms) patients versus controls (9+/-7ms, 22+/-15ms) (all p<0.05). The average time to activation for posterior and lateral wall was significantly higher in nonischemic patients, while the anterior septum activated later in ischemic patients. At 6-month follow-up, standard deviation and maximum delay did not vary in nonischemic while decreased in ischemic group. All changes persisted at 12 months. CONCLUSIONS: No baseline differences were observed between ischemic and nonischemic patients using studied indices. At 6- and 12-month follow-up, only ischemic patients presented a significant reduction in dyssynchrony values, although in both groups CRT did not lead to a complete normalization of LV synchronism.

Influence of cardiac-resynchronization therapy on heart rate and blood pressure variability: 1-year follow-up.

BACKGROUND: Several studies have shown that cardiac-resynchronization therapy (CRT) improves haemodynamic function, cardiac symptoms, and heart rate variability (HRV) and reduces the risk of mortality and sudden death in subjects with chronic heart failure (CHF). In subjects with CHF, power spectral values for the low-frequency (LF) component of RR variability < or =13 ms2, are associated with an increased risk of sudden death. AIMS AND METHODS: To assess whether spectral indexes obtained by power spectral analysis of HRV and systolic blood pressure (SBP) variability could predict malignant ventricular arrhythmias in patients with severe CHF treated with an implantable cardioverter-defibrillator (ICD) alone or with ICD+CRT. In addition, changes in non-invasive spectral indices using short-term power spectral analysis of HRV and SBP variability during controlled breathing in 15 patients with CHF treated with an ICD alone and 16 patients receiving ICD+CRT, were assessed pre-treatment and at 1 year. RESULTS: Arrhythmias necessitating an appropriate ICD shock were more frequent in subjects who had low LF power. CRT improved all spectral components, including LF power. CONCLUSIONS: Low LF power values predict an increased risk of malignant ventricular arrhythmias; after 1 year of CRT most non-spectral and spectral data, including LF power, improved. Whether these improvements lead to better long-term survival in patients with CHF remains unclear.

Autonomic cardiovascular control and diastolic dysfunction in hypertensive subjects.

BACKGROUND: Early hypertension is associated with left ventricular diastolic dysfunction due to increased end-diastolic pressure. This increase, through the cardiopulmonary reflexes, can influence autonomic cardiovascular control. METHODS: We assessed autonomic nervous system modulation of cardiovascular signals by power spectral analysis of RR interval and systolic arterial pressure variabilities in subjects with recently diagnosed hypertension with or without diastolic dysfunction and in normotensive control subjects. RESULTS: Both hypertensive groups had higher low-frequency (LF) power expressed in normalized units (NUs) than normotensive controls (p < 0.05; p < 0.001) during controlled breathing at rest. The LF spectral index measured after tilt was greater in hypertensive subjects with diastolic dysfunction than in those without (p < 0.05). LF NUs measured at rest correlated significantly with the E/A wave ratio and after tilt with the E-wave deceleration time. CONCLUSIONS: These results seem to indicate that in subjects with recently diagnosed hypertension sympathetic modulation of the sinus node prevails. During tilt, a maneuver designed to stimulate systemic arterial and cardiopulmonary baroreceptor reflexes, hypertensive subjects with diastolic dysfunction, who presumably also have higher end-diastolic pressures, seem to have greater sympathetic modulation of the sinus node than hypertensive subjects without diastolic dysfunction.

Power spectral analysis of heart rate variability as a predictive test in choosing the most effective length for tilt-training.

BACKGROUND: In patients with refractory neurally mediated syncope, tilt training--standing motionless against a wall for increased periods of time per day over one month--can often eliminate recurrent episodes and reduce presyncopal symptoms. We designed dual retrospective and prospective studies to assess cardiovascular autonomic function in subjects with recurrent syncope and identify the most effective length of tilt training between one and three months. METHODS AND RESULTS: In the retrospective study, before tilt training, and in the prospective study, before and after training, all subjects underwent a recording for short-term spectral analysis of heart rate and systolic blood pressure variability. Before tilt-training, autonomic nervous system function differs in patients with recurrent neurally mediated syncope who respond to tilt training for one month and those who do not. "Responders", patients experiencing no episodes of syncope during the 12-month follow-up, had higher low-frequency power of RR (LF(RR)) (p < 0.05) and LF(RR) in normalized units (NU) (p < 0.001) and lower high-frequency power (HF(RR)) (p < 0.05) and HF(RR)NU (p < 0.001) than "non-responders", patients reporting at least one syncopal episode during the 12-month follow-up. In the retrospective study, no difference was found between spectral data for "non-responders" with positive responses to tilt test with and without nitro derivatives. Prolonging tilt-training to three months increased the number of responders (late-responders) by 80% (p < 0.001) and power spectral analysis of heart rate variability (HRV) before tilt training can identify late-responders by their low LF(RR)NUs (<40) and high HF(RR)Nus (>60). Furthermore in late-responders, tilt training brings about a change in cardiovascular autonomic function: at 3 months, LF(RR)NUs increase and HF(RR)NU diminish. CONCLUSION: Power spectral analysis of HRV seems to be a useful tool to preselect patients who are most likely to benefit from prolonged therapy, thus increasing compliance.

