AUCTORES
Globalize your Research
Research Article | DOI: https://doi.org/10.31579/2641-0419/110
1 Director of research, The Heart and Vascular Institute, Germantown, TN USA
*Corresponding Author: Gary L Murray, The Heart and Vascular Institute, 7205 Wolf River Blvd, Germantown,
Citation: Gary L Murray (2020) Re-print-Ranolazine may be the Best and Safest Pharmacologic Therapy For Congestive Heart Failure, And Safe, Effective For Ventricular And Atrial Arrhythmias. J, Clinical Cardiology and Cardiovascular Interventions, 3(12); Doi:10.31579/2641-0419/110
Copyright: © 2020 Gary L Murray, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 19 November 2020 | Accepted: 27 November 2020 | Published: 08 December 2020
Keywords: ranolazine; congestive heart failure; ventricular arrhythmia; atrial arrhythmia
Background: Ranolazine (RAN) reduces cardiac sodium channel 1.5’s late sodium current(INaL ) in congestive heart failure (CHF), reducing myocardial calcium overload, potentially improving left ventricular ejection fraction(LVEF) and reducing arrhyth- mogenic after potentials. RAN blocks neuronal sodium channel 1.7(Nav 1.7), potentially altering parasympathetic and sympathetic (P&S) activity. RAN also selectively blocks inactivated atrial Nav 1.8, as well as ventricular IKr and ICaL, affecting atrial and ventric- ular arrhythmias.
Methods:
(1)Matched CHF patients were given RAN (1000 mg p.o. b.i.d.) added to guideline-driven therapy (RANCHF, 41 systolic, 13 diastolic) or no adjuvant therapy (control, NORANCHF, 43 systolic, 12 diastolic). Echocardiographic LVEF and P&S measures were obtained at baseline and follow-up (mean 23.7 months).
(2)A total of 59 patients with symptomatic PVCs were identified from full-disclosure Holters. Doses of 500 - 1,000 mg RAN b.i.d. were given to 34% and 66% of patients, respectively, and Holters were repeated (mean 3.1 months). Congestive heart failure (CHF) was defined as symptoms including dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and edema, with a brain natriuretic peptide
> 400. Systolic heart failure with reduced ejection fraction (HFr EF) vs. diastolic CHF (HFpEF) depended upon LVEF≥ 40%.
Results:
(1)LVEF increased in 70% of RANCHF patients, an average of 11.3 units. Mean LVEF remained unchanged in NORANCHF pa- tients. P&S measures indicated cardiovascular autonomic neuropathy (P<0.10 bpm2) in 20% of NORANCHF patients at baseline and 29% at follow-up (increasing in both groups). At baseline, 28% of patients had high sympathovagal balance (SB), RAN normalized SB in over 50% of these; in contrast, the NORANCHF group had a 20% increase in patients with high SB.
(2)Upon repeat Holters at a mean of 3.1 months after initiating RAN, 95% (56/59) of the patients had their PVC count reduced: 24% (14/59) had more than 90% decrease, 34% (20/59) had 71 to 90% decrease, and 17% (10/59) had 50 to 70% decrease. In the entire group, RAN reduced PVCs by 71% (mean 13,329 to 3,837; p < 0.001). Ventricular bigeminy was reduced by 80% (4,168 to 851; p < 0.001), ventricular couplets were reduced by 78% (374 to 81; p < 0.001), and ventricular tachycardia (VT) was reduced by 91% (56 to 5; p < 0.001). The PVC reduction was dose dependent without proarrhythmia.
Conclusions:
(1)RAN preserves or improves LVEF and decreases high SB in CHF.
(2)RAN offers an effective and safe pharmacologic treatment for symptomatic PVCs.
Despite advances in pharmacologic management [1-5] and device therapy [6], improvement in left ventricular (LV) function in congestive heart failure (CHF) patients, while statistically significant, remains relatively mild in many subjects. The late sodium current (INa) present in CHF causes an intramyocardial calcium (Ca++) overload that results in diastolic dysfunction and micro vascular compression that can worsen LV function [7]. RAN binds to amino acid F1760 of the cardiac sodium channel 1.5 (Nav1.5), thereby reducing the late INa. In a therapeutic concentration (6 μmol), intramyocardial Ca++ overload is reduced 50%. Additionally, RAN blocks neuronal sodium channel 1.7 (Nav1.7) in a strongly use-dependent manner via the local anesthetic receptor [8, 9]. Therefore, RAN may directly alter function of the parasympathetic and sympathetic (P&S) branches of the autonomic nervous system (ANS). We postulated these actions of RAN should result in favorable changes in LV function and P&S measures in CHF.
