tratamiento angina pecho

TRATAMIENTO FARMACOLOGICO DE LA ANGINA DE

PECHODr. Persio López Contreras

PUCMMMarzo 2011

Sunday, March 20, 2011

ANGINA DE PECHO

Angina de pecho estable crónica es la presencia de la sensación de opresión o ahogo en el pecho o áreas adyacentes, causada por isquemia miocárdica en asociación con estrés físico o emocional, y mejoría rápida de estos síntomas con el reposo o con nitroglicerina sublingual.


ANGINA DE PECHO

✴ Desbalance entre aporte y el consumo de O2 miocárdico

✴ En la mayoría de los pacientes hay estenosis (estrecheces) severas de una o más arterias coronarias epicárdicas

✴ Disfunción endotelial con vasoconstricción inapropiada durante el ejercicio

✴ La ateroesclerosis es la principal causa subyacente


PERFUSION MIOCARDICA


PERFUSION CORONARIA


DETERMINANTES DEL CONSUMO DE OXIGENO MIOCARDICO

✴ Frecuencia cardíaca✴ Fenómeno de treppe o

Bowditch✴ Estrés de la pared

✴ Presión x radio ÷ grosor de la pared

✴ Contractilidad

✴ DOBLE PRODUCTO....


ANGINA DE PECHO

✴ La perfusión miocárdica es diastólica✴ La extracción de O2 miocárdico es de 75%✴ Densidad capilar de 2000/mm3, 60-80% funcionales en

reposo✴ El endocardio tiene mayor extracción que el epicardio:

más susceptible a la hipoxia✴ Estenosis 25% lo comprometen, 60% trast. metabólicos, 75% trast. de

contractilidad y electrocardiográficos

✴ La resistencia aumenta x 4 con la reducción del radio (Ley de Poiseuille)

✴ La resistencia aumenta con la longitud de la estenosis o con estenosis secuenciales


Fatty-Streak Formation in Atherosclerosis

Ross R. N Engl J Med 1999;340:115-126

Ross R. N Engl J Med 1999;340:115-126


(ACS), whereas in the remaining studies, experimental pa-thology markers (that is, inflammatory molecules expressedin the plaque tissue) were compared with reference his-topathologic features, such as cap thickness, large lipidcore, and inflammatory cells. Thirty-two studies evaluatedcarotid artery samples, almost exclusively taken from livingpersons (n ! 31), given the easier availability of carotidartery samples after carotid endarterectomy, comparedwith coronary tree samples. Macrophage infiltration wasagain the most commonly evaluated hallmark feature ofvulnerability but only in 3 studies; other studies evaluatedthe tissue expression of molecules, such as matrix metallo-

proteinases and vascular endothelial growth factor. Studyoutcomes included either clinical disease (that is, symp-tomatic carotid disease) in 18 studies or other histopatho-logic features in the remaining 14 studies.

In this recent literature sample of histopathologystudies, most studies did not evaluate the histopatho-logic features of the proposed vulnerable plaque defini-tion. Instead, novel pathology markers with potentialclinical or research utility were sought, mainly by exam-ining the expression of molecules or cells within theplaque tissue. These studies may augur the future direc-tions of active investigations.

Figure. Normal arterial segment (A) compared with a vulnerable plaque (B) in longitudinal and cross-sectional views.

Plaque vulnerability features that have been included in the criteria of the vulnerable plaque definition are indicated.

Review Vulnerable Plaque: Scope of the Literature

390 21 September 2010 Annals of Internal Medicine Volume 153 • Number 6 www.annals.org

Ann Intern Med 2010; 153: 387-395.


