Case Report Resolution of Angina Pectoris and Improvement of …downloads.hindawi.com/journals/cric/2013/343027.pdf · 2019. 7. 31. · antiangina drugs, has shown a good outcome

Hindawi Publishing CorporationCase Reports in CardiologyVolume 2013 Article ID 343027 5 pageshttpdxdoiorg1011552013343027

Case ReportResolution of Angina Pectoris and Improvement of theCoronary Flow Reserve after Ranolazine Treatment in a Womanwith Isolated Impaired Coronary Microcirculation

Alessandro Santoro1 Vincenzo Schiano Lomoriello1 Ciro Santoro1

Riccardo Muscariello1 and Maurizio Galderisi12

1 Cardioangiology with CCU Department of Clinical and Experimental Medicine Federico II University Hospital 80131 Naples Italy2 Laboratory of Echocardiography Cardioangiology with CCU Department of Clinical and Experimental MedicineFederico II University Hospital 80131 Naples Italy

Correspondence should be addressed to Maurizio Galderisi mgalderiuninait

Received 11 January 2013 Accepted 14 February 2013

Academic Editors R Akdemir and H Kataoka

Copyright copy 2013 Alessandro Santoro et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

In a 61-year-old woman with well controlled arterial hypertension hypercholesterolemia and smoke and suffering from recurrentangina pectoris despite angiographically normal epicardial coronary vessels and maximal therapy the replacement of nitrateswith novel antiangina drug ranolazine after 6-month therapy induced a complete relief of angina and a relevant rising of thetransthoracic Doppler-derived coronary flow reserve (CFR) The present clinical case underlines therefore how in patients withchronic ischemic heart disease without epicardial coronary stenosis ranolazine can induce an improvement till the completesolution of the angina symptoms and a substantial increase of CFR as expression of the enhancement of themicrovascular coronaryfunctionThe improvement of both symptoms and coronarymicrovascular function is strictly linked to themechanism of action ofthe drug Ranolazine induces in fact a reduction of the intracellular late sodium current that leads to a reduction of the intracellularcalcium concentration thus producing a better myocardial diastolic relaxation process which in its turns enhances the myocardialperfusion The ranolazine acts therefore as a lusitropic drug that improves the diastolic dysfunction and the segmental ischemiathus affecting one of the first steps of the ischemic cascade

1 Introduction

Chronic angina pectoris represents a common impairingdisease that involves limitations in the work activities andaffects the individual quality of life [1]Though the revascular-ization procedures are developing day-by-day still a relevantnumber of patients (up to 20) keep showing the anginasymptoms even if they have been undergone a percutaneouscoronary angioplasty intervention (PCI) andor coronaryartery bypass and are treated by standard therapy (betablockers calcium antagonists and nitrites) with the maximaldosage [2] Although several causes might be consideredas responsible of this frequent treatment failure coronarymicrovascular impairment is one of the main determinanttaking part as well to the development of the angina symp-toms In addition the activity of the standard therapy is

based on hemodynamic effects which involve the reductionof myocardial oxygen consumption while novel mechanismsof action might be used to support and enhance the anti-ischemic effect Ranolazine an example of a new class ofantiangina drugs has shown a good outcome despite theabsence of hemodynamic effects with an increasing numberof clinical experiences that certify its value in the chronicischemic heart disease [3ndash5]

2 Clinical Case

Woman 61 years affected by a long lasting well controlledarterial systemic hypertension hypercholesterolemia andsmoke (20 cigarettes daily) In the last 3 years she presentedseveral angina episodes (5-6 per week) At June 2010 she

2 Case Reports in Cardiology

Coro PWD

2D Echo

ECG 12-deriv

BP (mmHg)

0 6 10

Dip 084 mgkg in 6 998400Amino120mg in 1998400 (up to 240mg in 2998400)

ECG 1-deriv(Echo monitor)

Time (min)

Figure 1 Scheme of ldquofastrdquo protocol with dipyridamole for evaluating CFR and regional wall motion according to the recommendations ofthe European Association of Echocardiography [6]

Figure 2 Surface ECG performed at the high-dose dipyridamole during stress echocardiography showing a clear depression of the antero-septal ST segment At the same time the patient referred angina pectoris

underwent a coronary angiography showing the absenceof significant stenosis of the epicardial coronary arteriesThe patient was treated with bisoprolol 10mg oid valsartan320mg oid isosorbide-5-mononitrate 60mg oid acetylsal-icylic acid (ASA) 100mg oid and rosuvastatin 20mg oidEven after this therapy the symptoms kept affecting thepatient In December 2010 she underwent a pharmacologicstress echocardiography with dipyridamole (084mgKg in6 minutes ldquofastrdquo protocol) to evaluate at the same timethe coronary flow reserve (CFR) and the regional wallmotion according to the stress echo recommendations of theEuropean Association of Echocardiography (Figure 1) [6] Inthe presence of angina pectoris and significant repolarization

phase abnormalities of the surface ECG (Figure 2) the stressecho showed an impaired CFR (lt2) (Figure 3) withoutregional wall motion alteration According to the results ofthe test an isolated microvascular coronary dysfunction wasdiagnosed (reduced CFR + normal regional wall motion)[6] Accordingly given that the symptoms were still presentit was decided to replace the isosorbide-5-mononitrate withranolazine for the first 2 weeks 375mg bid followed by500mg bid At the third month from the beginning ofthe therapy (March 2011) the patient referred a substantialreduction of the angina pectoris rate through the week(from 5-6 to 2 per week) and the complete resolution of thesymptoms inMay 2011 In June 2011 newpharmacologic stress