RAN’s inhibition of the late sodium current (INa), results in suppression of early and delayed after depolarization’s (EAD/ DAD), thereby reducing triggered ventricular ectopy. An increase of the late INa induces EAD/DAD resulting in triggered activity. The diastolic transient inward current in the long QT syndrome is caused by calcium overload and is inhibited by RAN. Because RAN has no known proarrhythmic effects and, to the contrary, protects against torsades de pointes, we hypothesized that RAN could be an effective and safe pharmacologic treatment for symptomatic premature ventricular contractions (PVCs).
(1) One hundred and nine systolic or diastolic, New York Heart Association(NYHA) class2-4CHFpatientswereincludedinthisstudy. They were treated according to standard heart failure guidelines [10]. In an open-label,unblinded fashion, patients were prescribed Ranolazine (RAN, 1000 mg po-bid) in addition to standard heart failure therapy (RANCHF, 41 systolic,13 diastolic) or no adjuvant therapy (control, NORANCHF, 43 systolic, 12 diastolic). Patients were matched for age, gender and history. Patient demographics are presented in Table I. Since patients were on maximally tolerated doses of beta-blocker and angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blockers (ARBs), only the diuretic dose was adjusted as needed. Diastolic CHF is defined as CHF with LV ejection fraction (LVEF) ≥0.40. Baseline 2D-echocardiograms were obtained and the LVEF calculated as the average of the apical 2 and 4 chamber Simpson’s method [11], and studies were repeated within 36 months (mean follow-up for RANCHF patients is 24.5 months and for NORANCHF 22.8 months, Table-II). The accuracy of the initial echocardiographic LVEF was confirmed by being within 5 ejection fraction units (EFUs) of the LVEF as measured by nuclear multigated acquisition. Serial changes in any patient of ≥±7 EFUs are considered clinically significant [12]. Other measurements are per American Society of Echocardiography guidelines [13]. CHF is classified as systolic or diastolic, rather than CHF with preserved (normal) LVEF or reduced LVEF, because the RANCHF group only had one subject with a normal LVEF.
Another 30 subjects without CHF or an indication for RAN (20 male, 10 female, average age 61 years) with “CHF-like” abnormal P&S activity with high SB (25/30, 83%), CAN (1/30, 3%) or both(4/30, 13%) were identified. Twenty (67%) had a history of coronary disease, but only 5 (17%) were not completely re- vascularized, and 3(10%) had a positive nuclear stress test. Sixteen (53%) were hypertensive, 11 (31%) were diabetic and 4 (13%) were on a beta-blocker. The causes of their abnormal P&S included chronic pain or anxiety, diabetes and hypertension. RAN 500-1000 mg bid was prescribed, and the P&S testing repeated on the 5th day. No subject had high BNP or low LVEF.
P&S function in response to Ewing challenges [14] was assessed noninvasively using the Physio, PS, Inc., Atlanta, GA, and ANX 3.0 Autonomic Function Monitor.
