Pharmacology of Cardio-Oncology: Chronotropic and Lusitropic Effects of B-Type Natriuretic Peptide in Cancer Patients with Early Diastolic Dysfunction Induced by Anthracycline or Nonanthracycline Chemotherapy

Menna, Pierantonio; Calabrese, Vito; Armento, Grazia; Annibali, Ombretta; Greco, Carlo; Salvatorelli, Emanuela; Marchesi, Francesco; Reggiardo, Giorgio; Minotti, Giorgio

doi:10.1124/jpet.118.249235

Cited by 11 publications

(13 citation statements)

References 40 publications

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“…Suppressing the activation of VGSC-I NaP by certain chemotherapeutic drugs, including anthracyclines, could reduce the cardiotoxicity associated with standard-of-care therapies [111]. Such a possibility is the focus of a proof-of-concept clinical study of the efficacy and safety of ranolazine in cancer patients [112]. It has also been shown that epilepsy-related mutations in SCN1A (encoding for Nav1.1) are associated with significantly shortened recurrence-free survival in CRCa patients treated with 5-fluoruracil adjuvant chemotherapy [113].…”

Section: Clinical Studiesmentioning

confidence: 99%

In Vivo Evidence for Voltage-Gated Sodium Channel Expression in Carcinomas and Potentiation of Metastasis

Djamgoz

Fraser

Brackenbury

2019

Cancers

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A wide body of evidence suggests that voltage-gated sodium channels (VGSCs) are expressed de novo in several human carcinomas where channel activity promotes a variety of cellular behaviours integral to the metastatic cascade. These include directional motility (including galvanotaxis), pH balance, extracellular proteolysis, and invasion. Contrary to the substantial in vitro data, however, evidence for VGSC involvement in the cancer process in vivo is limited. Here, we critically assess, for the first time, the available in vivo evidence, hierarchically from mRNA level to emerging clinical aspects, including protein-level studies, electrolyte content, animal tests, and clinical imaging. The evidence strongly suggests that different VGSC subtypes (mainly Nav1.5 and Nav1.7) are expressed de novo in human carcinoma tissues and generally parallel the situation in vitro. Consistent with this, tissue electrolyte (sodium) levels, quantified by clinical imaging, are significantly higher in cancer vs. matched non-cancer tissues. These are early events in the acquisition of metastatic potential by the cancer cells. Taken together, the multi-faceted evidence suggests that the VGSC expression has clinical (diagnostic and therapeutic) potential as a prognostic marker, as well as an anti-metastatic target. The distinct advantages offered by the VGSC include especially (1) its embryonic nature, demonstrated most clearly for the predominant neonatal Nav1.5 expression in breast and colon cancer, and (2) the specifically druggable persistent current that VGSCs develop under hypoxic conditions, as in growing tumours, which promotes invasiveness and metastasis.

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Section: Clinical Studiesmentioning

confidence: 99%

In Vivo Evidence for Voltage-Gated Sodium Channel Expression in Carcinomas and Potentiation of Metastasis

Djamgoz

Fraser

Brackenbury

2019

Cancers

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“…Loss or gain of hemoglobin is known to increase or decrease HR in cancer patients (Menna et al, 2018a). Hemoglobin effects on HR probably occur through a modulation of sympathetic reflexes from carotid body (Lahiri et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

“…We in fact demonstrated that high BNP levels caused cardiac relaxant effects (positive lusitropic effects) that compensated for impaired relaxation before this could be detected by echocardiography. High BNP levels and impaired relaxation were therefore characterized as mutually exclusive manifestations of diastolic dysfunction (Menna et al, 2018a). BNP lusitropy develops through the activation of receptor-coupled guanylyl cyclase, followed by cGMP formation and beneficial effects of protein kinase G on reducing myofilament tension in diastole (Bishu et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of Ranolazine versus Common Cardiovascular Drugs in Patients with Early Diastolic Dysfunction Induced by Anthracyclines or Nonanthracycline Chemotherapeutics: A Phase 2b Minitrial