Effects of pink grapefruit juice on QT variability in patients with dilated or hypertensive cardiomyopathy and in healthy subjects.

Recent evidence shows that pink grapefruit juice, which is a recommended dietary addition that contains high amounts of the antioxidant flavonoid naringenin, prolongs the corrected QT (QT(c)), a noninvasive electrophysiological marker of spatial myocardial repolarization, and does so by inhibiting the rapid component of the delayed rectifier K+ current (I(Kr)). Prompted by the observation that all class III antiarrhythmic drugs inhibit this current, thereby sometimes provoking torsades de pointes, we compared the effects of a liter of freshly squeezed pink grapefruit juice with those of 2 commonly used class III antiarrhythmics amiodarone and sotalol on the major noninvasive markers of temporal variability in myocardial repolarization used to stratify the risk of sudden death from malignant ventricular arrhythmias. In 32 subjects, 10 with postischemic dilated cardiomyopathy, 12 with hypertensive cardiomyopathy, and 10 healthy, we assessed QT(c) and QT variability index (QTVI) after administration of fresh pink grapefruit juice, placebo, amiodarone, or sotalol. After pink grapefruit juice and sotalol, all these indexes increased significantly from values observed after placebo (P<0.05) and from values after amiodarone (P<0.05). Conversely, after amiodarone, QT(c), but not QTVI, increased significantly from values after placebo (P<0.05). Presumably because of its high naringenin glycoside content, pink grapefruit juice prolongs cardiac repolarization and concurrently increases temporal cardiac repolarization dispersion. The potential proarrhythmic actions of pink grapefruit juice might be of concern in patients with major myocardial structural disorders.

QT variability strongly predicts sudden cardiac death in asymptomatic subjects with mild or moderate left ventricular systolic dysfunction: a prospective study.

AIMS: The most widely accepted marker for stratifying the risk of sudden cardiac death (SCD) in post myocardial infarction patients is a depressed left ventricular function. Left ventricular ejection fractions (EF) of 35% or less increase the risk of sudden death but values between 35 and 40% raise concern. The underlying pathophysiological mechanism is sustained ventricular tachycardia or fibrillation, both associated with increased cardiac repolarization variability. We assessed whether the indices of QT variability from a short-term electrocardiographic (ECG) recording predict sudden death. METHODS AND RESULTS: A total of 396 subjects with chronic heart failure (CHF) due to post-ischaemic cardiomyopathy, with an EF between 35 and 40% and in NYHA class I, underwent a 5 min ECG recording to calculate the following variables: QT variance (QT(v)), QT normalized for the square of the mean QT (QTVN), and QT variability index (QTVI). Corrected QT (QT(c)) was calculated from a 12-lead ECG recording. All participants were followed for 5 years. A multivariable survival model indicated that a QTVI greater than or equal to the 80th percentile indicated a high risk of SCD [hazards ratio (HR) 4.6, 95% confidence interval (CI) 1.5-13.4, P = 0.006] and, though to a lesser extent, a high risk of total mortality (HR 2.4, 95% CI 1.2-4.9, P = 0.017). The model including QTVI as a continuous variable confirmed a similar high risk for SCD (HR 2.9, 95% CI 1.3-6.5, P = 0.01) and for total mortality (HR 2.6, 95% CI 1.3-5.2, P = 0.008). CONCLUSION: Although asymptomatic patients with CHF who have a slightly depressed EF are at low risk of sudden death, the category is extraordinarily numerous. The QTVI could be helpful in stratifying the risk of sudden death in this otherwise undertreated population.

Increased QT variability in young asymptomatic patients with beta-thalassemia major.