P&S activity was computed simultaneously and independently based on concurrent, continuous time-frequency analyses of respiratory activity (RA) and heart rate variability (HRV) [15-19]. Parasympathetic activity (measured as the respiratory frequency area, RFa) is defined as the spectral power within a 0.12 Hz-wide window centered on the fundamental respiratory frequency (FRF) in the HRV spectrum. FRF is identified as the peak spectral mode from time-frequency analysis of RA. Effectively, FRF is a measure of vagal outflow as it affects the heart (a measure of cardio vagal activity). Sympathetic activity (low-frequency area, LFa) is defined as the remaining spectral power, after computation of RFa, in the low-frequency window (0.04-0.15 Hz) of the HRV spectrum. High sympathovagal balance (SB = LFa/RFa) is defined as a resting LFa/RFa ratio >2.5. P&S activity was recorded from a standard autonomic test, including 5 minutes rest; 1 minute paced breathing (6 breaths/min), a Valsalva challenge (including a 15-sec Valsalva maneuver) and a quick stand followed by 5 minutes of quiet stand. The average SB reported is the average of the ratios recorded during the sampling period, not a ratio of averages. Cardiovascular autonomic neuropathy (CAN) was defined in standard fashion [20, 21], reflecting very low, resting RFa (<0.10 bpm2) [22]. The P&S method is valid regardless of challenge or patient state or history. Normal SB is 0.42.5 and CAN define a high mortality risk, including silent MI, sudden cardiac death and acute coronary syndrome (ACS) [23-25]. Records including high-quality arrhythmia are omitted. P&S and HRV measures are correlated with outcomes. While the patient population is underpowered to make final health outcome assessments, we determined the occurrence of major adverse cardiac events (MACE), defined as cardiac death (determined from hospital records or death certificates), heart failure hospitalization and ventricular tachycardia or fibrillation (as determined by defibrillator therapy, or administration of intravenous amiodarone for arrhythmia termination) alone or as a composite endpoint. All subjects signed appropriate informed consent forms for the studies and treatments rendered.
Continuous data were assessed for normality with normally distributed data analyzed using Student t-tests and non-normally distributed data assessed using a Mann-Whitney test. Dichotomous data were analyzed using the Chi-square test or Fischer’s Exact Test. A p-value of ≤0.05 was considered significant. We determined that we needed 50 patients per group to have a sufficient sample size using an alpha of 0.05, difference of means of 6 units and expected standard deviation of 15 units with a power of 80%. All statistics are performed under SPSS v 1.4. Student t-tests are performed as two-tailed with equal variance. Significance values are determined on the null hypothesis that pre- and post-treatment values are equal.
(2) Using full-disclosure 24-hour Holters (Burlick), 59 adult patients with highly symptomatic, frequent PVCs were identified during routine outpatient clinic visits. The PVCs met criteria for “ventricular Para systole” (VP): non-fixed coupling, fusion, interpolation, and a mathematical relationship with R-R intervals. Doses of 500 and 1,000 mg b.i.d. were given to 34% and 66% of patients, respectively, depending on tolerability, without the side effects of headache, dizziness, nausea, or constipation, or the patients’ symptomatic improvement. Holters were repeated at 1 week and up to 2 years (mean: 3.1 months) and were compared. Response was defined as at least 50% reduction in PVC count and/ or at least 70% reduction in complex PVCs. All statistics, including means, standard deviations, and Student’s t-tests, were performed under SPSS v 14.1 (IBM). Student’s t-tests were performed as two- tailed tests with equal variance. Significant values were determined on the null hypothesis that the pre- and post-treatment values were equal. All patients were informed that RAN administration for PVCs was not approved by the U.S. Food and Drug Administration, hence it was off-label use, and gave appropriate informed consent
CHF
Overall, 109 age-, gender- and history-matched CHF patients treated according to standard heart failure guidelines [10] were included in the study, with 54 patients receiving RAN and 55 patients in the control group. Demographic comparisons are provided in Table-I and are similar between groups: 93% of the patients are evenly divided between NYHA class 2 and 3; 98% are on a beta-blocker (NORANCHF subjects at a slightly higher dose). Slightly more diastolic RANCHF patients have hypertension and chronic renal insufficiency.
Left ventricular ejection fraction
On follow-up, RANCHF patients had significantly higher LVEF (Table-II; systolic CHF: p<0.001, diastolic CHF: p = 0.003). Controls had no significant change in the mean LVEF. When viewed dichotomously (Table-III), 26/54 (48%) RANCHF patients experienced a clinically significant increase in LVEF (≥+7EFU) as compared to 4/55 controls (7%, p<0.001, Table-III).From the systolic RANCHF subgroup, 17/41 (41%) subjects experienced a clinically significant increase (>7 EFUs) in LVEF as compared to 9/13 (69%) diastolic RANCHF patients (p<0.001). Final LVEF in cohort patients experiencing MACE was significantly lower than in those who were MACE-free (Table-IV and Table-V, p = 0.005). In the RANCHF group MACE subpopulation, the initial to final LVEF increase was less than in patients without MACE, 6 EFUs vs. 9 EFUs (Table-IV, p<0.020).In control patients, insignificant changes in LVEF occurred regardless of MACE or not (p>0.050).