Case Reports in Cardiology 3

At rest High-dose dyp

33 cms 61 cms

CFR = 185

Figure 3 High-dose dipyridamole induced CFR during the same stress echocardiography of Figure 2

At rest High-dose dip

30 cms 120 cms

CFR = 4

Figure 4 CFR evaluation after 6-month therapy with ranolazine

echo was repeated Again in the absence of regional wallmotion abnormalities the test showed a completely normalCFR with a relevant improvement in comparison with thepreviously performed test (from 185 to 400) (Figure 4) Ofinterest the patient did not exhibit any kind of symptomsduring and after the stress echo and the surface ECG wastotally normal (Figure 5) The patient is yet under treatmentwith ranolazine (combined with bisoprolol valsartan ASAand rosuvastatin) and she is completely free of symptoms ofangina pectoris

3 Discussion

The present clinical case underlines how in patients withchronic ischemic heart disease without epicardial coronarystenosis the replacement of nitrates with ranolazine canobtain (1) an improvement till the complete solution of theangina symptoms (2) a relevant increase ofCFRas expressionof the enhancement of the microvascular coronary function

The women affected by angina pectoris and stress-induced ischemia but free of obstructive coronary disease

often show an isolated microvascular coronary dysfunctionthat brings not only a low quality of life but also an adverseprognosis for cardiovascular events during the follow-up [7]

The persistence of the angina though a maximal anti-ischemic therapy represents a therapeutic issue that needs tobe faced In the present clinical case ranolazine showed notonly to be useful in reducing the frequency till the resolutionof the angina episode but also in improvingCFR substantially

According to the recommendation of the EuropeanAssociation of Echocardiography [6] the stress echo withdipyridamole represents a very accurate test in order todistinguish an epicardial coronary stenosis from an isolatedcoronary microvascular dysfunction the first one shows areduction of the CFR with impairment of the regional wallmotion and the latter shows a reduction of the CFR withoutregional wall motion abnormalities or even a supernormalwall motion In our experience a reduced CFR + normalregional wall motion pointed out an impaired function ofthe coronary microcirculation where a previous coronaryangiography had already shown a coronary three free ofstenosis In this setting after almost 6 months of therapy


Figure 5 Surface ECG performed at high-dose dipyridamole during stress echocardiography after 6-month therapy with ranolazine At thesame time the patient was completely asymptomatic

Myocardialischemia

Inhibition

Ranolazine

Diastolic wallstress NCX

Ca++

overload

Late current

[Na+]iuarr

Figure 6 Mechanism of action of ranolazine The pharmacologi-cally induced reduction of the late sodium current ameliorates themyocardial diastolic relaxation by reducing the diastolic wall stressThis finally produces an improvement of segmental myocardialischemia

ranolazine caused a relevant rising of the CFR that is strictlylinked to its mechanism of action Ranolazine induces areduction of the intracellular late sodium current that leadsto a reduction of the intracellular calcium concentration thusproducing a diastolic relaxation improvement which in itsturns enhances the myocardial perfusion [8] The coronaryflow is substantially greater during the diastolic phase of thecardiac cycle thus it is evident that the smaller vessels theones that make up the microvascular circulation are the onethat benefitmore from the effect of the decompression causedby ranolazine during the myocardial relaxation process Theranolazine acts therefore as a lusitropic drug that improvesthe diastolic dysfunction and the segmental ischemia thusaffecting one of the first steps of the ischemic cascade(Figure 6)The results of the presented clinical case reflect theones produced by a recently published clinical study where a4-week therapy with ranolazine showed to be useful reducingthe recurrence of the angina symptoms and improving theCFR assessed by cardiac magnetic resonance after adenosine

infusion in a population of women without obstructivecoronary disease [9]

References

[1] US Department of Health and Human Services NationalCenter for Health Statistics Third National Health and Nutri-tion Examination Survey (NHANES III) 1988ndash1994 (CD-ROM)Series 11 No 1 Centers for Disease Control and PreventionHyattsville Md USA 1997

[2] P W Serruys F Unger J E Sousa et al ldquoComparison ofcoronary-artery bypass surgery and stenting for the treatmentof multivessel diseaserdquo The New England Journal of Medicinevol 344 no 15 pp 1117ndash1124 2001

