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Coronary flow in Aortic : Pathophysiological and Clinical Insights

Paolo G Camici MD FESC FACC FAHA FRCP Vita-Salute University and San Raffaele Scientific Institute Milan Mechanisms of myocardial ischaemia

Epicardial Coronary microcirculation

Atherosclerotic disease Vasospastic disease Microvascular dysfunction

Stable plaque Vulnerable plaque Impairs coronary physiology and myoc. blood flow Focal/transient Persistent in subjects with risk factors Plaque rupture vasospasm vasospasm Reduction In CFR Thrombosis

Prinzmetal Myocardial Contributes Induces severe Demand infarction to myoc. Isch. acute isch. ischaemia Acute coronary in stable “takotsubo” ± angina syndromes/infarction athero. disease Mechanisms of myocardial ischaemia

Epicardial coronary arteries Coronary microcirculation

Atherosclerotic disease Vasospastic disease Microvascular dysfunction

Stable plaque Vulnerable plaque Impairs coronary physiology and myoc. blood flow in subjects with risk factors Focal/transient Persistent Plaque rupture vasospasm vasospasm Reduction In CFR Thrombosis

Prinzmetal Myocardial Contributes Induces severe Demand angina infarction to myoc. Isch. acute isch. ischaemia Acute coronary in stable “takotsubo” ± angina syndromes/infarction athero. disease

These three mechanisms can overlap The emerging concept of coronary “microvascular disease”

The tip of the iceberg - Resolution >500 µm Resolution <500 µm

Courtesy of M Gibson MD Maximum myocardial blood flow is an index of microvascular function

Normals In normal subjects myocardial blood flow (MBF) increases 3-5 fold during Flow deficit

near-maximal pharmacologic MBF vasodilatation (i.v. adenosine)

Pts with impaired microvascular function Rest Adenosine In the absence of coronary stenosis, maximum MBF reflects microvascular function PET: the gold standard for the noninvasive measurement of myocardial blood flow

15 13 PET with H 2 O or NH 3 allows accurate, reproducible and non-invasive measurement of absolute (ml/min/g) myocardial blood flow in man

Reproducibility of PET MBF measurement

Accuracy of PET MBF measurement y=0.15+0.97x, r=0.87, r 2=0.76 6 ) -1 5 min

-1. 4 g . 3 2 1 PET MBF (mL MBF PET 0 1 2 3 4 5 6 Camici PG and Rimoldi OE. J Nucl Med. 2009; 50:1076–1087 Microspheres MBF( mL.g-1. min -1) NORMALS

6 5 in patients with LVH 4

3

2

1

Myocardial bloodMyocardial (ml/min/g) flow • Angina and/or ischemic signs on 0 Baseline Dipyridamole ECG are common in patients with

HC primary or secondary LVH

6 5 • In the majority of cases patients 4 with LVH suffer from angina 3 despite angiographically normal 2

1 coronary arteries Myocardial bloodMyocardial (ml/min/g) flow

0 Baseline Dipyridamole

LVH • Coronary flow reserve is reduced 6 suggesting dysfunction of the 5 microcirculation

4

3

2

1 Myocardial bloodMyocardial (ml/min/g) flow 0 Baseline Dipyridamole Camici et al. Eur J 1997; 18: 108-116 N Engl J Med. 2007;356:830-40

Mechanisms of CMD in LVH CFR is reduced in patients with hypertrophic (HCM) and those with LVH secondary to systemic .

In these 2 patient groups, the reduction of CFR is primarily sustained by an increase in the vascular component of resistance because of anatomic changes in the intramural coronary arteries.

Normal subject Hypertensive HCM

• Myocites hypertrophy • Perimyocitic fibrosis • Thickening of the wall of intramyocardial arterioles: increased wall/lumen ratio Camici & Crea N Engl J Med. 2007;356:830-40 Microvascular Microvascular Remodeling Dysfunction

Myocardial Ischemia

Atrial Myocardial Symptoms Fibrosis Heart Failure Death

Camici et al. J Am Coll Cardiol 2009 LV Remodeling Diastolic and Systolic Dysfunction The pathogenesis of angina pectoris in patients with and normal coronary arteries remains uncertain.

We measured the maximal velocity of coronary blood flow in the left- anterior descending coronary artery at the time of elective open-heart surgery in 14 patients with aortic stenosis and LVH (13 had angina) and in 8 controls without LVH.

The ratio of peak velocity of coronary blood flow, after a 20-second occlusion, to resting velocity was decreased by more than 50 per cent (P<0.05) in the patients with aortic stenosis.

These data demostrate a selective and marked decrease in coronary reserve to the hypertrophied left in patients with severe aortic stenosis. The impairment in coronary reserve is probably an important contributor to the pathogenesis of angina pectoris in these patients. (Circulation. 2002;105:470-476.) Total MBF as a function of LV mass in Ao stenosis

(Circulation. 2002;105:470-476.) Total and transmural MBF in Ao stenosis: Effect of extravascular compressive (LVRPP) and trans-valvular gradient

(Circulation. 2002;105:470-476.) Total and transmural MBF in Ao stenosis: relation to AVA

(Circulation. 2002;105:470-476.) CFR vs. diastolic perfusion time

(Circulation. 2002;105:470-476.)

Summary and conclusions

Microcirculatory dysfunction in patients with AS may explain ‘angina’ in absence of coronary artery stenosis

The severity of CFR reduction is related to indices of extravascular compressive forces such as external workload (LVRPP), transvalvular gradient, and mainly AVA as well as DPT;

This is consistent with the finding that defects on exercise thallium-201 scans are often observed in the patients with the most severe aortic stenoses despite the absence of significant ;

The subendocardial and subepicardial curves correlating CFR and AVA intersect at 0.92 cm2, a figure that approximates closely to previously defined criteria of severe AS. (Circulation. 2003;107:3170-3175.) Changes in CFR as a function of LV mass and AVA

(Circulation. 2003;107:3170-3175.) Changes in CFR as a function of DPT

(Circulation. 2003;107:3170-3175.) Summary and conclusions

There was significant regression of LVM in all patients after AVR and a related reduction in total left ventricular blood flow;

There was a significant increase in CFR after AVR;

The changes in coronary microcirculatory function were not directly related to regression of LVM;

The improvement in CFR was more closely related to changes in hemodynamic variables, including AVA and DPT;

Whether these changes in microvascular function bear any prognostic significance remains to be determined.