Other echocardiographic data
Systolic RANCHF patients demonstrated a decrease in left ventricular internal dimension in systole (LVIDs). Diastolic RANCHF patients demonstrated a slight increase in LVID diastole (LVIDd) coupled with a slight decrease in LVIDs. Baseline LVID (Table-II) trended similar between groups (p>0.050). LVIDd averaged 5.88 and 6.09 cm for systolic RANCHF and NORANCHF patients, and 5.16 and 5.28 cm for diastolic RANCHF and NORANCHF patients, respectively. LVIDs averaged 4.94 and 5.21 cm for systolic RANCHF and NORANCHF patients, and 4.08 and 4.03 cm for diastolic RANCHF and NORANCHF patients, respectively. RANCHF vs. NORANCHF Patients had significantly lower LVIDs at follow-up (>0.36 cm,p<0.001, Table-II). No significant differences (p>0.050) in baseline or follow-up LVIDd or LAD occurred between experimental groups, although LAD tended to decrease in the systolic RANCHF cohort (4.6 to 4.3 cm, Table- II, p = 0.084).
Autonomic (P&S and HRV) measures
Arrhythmia-free, P&S studies were accomplished every 6 months for 95/109 (87%) patients; 13% of the patients (8 RANCHF and 6 NORANCHF) had arrhythmias precluding a complete assessment. While P&S measures are readable [26], HRV analyses are contraindicated for arrhythmia [27]. Autonomic measures of the RANCHF and control groups are presented in Table VI. The average RANCHF patient demonstrated significant P&S responses to RAN (p≤0.050), except for paced breathing RFa (a parasympathetic stimulus; p = 0.065).This included significant reductions in absolute and relative measures of sympathetic activity. None of the Time Domain Ratio responses to RAN were significant (p≥0.050). The absolute and relative resting sympathetic changes from baseline to follow-up in the control patients were also significant. Sympathetic activity remained high for cohort patients with events (Table-IV and Table-V), even though SB demonstrated a relative decrease from 6.25 to 4.86 (unit less). The high pre-RAN SB (higher than the ratio of the averages might suggest, (Table-IV) is due to two patients with severe CAN. Post-RAN, these patients were found to no longer be in CAN and demonstrated an increase of ≥7 EFUs, on average (p = 0.0002). The parasympathetic response to deep breathing is slight. The change in RFa is well correlated with the changes in LVEF (p<0.001). The exhalation to inhalation (E/I) ratio decreases (not significant). The sympathetic (LFa) decrease with Valsalva challenge. The VR decreases (not significant).The Valsalva challenge responses are well correlated with the changes in LVEF (p<0.001).
Sympathetic withdrawal (SW) was demonstrated by 9/15 RANCHF patients. These patients all demonstrated an abnormal BP response to standing. Upon follow-up, these patients demonstrated an average increase in sympathetic activity (a normalized response) as compared with rest, with improved standing BP, Only four RANCHF patients continued to demonstrate SW. The stand responses are well correlated with changes in LVEF (p<0.001).For NORANCHF cohort patients (Table-V), the relative sympathetic measure (SB) increased (p<0.05). In the RANCHF group without events (Table-IV), the relative measure (SB) decreased. These SB changes are significantly associated with changes in LVEF (p<0.001). The associated average increase in LVEF is more than +9 EFUs. The patients without events started in balance (normal SB) and remained in balance. The resting changes are well correlated with the changes in LVEF (p<0.001). The pre- and post-RAN resting P&S responses in both the subpopulations with and without events are significant (p≤0.025). The pre- and post-RAN deep breathing parasympathetic measures (RFa) in both the subpopulations with and without events are significant (p≤0.011), but not the increases in E/I ratio (p>0.321). Nearly half (14/27) of the pre-RAN event patients demonstrated SW in response to stand, indicating orthostatic dysfunction. These findings are associated with abnormal blood pressure responses to stand. Post-RAN, the average patient without events reversed their SW. This is a normalized response. Only six patients continued to demonstrate SW after history of RAN. The pre- and post- RAN autonomic responses to stand in both subpopulations are significant (p≤0.045).