[3] B R Chaitman C J Pepine J O Parker et al ldquoEffects ofranolazine with atenolol amlodipine or diltiazem on exercisetolerance and angina frequency in patients with severe chronicangina A randomized controlled trialrdquo Journal of the AmericanMedical Association vol 291 no 3 pp 309ndash316 2004

[4] P H Stone N A Gratsiansky A Blokhin I Z Huang andL Meng ldquoAntianginal efficacy of ranolazine when added totreatment with amlodipine the ERICA (Efficacy of Ranolazinein Chronic Angina) trialrdquo Journal of the American College ofCardiology vol 48 no 3 pp 566ndash575 2006

[5] B M Scirica D A Morrow H Hod et al ldquoEffect of ranolazinean antianginal agent with novel electrophysiological proper-ties on the incidence of arrhythmias in patients with non-ST-segment-elevation acute coronary syndrome results fromthe metabolic efficiency with ranolazine for less ischemiain non-ST-elevation acute coronary syndrome-thrombolysisin myocardial infarction 36 (MERLIN-TIMI 36) randomizedcontrolled trialrdquoCirculation vol 116 no 15 pp 1647ndash1652 2007

[6] R Sicari P Nihoyannopoulos A Evangelista et al ldquoStressechocardiography expert consensus statementmdashexecutive sum-mary European Association of Echocardiography (EAE) (aregistered branch of the ESC)rdquo European Heart Journal vol 30no 3 pp 278ndash289 2009

[7] B D Johnson L J Shaw S D Buchthal et al ldquoPrognosis inwomen with myocardial ischemia in the absence of obstructivecoronary disease results from the National Institutes of Health-National Heart Lung and Blood Institute-Sponsored WomenrsquosIschemia Syndrome Evaluation (WISE)rdquo Circulation vol 109no 24 pp 2993ndash2999 2004


[8] L Belardinelli J C Shryock and H Fraser ldquoInhibition of thelate sodium current as a potential cardioprotective principleeffects of the late sodium current inhibitor ranolazinerdquo Heartvol 92 supplement 4 pp iv6ndashiv14 2006

[9] P K Mehta P Goykhman L E J Thomson et al ldquoRanolazineimproves angina in women with evidence of myocardialischemia but no obstructive coronary artery diseaserdquo JACCCardiovascular Imaging vol 4 no 5 pp 514ndash522 2011

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Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Coro PWD

2D Echo

ECG 12-deriv

BP (mmHg)

0 6 10

Dip 084 mgkg in 6 998400Amino120mg in 1998400 (up to 240mg in 2998400)

ECG 1-deriv(Echo monitor)

Time (min)

Figure 1 Scheme of ldquofastrdquo protocol with dipyridamole for evaluating CFR and regional wall motion according to the recommendations ofthe European Association of Echocardiography [6]

Figure 2 Surface ECG performed at the high-dose dipyridamole during stress echocardiography showing a clear depression of the antero-septal ST segment At the same time the patient referred angina pectoris

underwent a coronary angiography showing the absenceof significant stenosis of the epicardial coronary arteriesThe patient was treated with bisoprolol 10mg oid valsartan320mg oid isosorbide-5-mononitrate 60mg oid acetylsal-icylic acid (ASA) 100mg oid and rosuvastatin 20mg oidEven after this therapy the symptoms kept affecting thepatient In December 2010 she underwent a pharmacologicstress echocardiography with dipyridamole (084mgKg in6 minutes ldquofastrdquo protocol) to evaluate at the same timethe coronary flow reserve (CFR) and the regional wallmotion according to the stress echo recommendations of theEuropean Association of Echocardiography (Figure 1) [6] Inthe presence of angina pectoris and significant repolarization

phase abnormalities of the surface ECG (Figure 2) the stressecho showed an impaired CFR (lt2) (Figure 3) withoutregional wall motion alteration According to the results ofthe test an isolated microvascular coronary dysfunction wasdiagnosed (reduced CFR + normal regional wall motion)[6] Accordingly given that the symptoms were still presentit was decided to replace the isosorbide-5-mononitrate withranolazine for the first 2 weeks 375mg bid followed by500mg bid At the third month from the beginning ofthe therapy (March 2011) the patient referred a substantialreduction of the angina pectoris rate through the week(from 5-6 to 2 per week) and the complete resolution of thesymptoms inMay 2011 In June 2011 newpharmacologic stress



33 cms 61 cms

CFR = 185



30 cms 120 cms

CFR = 4



3 Discussion








Myocardialischemia

Inhibition

Ranolazine


Ca++

overload

Late current

[Na+]iuarr




References
















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















33 cms 61 cms

CFR = 185



30 cms 120 cms

CFR = 4



3 Discussion








Myocardialischemia

Inhibition

Ranolazine


Ca++

overload

Late current

[Na+]iuarr




References
















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Myocardialischemia

Inhibition

Ranolazine


Ca++

overload

Late current

[Na+]iuarr




References
















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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Case Report Resolution of Angina Pectoris and Improvement of …downloads.hindawi.com/journals/cric/2013/343027.pdf · 2019. 7. 31. · antiangina drugs, has shown a good outcome