Minotti

Menna

Calabrese

et al. 2019

J Pharmacol Exp Ther

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We have reported that anthracyclines and nonanthracycline chemotherapeutics caused diastolic dysfunction in cancer patients without cardiovascular risk factors. Diastolic dysfunction occurred as early as 1 week after the last chemotherapy cycle and manifested as impaired myocardial relaxation at echocardiography or persistent elevations of B-type natriuretic peptide (BNP) or troponin. The antianginal drug ranolazine shows cardiac relaxant effects that we considered of value to treat early diastolic dysfunction induced by cancer drugs; therefore, 24 low-risk patients with post-chemotherapy diastolic dysfunction were randomized (1:1) to ranolazine or the investigator's choice of common cardiovascular drugs, such as b-blockers and/or angiotensin-converting enzyme inhibitors or loop diuretics (best standard therapy, BST). After 5 weeks, 12 of 12 patients on ranolazine recovered from diastolic dysfunction, whereas 3 of 12 patients on BST did not improve; however, adverse events (not serious) were apparently more frequent for ranolazine than for BST (4/12 vs. 1/12). Ranolazine did not lower blood pressure, whereas BST reduced systolic pressure and caused a trend toward a reduced diastolic pressure. Most patients at randomization showed tachycardia resulting from chemotherapy-related anemia. Hemoglobin recovery contributed to normalizing heart rate in these patients; however, some patients in the ranolazine arm developed tachycardia through chronotropic effects of high BNP levels and returned to a normal heart rate through the effects of ranolazine on decreasing BNP levels. This minitrial describes the potential effects of ranolazine on relieving chemotherapy-related diastolic dysfunction; however, clinical implications of these findings need to be characterized by studies with an adequate sample size. SIGNIFICANCE STATEMENT The antianginal drug ranolazine causes cardiac relaxant effects that might relieve diastolic dysfunction. In a clinical pharmacology study, 24 patients were randomized (1:1) to receive ranolazine or common cardiovascular drugs to treat early diastolic dysfunction induced by anthracycline-based or nonanthracycline chemotherapy. Ranolazine relieved diastolic dysfunction in these patients. The safety profile of ranolazine in cancer patients is similar to that of the general population. Compared with common cardiovascular drugs, ranolazine relieved diastolic dysfunction without lowering blood pressure. The sample size of this study was nonetheless too small to permit considerations about the potential clinical value of ranolazine for oncologic patients with early diastolic dysfunction induced by anthracyclines or nonanthracycline chemotherapeutics. This information should be obtained by studies with an adequate sample size.

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“…with or without rituximab (R), the most commonly used in first--line treatment for aggressive lymphomas, is among the most potent chemotherapeutic agents which has truly revolutionized the management of NHL [1]. However, doxorubicin utility is compromised by cardiotoxicity, manifesting initially as asymptomatic cardiac dysfunction detected by imaging studies, heart rhythm disturbance and diastolic dysfunction, evolving irreversibly to congestive heart failure (CHF) and premature cardiac deaths [2][3][4]. The introduction of cardiac imaging technology and detection of even asymptomatic left ventricular (LV) dysfunction revealed the higher incidence of anthracycline-induced cardiotoxicity than previously estimated [5].…”

mentioning

confidence: 99%

Role of biomarkers and electrocardiography assessment as individual predictors of anthracycline cardiotoxicity in lymphoma patients

2019

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The significant progress in the treatment of non-Hodgkin lymphomas, translating into prolongation of overall survival results in the manifestation of long-term adverse events, like anthracycline-related cardiotoxicity. Despite the dose-dependent cardiac dysfunction and the presence of risk factors, the increasing probability of cardiotoxicity arises from individual predisposition. Identification of high--risk patients gives the opportunity to implement the prevention strategies to reduce the incidence of cardiac complications.The study evaluated the utility of biomarkers: N-terminal B-type natriuretic peptide, troponin I and electrocardiography with spatial QRS-T angle assessment, as indicators of individual sensitivity of cardiomyocytes to doxorubicin resulting in myocardial damage. Thirty-five treatment-naïve patients at increased risk of cardiotoxicity, were subjected prospectively during (R)-CHOP treatment to echocardiographic assessment and analysis of biomarkers: TnI and NT-proBNP plasma level and spatial QRS-T assessment before and 24 hours after each cycle of chemotherapy.The analysis of QRS-T angle was consistent with the results of NT-proBNP assessment and allowed to identify, after the first cycle of chemotherapy, patients at increased risk of developing cardiovascular complications, who require thorough echocardiographic analysis and primary cardioprotection implementation. Our data did not reveal the role of TnI in the identification of cardiac events. Our findings, though promising, should be confirmed in a larger group of patients in real-life or clinical trials.

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Pharmacology of Cardio-Oncology: Chronotropic and Lusitropic Effects of B-Type Natriuretic Peptide in Cancer Patients with Early Diastolic Dysfunction Induced by Anthracycline or Nonanthracycline Chemotherapy

Cited by 11 publications

References 40 publications

In Vivo Evidence for Voltage-Gated Sodium Channel Expression in Carcinomas and Potentiation of Metastasis

In Vivo Evidence for Voltage-Gated Sodium Channel Expression in Carcinomas and Potentiation of Metastasis

Pharmacology of Ranolazine versus Common Cardiovascular Drugs in Patients with Early Diastolic Dysfunction Induced by Anthracyclines or Nonanthracycline Chemotherapeutics: A Phase 2b Minitrial

Role of biomarkers and electrocardiography assessment as individual predictors of anthracycline cardiotoxicity in lymphoma patients

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