Table-V presents baseline and follow-up P&S measures and LVEF in the NORANCHF patients with and without events. P&S changes were significant (p≤0.050) for patients with events. Their SB started high and increased upon follow-up. The patients without events demonstrated opposite absolute changes upon follow-up. However, the net result was an increase in SB to above normal. Only the E/I ratio change for the patients with events was significant (p = 0.013).
Five days of RAN administered to 30 subjects without CHF or angina, but with “CHF- like” dysautonomia improved high SB and CAN in 27/30 (90%), normalizing SB and CAN in 20/30 (67%) of subjects (Table-VII). P&S responses returned to baseline after discontinuing RAN.
Health outcome assessment
The composite MACE endpoint occurred in 17/54 (31.5%) RANCHF patients and 21/55 (38.2%) control patients. When evaluated separately, each MACE endpoint was lower in the RANCHF patients.
RESULTS-(2) PVCS
Patient demographics are summarized in Table VIII. Mean age was 63 years, 58% were males, mean left ventricular ejection LVEF was 0.60 with only 8% having a history of CHF( two systolic, three diastolic), 73% were hypertensive, 34% had coronary artery disease (CAD; all re-vascularized), 34% were taking a beta blocker, and the mean RAN dose was 866 mg per day. All patients experienced palpitations, 65% had dizziness, and 33% complained of fatigue.
Ninety-five% (56/59) of patients had their ventricular ectopy reduced by RAN. Over 40% of patients had at least 10,000 PVCs, and over 25% had greater than 20,000 PVCs. In the entire group, RAN reduced PVCs by 71% (mean: 13,329 to 3,837; p < 0.001). Approximately 24% (14/59) of patients had more than 90% decreases in PVCs, 34% (20/59) had 71 to 90% decrease, and 17% (10/59) had 50 to 70% decreases. Ventricular bigeminy was reduced by 80% (4,168 to 851; p < 0.001), couplets were reduced by 78% (374 to 81; p < 0.001), and ventricular tachycardia (VT) reduced by 91% (56 to 5; p < 0.001). The maximum reduction in PVCs was from 47,211 with 29,573 ventricular bigeminy to 13 PVCs per 24 hour, and no bigeminy, accompanied by a robust resolution of the patient’s incapacitating fatigue. This patient stated: “My life has been returned to me. I can return to work”. No proarrhythmia was observed, and there were no significant side effects of treatment. Approximately 6% of patients reported one or more of the following side effects: Constipation, dizziness, nausea, or headache. One of the initial three non-responders had response 1.5 years later with 16,890 PVCs and 10,114 ventricular bigeminy reduced to only 3 PVCs per 24 hours.
Discussion-(1)
In the past 30 years, improvements in LV function and outcomes in systolic CHF have been attributed to pharmacologic therapy addressing the neurohumoral paradigm, together with the advent of device therapy [1-6]. However, even more Improvement is needed. This has triggered stem cell trials [28] and a search for new pharmacologic agents. To date, no therapy in diastolic CHF has shown improved survival. RAN is a first in class drug. It reduces the late sodium current (INa) resulting in a 50% reduction of the intramyocellular Ca++ overload caused by the late INa via the Na+/Ca++ exchanger [7].This improves diastolic and micro vascular dysfunction [29], and should result in improved LV systolic function. Since LVEF is widely accepted as one of the most important prognostic indicators in CHF [30], we focused on its changes after RAN was added to guideline-driven therapy.
In therapeutic concentrations (2-6 μmol), RAN also inhibits neuronal Nav1.7 via the local anesthetic receptor in a use-dependent fashion [8, 9]. Consequently, RAN potentially can alter ANS function directly, improving P&S measures. High sympathetic tone (high SB) with critically low parasympathetic activity (CAN) indicates high mortality risk, and has been associated with sudden cardiac death, CHF and ACS [20-25, 31]. This study is the first to correlate CHF outcomes with changes in both LVEF and P&S measures.