The Challenge of Terminology: CulpritPlaque Versus Vulnerable Plaque

Culprit Plaque, a Retrospective TerminologyInterventional cardiologists and cardiovascular pathologists ret-rospectively describe the plaque responsible for coronary occlu-sion and death as a culprit plaque, regardless of its histopatho-logic features. For prospective evaluation, clinicians need asimilar term for describing such plaques before an event occurs.Plaque rupture was reported sporadically by pathologists in theearly 20th century; it became a focus of attention of pioneeringscientists in the 1960s (Table 2) and was later documentedfurther by others.11–15

Since the 1970s, scientists have been seeking the mechanismsresponsible for converting chronic coronary atherosclerosis toacute coronary artery disease.11–15,17 As insights into this processhave evolved, the relevant terminology has been continuallyupdated. In the 1980s, Falk11 and Davies and Thomas15 used“plaque disruption” synonymously with “plaque rupture.” Later,Muller and colleagues18,19 used “vulnerable” to describe rupture-prone plaques as the underlying cause of most clinical coronaryevents. When this functional definition was proposed, the plaqueconsidered responsible for acute coronary events (based onretrospective autopsy studies) had a large lipid pool, a thin cap,

and macrophage-dense inflammation on or beneath its surface(Figure 3).

Over the past several years, “vulnerable plaque” has beenused sometimes to denote this concept and at other times todenote the specific histopathologic appearance of the above-described plaque. This dual usage is confusing, particularly asplaques can have other histologic features (see Figure 2) thatmay also cause acute coronary events.5

Vulnerable Plaque, a Future Culprit PlaqueThe term “vulnerable” is defined by English dictionaries as“susceptible to injury or susceptible to attack,”20 as in “We arevulnerable both by water and land, without either fleet or army”(Alexander Hamilton). It denotes the likelihood of having anevent in the future. The term vulnerable has been used in variousreports in the medical literature, all of which describe conditionssusceptible to injury. In this regard, the term “vulnerable plaque”is most suitable to define plaques susceptible to complications.An alternative term, “high-risk plaque,” has been recentlyproposed.18 The term “high-risk” is often used to describe the

TABLE 1. Underlying Pathologies of “Culprit” Coronary Lesions

Ruptured plaques (!70%)

Stenotic (!20%)

Nonstenotic (!50%)

Nonruptured plaques (!30%)

Erosion

Calcified nodule

Others/Unknown

*Adapted from Falk and associates,6 Davies,7 and Virmani and colleagues.7

TABLE 2. Descriptions Used by Pioneers for Culprit Plaques93,94

Author Year Description Used

Olcott 1931 Plaque rupture

Leary 1934 Rupture of atheromatous abscess

Wartman 1938 Rupture-induced occlusion

Horn 1940 Plaque fissure

Helpern 1957 Plaque erosion

Crawford 1961 Plaque thrombosis

Gore 1963 Plaque ulceration

Byers 1964 Thrombogenic gruel

Chapman 1966 Plaque rupture

Constantinides 1966 Plaque rupture

Figure 2. Different types of vulnerable plaque as underlying cause of acute coronary events (ACS) and sudden cardiac death (SCD). A,Rupture-prone plaque with large lipid core and thin fibrous cap infiltrated by macrophages. B, Ruptured plaque with subocclusivethrombus and early organization. C, Erosion-prone plaque with proteoglycan matrix in a smooth muscle cell-rich plaque. D, Erodedplaque with subocclusive thrombus. E, Intraplaque hemorrhage secondary to leaking vasa vasorum. F, Calcific nodule protruding intothe vessel lumen. G, Chronically stenotic plaque with severe calcification, old thrombus, and eccentric lumen.