BACKGROUND: Despite recent progress in iron chelation therapy, sudden cardiac death due to malignant ventricular arrhythmias remains a vexing, clinical problem in patients with beta-thalassemia major (TM). In this study we assessed whether the major indices of QT variability, emerging tools for risk stratification of sudden cardiac death, differ in young asymptomatic patients with TM and healthy persons. METHODS: Thirty patients with TM and 30 healthy control subjects underwent a 5-min electrocardiography recording to calculate the following variables: QT variance (QT(v)), QT(v) normalized for mean QT (QTVN) and QT variability index (QTVI). All subjects also underwent a two-dimensional and Doppler echocardiography study and magnetic resonance imaging (MRI) to determine cardiac and hepatic T2* values. RESULTS: No differences were observed in clinical and conventional echo-Doppler findings in healthy control subjects and patients with TM whereas QT(v), QTVN and QTVI values were significantly higher in patients than those in controls (QT(v), P < 0.001; QTVN, P < 0.05 and QTVI, P < 0.001) and cardiac T2* and hepatic MRI T2* values were significantly lower in patients with TM (P < 0.001). The indices of temporal QT variability correlated significantly with MRI data. CONCLUSIONS: Young asymptomatic patients with TM have increased cardiac repolarization variability as assessed by QT variability indices, probably due to cardiac iron deposition. These easily assessed, non-invasive markers could be used to identify increased myocardial repolarization lability early in asymptomatic patients with TM.

Age and QT variability index during free breathing, controlled breathing and tilt in patients with chronic heart failure and healthy control subjects.

UNLABELLED: The QT variability index (QTVI) indicates temporal dispersion in myocardial repolarization, and a high QTVI is associated with a propensity for sudden death from malignant ventricular arrhythmias in subjects at high risk. In this study, the authors assessed the effects of free breathing, controlled breathing, and sympathetic stress (tilt) on the QTVI in patients with chronic heart failure (CHF) and healthy control subjects. The authors also examined the influence of age on the same variables. To obtain normative data, they calculated 95% confidence intervals for healthy subjects grouped according to age. Under all experimental conditions, the QTVI was larger in the CHF group overall and in the age subsets than in controls. In patients and controls, the QTVI increased significantly during tilt, although no differences were found between the QTVI measured during free and controlled breathing. In healthy controls, the following variables correlated significantly with the QTVI: age and baseline heart rate (P < 0.001). In patients with CHF, aging had no influence on the QTVI. CONCLUSION: Age, sympathetic stress, and CHF all tend to increase the QTVI and could potentially induce sudden death. Further studies should assess the usefulness of the QTVI as a marker predicting sudden cardiac death under the various conditions of risk.

Factors influencing heart rate variability power spectral analysis during controlled breathing in patients with chronic heart failure or hypertension and in healthy normotensive subjects.

A decreased LFP (low-frequency power) spectral component of HRV [HR (heart rate) variability] is a risk factor for sudden death in patients with CHF (chronic heart failure). In the present study, we evaluated factors (age, arterial pressures and HR) influencing LFP and HFP (high-frequency power) components in short-term recordings during controlled breathing in patients with CHF or hypertension, and healthy normotensive subjects. In patients with CHF, we also compared LFP values with known markers of sudden death [NYHA (New York Heart Association) class, HR and ejection fraction]. All HRV measures were significantly lower in patients with CHF than in hypertensive and normotensive subjects (P<0.001), and in hypertensive than in normotensive subjects (P<0.05). Stepwise multiple regression analysis showed that, in patients with CHF, LFP was inversely associated with NYHA class (beta=-0.5, P<0.0001) and HR (beta=-0.2, P=0.001) and was positively associated with ejection fraction (beta=0.28, P<0.0001). In patients with CHF, LFP remained unchanged with age. In normotensive and hypertensive subjects, HFP decreased with age, but in patients with CHF it did not. In the >/=60<70 and >/=70 years of age subgroups, we found no difference between HFP in the three groups studied. Hence, in normotensives and hypertensives, LFP tended to diminish with age (beta=-0.4, P<0.0001 in normotensives; beta=-0.4, P<0.001 in hypertensives) and was inversely associated with HR (beta=-0.2, P=0.002 in normotensives; beta=-0.3, P=0.002 in hypertensives). Conversely, in patients with CHF, LFP is predominantly influenced by NYHA class, HR and ejection fraction, but not by age. LFP might therefore increase the sensitivity of factors already used in stratifying the risk of sudden death in patients with CHF.