We found RAN significantly increased LVEF by 6.4 EFUs in systolic CHF patients and 9.5 EFUs in diastolic CHF (Table-II). In the NORANCHF group, final LVEF fell 1 EFU in the systolic CHF patients and 0.5 EFU in the diastolic CHF patients (Table- II). These LVEF changes represent mean values of the cohort groups. In the systolic RANCHF patients, the increase in LVEF was solely due to a decrease in LVIDs (Table-II). In diastolic RANCHF patients, the increase in LVEF was due to a slight increase in LVIDd (suggesting increased diastolic filling) coupled with a slight decrease in LVIDs (suggesting improved systolic emptying; Table-II). Individually, only 1/54 (2%) RANCHF patients decreased LVEF by ≤−7 EFUs and 26/54 (48%) RANCHF patients increased LVEF by ≥+7 EFUs, with the remaining 50% of patients showing little LVEF change (p<0.001, Table-III). Increases in the RANCHF patients’ LVEF were sufficient to avoid defibrillator implantation in 10 subjects, resulting in substantial cost savings. In the control group, 8/55 (15%) decreased LVEF by ≤−7EFUs, and only 4/55 (7%) patients increased LVEF by ≥+7EFUs, with the remaining 43/55 (78%) demonstrating little change (Table. III). Therefore, LVEF is more than 6 times as likely to increase and 1/8TH as likely to decrease following RAN therapy in CHF patients. LVEF can increase regardless of the initial LVEF. RAN increased LVEF by ≥+7 EFUs in 17/41 (41.5%) systolic CHF patients vs. 9/13 (69%) diastolic CHF patients (p<0.001). Furthermore, when RAN increased LVEF by ≥+7 EFUs, 9/26 (35%) patients had a history of CAD, whereas 17/26 (65%) did not (p<0.001). Since almost 80% of the CAD patients were re-vascularized, and only 14% had a positive stress test, we feel the smaller increases in LVEF in CAD patients were due to LV scarring secondary to remote myocardial infarctions. Finally, whether or not LVEF increased by ≥+7 EFUs did not depend upon the maximum tolerated dose of beta-blocker (94% took carvedilol), as the mean daily dose differed by only 0.5 mg. Autonomic (P&S and HRV) measures have been documented to be associated with LVEF and cardiovascular risk (32).Table VI presents the P&S and LVEF data without regard to clinical outcomes. RANCHF patients demonstrated a decrease in SB from 2.42 to 1.98 (p = 0.019) mainly resulting from a reduction in LFa, for example, a sympatholytic effect. Sympatholytic, such as beta-blockers, are known to be cardio protective. This protection is at least in part due to a decrease in SB (balance) toward 1.0 indicating less sympathetic activity and a relative Increase in parasympathetic activity [33]. And it is associated with reduced CAN risk. NORANCHF patients almost doubled their initially high-normal SB as a result of a marked increase in LFa with only a small increase in RFa, increasing the risk for MACE. The ANS responses to standing were more normal after RAN, indicating improved ANS function and reduced risk of orthostasis. Orthostasis not uncommonly limits the doses of beta- blockers and ACE-Is/ARBs CHF patients can tolerate. Conversely NORANCHF patients on average displayed a more abnormal standing response during follow-up, resulting from a decrease in LFa (SW) consistent with worsening of ANS function, increasing the risk for orthostatic. In contrast to the dramatic LFa changes noted in both groups, RFa (parasympathetic) Activity changes were very small, consistent with the lack of significant changes in the Time Domain Ratios, and CAN was not, on average, improved. The lack of a significant impact upon CAN means RAN’s reduction of SB might be an important mitigating factor reducing the CV risk of CAN. Differences in ANS measures in patients with or without events are presented in Tables-IV and Table-V.
While this study was an open enrollment (nonrandomized) trial and underpowered to make final health outcome assessments, we found a qualitative reduction in the composite endpoint of cardiac death, CHF admissions and therapies for Ventricular Tachycardia and Ventricular Fibrillation (VT/VF) in the RANCHF group. There was a 40% event reduction, with 57% fewer deaths, 60% fewer VT/ VF therapies, and 20% fewer CHF hospitalizations. The initial LVEF was lower in MACE patients than in non-MACE patients (Table-V and Table- VI). Only the RANCHF group increased LVEF during follow-up, and the increase was more in patients without events. The increase in MACE patients’ LVEF (Table-IV) was the same as the LVEF increase of the entire systolic RANCHF group (Table- II), yet RANCHF patients had 40% fewer events. Therefore, high sympathetic activity as indicated by high SB was more predictive of MACE than a change in LVEF. When SB was ≤2.5 or LVEF was ≥0.32, 81% or 79% of subjects, respectively, were MACE free; when SB was >2.5, 59% of patients suffered MACE vs.50% of patients when LVEF was <0.32. Since 5 days of RAN administration to patients without CHF (or angina) resulted in similar P and S changes to the CHF patients, this strongly suggests a direct effect of RAN upon P and S independent of hemodynamics.