1666 Circulation October 7, 2003


studies published by Henney et al demonstrating the presenceof stromelysin mainly in macrophages in coronary arteries.41

In the mid 1990s, Zorina Galis et al demonstrated 3 matrixmetalloproteinase (MMP) classes (interstitial collagenase,MMP-1; gelatinases, MMP-2 and MMP-9; and stromelysin,MMP-3) expressed primarily in the shoulder regions ofadvanced plaques along with their endogenous inhibitors(tissue inhibitors of matrix metalloproteinases [TIMPs] 1 and2).42–44 MMP enzymatic activities were demonstrated by insitu zymography (in vitro, lysis of a thin film of collagensubstrate) showing focal overexpression of activated MMP asa potential mechanism that promotes destabilization. Further-more, Shah et al showed that monocyte-derived macrophagesexposed in vitro to fibrous caps dissected from human aorticor carotid plaques resulted in degradation of the fibrous cap.36

Incidence and Frequency of the TCFABurke et al, from our laboratory, not only defined vulnerableplaques (as defined above) but also were among the first toshow that vulnerable plaques were commonly observed inpatients dying a sudden coronary death and were morecommon in plaque ruptures than in stable plaques.27 Thenumber of vulnerable plaques correlated with both high totalcholesterol and the total cholesterol/high-density lipoproteincholesterol ratio.27 In subjects dying of plaque rupture,additional lesion sites remote from the culprit plaque typi-cally show TCFAs in 70% of cases. On the other hand,TCFAs are less frequent (30%) in cases where death isattributed to fibrocalcific plaques with flow-limiting stenosis,regardless of MI status, or plaque erosion. Therefore, it mustbe emphasized that not all TCFAs are likely to progress torupture; however, it is important to further define the essentialsurrogates of lesion instability at the highest risk of rupture.29

In an additional 38 hearts from sudden coronary deathswith severe luminal narrowing, in which the arteries had beenserially cut from coronary ostium to a distal intramyocardial

location, mean luminal narrowing was least in sections withTCFAs (59.6%), intermediate for lesions with hemorrhageinto a plaque (68.8%) and greatest in acute plaque ruptures(73.3%) or healed plaque ruptures (72.8%). Overall, nearly75% of lesions showed !75% cross-sectional luminal-narrowing or (!50% diameter stenosis), which may be auseful indicator for the detection of vulnerable plaque.Moreover, the location is also important, as approximately50% of the TCFAs occur in the proximal portions of themajor coronary arteries (left anterior descending " leftcircumflex " right coronary artery), with another one third inthe midportion and the remaining few in distal segments.28

A similar regional distribution of TCFAs is found for acuteand healed plaque ruptures. Clinical studies in AMIpatients also confirm that the proximal portions of all 3major coronary arteries are the most common locations forthrombotic occlusion.45

Remodeling, as mentioned above, can also be an impor-tant sign of vulnerability. In this regard, plaque ruptureshad the highest remodeling index, followed by lesions withhemorrhage " TCFAs " healed plaque ruptures " fibro-atheromas.46 Conversely, lesions of total occlusion orerosion exhibited negative remodeling.46 From this study,it becomes evident that all lesions derived from or relatedto plaque rupture show positive remodeling, which mayrepresent one important surrogate for detecting lesionvulnerability.

Mechanical Stress, Lesion Vulnerability,and Rupture

A limited number of biomechanical and imaging studiesstarted to emerge in the early 1990s addressing the role ofhemodynamic shear stress in the destabilization of vulnerableplaques.47–49 The underlying premise is based on observa-tions that atherosclerosis is a focal point, where ruptureoccurs more frequently at the proximal side of the stenosis

Figure 3. Illustration empha-sizes the importance of colla-gen synthesis and breakdownin the maintenance of theintegrity of the fibrous cap.Vascular smooth muscle cellssynthesize essential extracellu-lar matrix proteins such as col-lagen and elastin from aminoacids. This process may beinhibited by interferon-! (IFN-!)secreted by activated T cells,thereby disrupting collagensynthesis, which may interferewith the maintenance andrepair of collagen frameworksupporting the fibrous cap.Importantly, the expression ofCD40 ligand on T cells maypromote tissue proteolysisthrough the release and activa-

tion of matrix-degrading enzymes produced by vascular smooth muscle cells and inflammatory macrophages. Activated macrophageswithin the fibrous cap can secrete tissue proteases that support the breakdown of collagen and elastin to peptides and amino acids.The loss of structural molecules provided by the extracellular matrix can thin and weaken the fibrous cap, rendering it particularly sus-ceptible to rupture and acute coronary syndromes. Additional factors involved in the activation of macrophages include tumor necrosisfactor-" (TNF-"), macrophage colony-stimulating factor (M-CSF), and macrophage chemoattractant protein-1 (MCP-1), among others.Reproduced with permission from the American Heart Association (Circulation 1995;91:2844–2850), with modifications by Peter Libby.