Discussion-(2) PVCS
RAN has several electrophysiological effects with no known proarrhythmia [34-35]. IKr and late INa are inhibited at concentrations within therapeutic range. In addition, RAN has been shown to inhibit the diastolic transient inward current [36] resulting in suppression of after depolarization. Although the QT interval is prolonged by approximately 6 ms due to IKr inhibition, there is no trans mural dispersion of repolarization, and RAN is protective against torsades de pointes [37].
EAD/DAD is causes of triggered ventricular ectopy [38-39] and can be induced by late INa that RAN inhibits. DAD are due to spontaneous release of Ca++ from the sarcoplasmic reticulum, and EAD are directly due to Ca++ entry through the Ca++ window current, except in Purkinje fibers where EAD are due to late INa window current(35,39) Some clinical scenarios of EAD/DAD- mediated ventricular arrhythmias include CHF [40], catechol aminergic polymorphic VT(41) hypokalemia [42] left ventricular hypertrophy (LVH) [43] long QT syndrome [44] and cocaine use [45] Our patients met criteria for VP [46-47] This is the second study reporting effects of RAN on PVCs in humans, but the first focusing exclusively on triggered ventricular ectopy.
VP (PVCs with variable coupling, fusion, interpolation, and a mathematical relationship with R-R intervals) occurs in 1 of 1,300
patients and can be a highly symptomatic arrhythmia, which is thought to be caused by EAD/DAD [46-47]. Prognosis depends upon any coexisting cardiac disease. Rarely does ventricular fibrillation or syncope occur, and VT is slower than reentrant VT. Several drugs have been tried as treatment for VP. Verapamil produced a satisfactory response in 18% of treated patients A report of two patients responding to adenosine has been published Dilantin was successful in one patient Cardiac pacing succeeded in two patients [48-51]. Amiodarone produced good results in nine patients only 33% of patients with VP responded to the usual sodium channel blockers [52].
Activation of late INa (for example, by phosphoralization by Ca++/calmodulin kinase ll), may be a common myocardial response to stress. Therefore, RAN may have a therapeutic role in treating many cardiac conditions, including unstable ischemic patients with PVCs and patients with atrial fibrillation [53].
RAN was very well tolerated, with only 6% of patients experiencing headache, dizziness (not BP-related, but a direct CNS effect), nausea, or constipation, with no known organ toxicity except in DMII patients with class 4, 5 renal failures. Patients’ symptoms improved proportionally to PVC reduction. In canine ventricular wedge preparations, RAN did not induce torsades de pointes, reduced the action potential duration of M cells, and suppressed EAD induced by d-sotalol and hypoxia [54-55]. These are potential explanations of why RAN administration caused no proarrhythmia in this study. RAN is metabolized by CYP 3A so that inhibitors of this enzyme, such as ketoconazole, diltiazem, verapamil, macrolid Antibiotics, HIV protease inhibitors, and grapefruit juice, increase RAN levels. Inhibitors of g-glycoprotein increase plasma levels two- to threefold. RAN increases digoxin concentrations 1.4- to 1.6-fold, and simvastatin Cmax is doubled.
The patient population hersein reported seems reasonably typical of adults who would be referred to a cardiology practice primarily for ventricular arrhythmia evaluation and therapy. Patients were essentially Medicare-age with multiple Comorbidities, but well-preserved LVEF and highly symptomatic with palpitations, dizziness, and fatigue. Syncope and cardiac arrest were not methods of presentation.
In summary, RAN was found to be highly effective in suppressing triggered VPC. Isolated PVCs were reduced from 13,329 to 3,837, ventricular bigeminy reduced from4,168 to 851, ventricular couplets reduced from 374 to 81, and VT was reduced from 56 to 5, representing reductions of 71%, 80%, 78%, and 91%, respectively. One of the initial three non-responders demonstrated a remarkable response 1.5 years later with 16,890 PVCs reduced to only 3 PVCs per 24 hours (99% reduction). The presenting symptoms were improved in proportion to PVC reduction (marked decrease in palpitations, fatigue, and dizziness).
Limitations (1)
This is a single-center study. Recently, it was proposed that diastolic CHF be defined as CHF with LVEF≥0.50 [10]. Had we used this definition, only one of our diastolic RANCHF patients would have remained, increasing the systolic RANCHF group to 50 patients. With a new definition of systolic CHF requiring an
LVEF<0.50 (instead of ≤0.40), RAN would have increased LVEF ≥+7 EFUs in 26/53 (49%) systolic CHF patients, an increase from the 14/41 (34%) herein reported (p<0.001), with RAN being the last add-on therapy. Using spectral analysis of HRV to estimate cardiac sympathetic activity in CHF has its limitations. The sinoatrial node becomes less responsive to norepinephrine and acetylcholine, so HRV decreases despite high norepinephrine levels. Therefore, absolute cardiac LFa is inversely related to sympathetic outflow to muscle. Spectral analysis measures the modulation of autonomic neural outflow to the heart. SB reflects this modulation and an SB>2.5 have a positive predictive value of 61% for MACE. In comparison to 123 Iodine, Metaiodobenzylguanidine (MIBG) imaging to assess cardiac sympathetic activity, only 29% of CHF patients with high MIBG washout suffered MACE within a mean follow-up of 31 months [56].
Limitations (2)
This is a single-center open-label study. A larger, randomized prospective study might be useful in confirming these results. Furthermore, RAN can suppress the more common reentrant PVCs [54]. Reentrant patients weren’t studied, but if RAN were a successful therapy because of its safety, then RAN could be the first drug choice to treat the majority of patients with symptomatic PVCs.
Conclusions (1)
RAN preserved or improved LVEF during a 24 month follow-up period when added to guideline-driven therapy in CHF. Since LVEF has long been considered one of the most important prognostic indicators in CHF, and since RAN seems free of the potentially harmful side effects of some of the agents that increase LVEF (such as catecholamines, phosphodiesterase inhibitors, and Entresto), RAN has the potential to improve CHF mortality and morbidity without significant adverse effects.
Reduced sympathetic tone (LFa) and SB were present in RANCHF patients; the lowest measures of both were in RAN treated patients without MACE. When SB was ≤2.5, only 19% of subjects experienced MACE. High SB with low RFa (<0.1bpm2, defined as CAN) is associated with increased mortality and morbidity risk. Therefore measuring P&S function should improve our ability to risk-stratify our patients and adjust their management accordingly. Periodic P&S measures have become just as a routine management tool in our CHF patients as assessment of LVEF or measurement of (pro-) brain natriuretic peptide.
Conclusions (2)
RAN offers a safe, effective pharmacologic therapy for symptomatic VP patients whose PVCs are due to triggered activity, with no known proarrhythmia. It may have a role to play in treating symptomatic PVCs in Patients with LVH, CHF, hypokalemia, acute hypoxia, oxidative stress, catecholaminergic polymorphic VT, cocaine-related PVCs, and drug-induced torsades de pointes [57]. It is the pharmacologic treatment of choice for VP.
Conflict of Interest
The author reports no conflicts of interest
Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.
Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.
Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.
Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.
We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.
The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.
Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.
Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.
Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.
Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.
Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.
This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.
Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.
As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.
Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.
International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.
Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.
Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.
I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!
"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.
Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.
The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.
Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.
Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.
Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.
Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.
Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”
Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner
My Testimonial Covering as fellowing: Lin-Show Chin. The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews.
My experience publishing in Psychology and Mental Health Care was exceptional. The peer review process was rigorous and constructive, with reviewers providing valuable insights that helped enhance the quality of our work. The editorial team was highly supportive and responsive, making the submission process smooth and efficient. The journal's commitment to high standards and academic rigor makes it a respected platform for quality research. I am grateful for the opportunity to publish in such a reputable journal.
My experience publishing in International Journal of Clinical Case Reports and Reviews was exceptional. I Come forth to Provide a Testimonial Covering the Peer Review Process and the editorial office for the Professional and Impartial Evaluation of the Manuscript.