1286 Arterioscler Thromb Vasc Biol July 2010


Hansson G. N Engl J Med 2005;352:1685-1695


ANGINA DE PECHO

Texto


FACTORES CONTRIBUYENTES A LA ANGINA VARIANTE, DE PRINZMETAL O

VASOSPASTICA✴ Tabaquismo✴ Cocaína✴ Hipomagnesemia✴ Resistencia a la insulina✴ Deficiencia de vitamina E✴ Administración de antimigrañosos: sumatriptán,

ergotamina✴ Hiperventilación✴ Exposición al frío


ANGINA DE PECHOMETAS DEL TRATAMIENTO

✴ Reducir la frecuencia de aparición de los síntomas y su severidad

✴ Aumentar la tolerancia a los esfuerzos✴ Reducir la incidencia de Síndromes Coronarios

Agudos✴ Angina Inestable✴ Infarto sin elevación del segmento S-T✴ Infarto transmural

✴ Reducir la mortalidad


ANGINA DE PECHOTRATAMIENTO

✴ NITRATOS✴ BETABLOQUEADORES✴ CALCIOANTAGONISTAS✴ METABOLICOS✴ BRADICARDIZANTES (IVABRADINA)✴ INHIBIDORES DE LA ECA✴ ESTATINAS✴ ANTIAGREGANTES PLAQUETARIOS✴ NICORANDIL


NITRATOS

✴ Esteres nítricos y nitrosos de polialcoholes✴ Metabolizados activamente en hígado✴ Rápida acción por vía sublingual o inhalados✴ Nitroglicerina: prototipo✴ Biodisponibilidad baja por VO (<10-20%)✴ Metabolitos activos: 2 dinitroglicerinas, 2 mononitros✴ Dinitrato de isosorbide: VM 4-6 horas✴ 5-MNIS: metabolito activo de VM larga


NITRATOS


NITRATOS

✴ Relajan todos los tipos de músculo liso, venoso > arterial (pulmonar y sistémico)

✴ Efecto antiagregante plaquetario débil (c-GMP)✴ Aumentan flujo por vasos colaterales✴ NTG: toxicidad por cianuro (dosis muy altas)✴ Rápido desarrollo de tolerancia:

✴ Intervalo libre de nitratos, dosis asimétricas✴ Efectos secundarios: CEFALEA, taquicardia, hipotensión

ortostática (extrema al combinar con sildenafil, inhibidor de la PDE), retención de Na y agua


ANGINA DE PECHO


NITRATOS


BETABLOQUEADORES


BETABLOQUEADORES

✴ Bloqueo competitivo de los receptores β✴ Muy efectivos en angina de todos tipos, reducción de

mortalidad post-IAM✴ Reducen la FC y contractilidad✴ Efectivos en reposo y ejercicio✴ Efectivos en combinación con nitratos y Ca++

Antagonistas (especialmente dihidropiridinas) ✴ Antihipertensivos✴ Antiarrítmicos


BETABLOQUEADORESCONTRAINDICACIONES

✴ Asma bronquial, broncoespasmo✴ Bradicardia severa✴ Bloqueo A-V✴ Síndrome del seno enfermo (taquicardia/bradicardia)✴ Cuidado especial en Insuficiencia Ventricular Izq.✴ Insuficiencia arterial de MIs descompensada✴ Cuidado con hipoglucemia✴ Otros: letargo, depresión, sueños vívidos,

constipación, impotencia


BETABLOQUEADORES


MECANISMO DE ACCION DE Ca++ ANTAGONISTAS


ANGINA DE PECHO


ANGINA DE PECHO

BENZOTIAZEPINAS:! Diltiazem! Clentiazem

FENILALQUILAMINAS:•Verapamil•Galopamil•Tiapamil•Anipamil•Riapamil


ANGINA DE PECHO


Calcioantagonistas: Dihidropiridinas

Nifedipina Nisoldipina Nimodipina Nitrendipina Israpidina Amlodipina Lacidipina Lercanidipina

Felodipina Clinidipina Niludipina Benidipina Clevidipina Pranidipina Elgodipina Manidipina


Selectividad Vascular de Dihidropiridinas respecto a miocardio:

Dihidropiridina Relación

Lercanidipina 730

Lacidipina 193

Amlodipina 95

Felodipina 6

Nitrendipina 3


TRIMETAZIDINA

Basal Dos semanas tto.


IVABRADINACORRIENTE If

✴ Activada por hiperpolarización celular.✴ If: funny, chistosa, activada en diástole,

permite el paso de Na al interior y salida de K

✴ Principal determinante de la corriente de despolarización diastólica

✴ Mediada por receptores HCN (hiperpolarization- activated, cyclid nucleotid-gated)

✴ Cuatro isoformas, expresadas en corazón, cerebro y retina

✴ HCN4 en nodo sinusal. Escasa en nodo A-V y Purkinje


CORRIENTE If

✴ Estado basal, a -60 mV, 23% canales activados

✴ 87% canales activos bajo estimulación beta: aumento del AMP cíclico

✴ Acetilcolina la inhibe bradicardia✴ If 20 veces más sensible que otros

canales (Ik, ICaL, ICaT)✴ Ausencia de HCN4: FC 40% más

lenta✴ Ausencia de HCN4: No respuesta a

cAMP. ✴ If responsable en parte del

cronotropismo ß ✴ Efecto sólo en fase 4 potencial

acción


EFECTO DE LA IVABRADINA EN EL CANAL HCN4


EFECTO DE IVABRADINA SOBRE FASE 4


IVABRADINA

✴ Bloqueador selectivo de corriente If✴ Agente bradicardizante puro✴ Ausencia de efectos inotrópicos o vasculares✴ Reduce MVO2

✴ Aumenta tiempo de perfusión diastólica✴ Mejora el balance entre aporte y consumo O2


Borer J. Circulation 2003; 107: 817.

EFECTOS ANTI-ISQUEMICOS DE IVABRADINA


EFICACIA Y SEGURIDAD DE IVABRADINA EN ANGINA DE PECHO

Lopez Bescos et al. 2009. Cardiology. 2007; 108: 387.


EFICACIA ANTIANGINOSA Y SEGURIDAD DE IVABRADINA COMPARADA A AMLODIPINA

Ruzyllo W, Tendera M . et al. Drugs 2007; 67: 393


MAYOR EFICACIA ANTI-ISQUEMICA DE IVABRADINA SOBRE ATENOLOL

Tardif JC. Eur Heart J 2005 26:2529.


ASSOCIATEIvabradina + atenolol

Tardiff JC, et al. Eur Heart J. 2008; 29(suppl): 386.


Comment

www.thelancet.com Vol 372 September 6, 2008 779

BEAUTIFUL results—the slower, the better?In today’s Lancet, Kim Fox and colleagues report the BEAUTIFUL results (from the trial called morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary artery disease and left-ventricULar dysfunction).1 If channels, in the sinoatrial node, are responsible for an inwardly directed current. This current has the noteworthy property of being activated by hyper polari sation. Therefore the channel is activated during the resting potential stage and accelerates diastolic depolarisation of the sinus node and thus its pacemaker function. Because of this strange behaviour it was named funny current (I for current, f for funny).2

The BEAUTIFUL investigators studied patients with coronary artery disease, documented by previous angio graphy, myocardial infarction, and percutaneous or surgical revascularisation, and who also had left-ventricular dysfunction. Also reported is a subanalysis, which investigated the e! ect of heart rate on the primary composite of cardiovascular death, hospitalisation for acute myocardial infarction, and new onset or worsening of heart failure.3 BEAUTIFUL addresses the potentially important clinical and pathophysiological relevance of heart-rate reduction.

Previous studies showed the e! ect of heart rate on outcome in the general population4 or in patients with hypertension,5 coronary heart disease,6 myocardial infarction,7 and heart failure.8 Data have largely been generated from epidemiological studies, and have led to the conclusion that heart rate might be a general denominator for pathophysiological mechanisms involved in cardiovascular complications.9,10 High heart rate is associated with important comorbidities in high-risk patients, such as those with microalbuminuria.11 Increased risk has been observed at rather low heart rates of 70–80 per min.4–11

Many pathophysiological studies identifi ed poten tial mechanisms involved in the development of athero-sclerosis, ventricular remodelling, and chronic heart failure, as well as comorbidities associated with these conditions (fi gure). The crucial remaining question is whether heart-rate reduction by drugs can reverse cardio-vascular abnormalities—an epidemiologically lower resting heart rate might be associated with higher levels of physical exercise, less obesity, fewer comorbidities, and

thus lower global cardiovascular risk that is not merely related to heart rate.

Clinical investigations into heart-rate reduction have been rendered possible by the development and clinical introduction of If-channel inhibitors such as ivabradine.12 Ivabradine has antianginal e! ects even when compared with a " blocker,13 and angina is an approved indication for its use. In an atherosclerosis model, ivabradine reduced plaque load by 60–70%, when heart rate was reduced by 15%.14 Heart-rate reduction by " blockers might be one benefi cial mechanism achieved after myocardial infarction15 and in heart failure.16 Therefore heart-rate reduction beyond " blockade by drugs appeared promising.

The BEAUTIFUL investigators have added sub stantially to current knowledge by doing a well-designed and adequately powered controlled trial with relevant endpoints in patients, most of whom were pretreated

Published OnlineAugust 31, 2008DOI:10.1016/S0140-6736(08)61172-1

See Articles pages 807 and 817

Heart rate!

+

+ +

+

+ AtherosclerosisOxidative stress#Plaque stability$Arterial sti!ness#

IschaemiaOxygen consumption#Diastole length$Coronary perfusion$

RemodellingCardiac hypertrophy#

Events"?

ComorbiditiesMicroalbuminuria#

Heart rate" Inhibition

If channel

Ivabradine

Chronic heart failureTachycardiomyopathy#Oxygen demand#Ventricular e%ciency#Ventricular relaxation#

Figure: Potential role of heart rate in cardiovascular pathologyHigh heart rate is a risk factor for the development of atherosclerosis. High heart rate leads to ischaemia, remodelling of heart and vessels, and contributes to comorbidities in hypertension and in chronic heart failure. Figure shows potential mechanisms with experimental or clinical evidence. If channels are exclusively located in sinoatrial node and are responsible for inwardly directed current, which accelerates diastolic depolarisation of sinus node and thus its pacemaker function. The If channel can be inhibited by ivabradine. Green dots=If current.

Reil JC, Bohm M. Lancet 2008; 372: 779-781.


ANGINA DE PECHO

✴ TRATAMIENTO COMPLEMENTARIO:✴ ANTIAGREGANTES PLAQUETARIOS✴ ESTATINAS: reducción agresiva de LDL✴ I-ECAs.

✴ REVASCULARIZACION CORONARIA✴ Angioplastía + stents✴ Revascularización coronaria

✴ CONTRAPULSACION EXTERNA


ANGINA DE PECHO

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ANGINA DE PECHO


tratamiento angina pecho

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