Coronary microvascular dysfunction

in arterial hypertension

Paolo G Camici, MD, FESC, FACC, FAHA, FRCPVita-Salute University and San Raffaele Hospital Milan

9070503010-10

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Y = 6.73 - 0.13x + 7.8x̂ 2 r = 0.77 (N = 35)

Percent diameter stenosis

= patients with CAD

= normal subjects

Percent diameter stenosis

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In vivo anatomy

ATS: Coronary stenosis

Coronary ATS and Myocardial Ischemia

Camici et al. New Engl J Med 1994; 330: 1782-1788

Stress MPI

Rest MPI

Regional perfusion abnormality

CFR reduction with stenosis severity

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NHLBI,n=1755

COURAGE,n=2287

SYNTAX,n=1800

BARI-2D,n=1434

Angina is frequent after PCI% of patients with angina at baseline versus 1 year post-PCI

CAD + diabetes

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2 3 4

1- Holubkov R et al. Am Heart J. 2002;144:826-833. 2- Boden WE et al. N Engl J Med. 2007;356:1503-1516.

3- Cohen DJ et al. N Engl J Med. 2011;364:1016-1026. 4- Dagenais GR et al. Circulation. 2011;123:1492-1500.

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Case report

• Female, DoB 25/06/1964

• Family history for hypertension

• Never smoked

• Menopause since 7 years

• Hypertension diagnosed during pregnancy

• Since 4-5 years she complains of retrosternal pain with radiation to the left armthat occur both during exercise and at rest. During the episode sometimes shealso experiences dyspnea.

• Recently she was admitted to hospital (ECG shows ST depression) for a prolonged episode of chest (no troponin). Coronary angiography shows normalsmooth epicardial coronary arteries.

Baseline ECG

ECG during chest pain

The emerging concept of coronary “microvascular disease”

Courtesy of M Gibson MD

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

Camici PG, Crea F. N Engl J Med. 2007;356-830-40.

Crea F, Camici PG, Bairey Merz CN Eur Heart J. 2014 May;35(17):1101-11

Data adjusted for the modified Duke clinical risk score and rest LVEF

Microvascular dysfunction and MACE at follow up

Patients with microvascular angina aremore likely to develop HFpEF

Taqueti et al. Eur Heart J. 2017;39:840-9.

Signs and/or symptoms of angina

Objective evidence of myocardial ischemia

Absence of obstructive CAD (or coronary stenoses not responsible for ischemia)

Coronary microvascular dysfunction (i.e. CFR <2.5 or microvascular spasm)

Abbreviations: CAD, coronary artery disease; CFR, coronary flow reserve

In normal subjects myocardial

blood flow (MBF) increases 3- to 5-fold

during near-maximal pharmacologically

induced vasodilatation (i.v. adenosine)

In the absence of coronary stenosis,

maximum MBF reflects microvascular function

There is no in vivo technique for imaging the coronary microcirculation; Maximum myocardial blood flow is an index of microvascular function

MBF

Flow deficit

Patients with impaired

microvascular function

Normal subjects

Camici PG, Rimoldi OE. J Nucl Med. 2009; 50:1076–1087.

PET with H215O or 13NH3 allows accurate, reproducible and non-invasive

measurement of absolute (ml/min/g) myocardial blood flow in man

PET: the gold standard for the non-invasivemeasurement of myocardial blood flow

Reproducibility of PET MBFmeasurement

Accuracy of PET MBFmeasurement

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PET

MB

F (m

L. g-1

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-1)

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Microspheres MBF (mL.g-1.min-1)

y=0.15+0.97x, r=0.87, r2=0.76

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Baseline Adenosine

Baseline 1 Baseline 2 Ado 1 Ado 2

Microspheres MBF (mL.g-1.min-1)

In the absence of obstructive CAD a reduced CFR suggests microvascular dysfunction

Symptoms associated with Coronary Microvascular Dysfunction

Symptoms of myocardial ischemia

a. Predominantly effort angina (±rest) b. Angina equivalents (i.e. shortness of breath)c. Predominantly rest angina

Typically diffuse reduction of CFR

Microvascular Angina in Hypertension

• Angina and/or ischemic signs on ECG are common in patients with primary or secondary LVH

• Maximum myocardial blood flow and CFR are reduced despite angiographically normal coronary arteries

Rimoldi O & Camici PG. J Hypert 2014

Structural changes

Mechanisms of Coronary Microvascular Dysfunction“Vascular”

Camici PG, d'Amati G, Rimoldi O Nat Rev Cardiol. 2015 Jan;12(1):48-62

Remodelling of coronary arterioles

Normal heart

• Peri-myocitic fibrosis• Thickening of the wall

of intramural arterioles• Increased wall/lumen ratio

Camici & Crea N Engl J Med. 2007;356:830-40

Hypertension

Normal EpicardialCoronary Arteries

Microcirculation

Coronary arteriolar remodellingprecedes onset of hypertensionIn the SHR model

Lazzeroni D, Rimoldi O and Camici PG Circulation J 2016

Fibrosis in primary and secondary LVH

In HCM the late enhancement was predominantly antero-septaland infero-septal whilst in AH no specific pattern of fibrosis could be identified

Rudolph et al. J Am Coll Cardiol 2009;53:284-91

Microvascular ischemia

The pathway from hypertension to HF “Role of microvascular ischemia”

Adapted from Drazner et al, Circulation, 2011

Can we treat microvascular remodelling in LVH?

Thickened small intramural vessel with luminal narrowing (Bar indicates 20 μm)

Kanzaki Y et al. Circulation 2012;125:738-739

Pro- and anti-growth stimuli

The homogeneity of cardiac tissue is achieved through a balanced equilibrium between stimulator and inhibitor signals of cell growth

Stimulatorsangiotensin II aldosteronedeoxycorticost.endothelincatecholamine

Inhibitorsnitric oxidebradykinin prostaglandinANPglucocort.

Neglia D, et al. J Hypertens. 2011;29:364-372.

*P<0.01n=20 Baseline After 6 months’ treatment

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Left ventricular mass

(MRI)

Blood pressure

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Systolic blood

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Diastolic blood

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Effects of perindopril/indapamide on blood pressure and LVH

Myocardial blood flow in patients after 6 months treatment with perindopril/indapamide

Hyperaemic (dipyridamole)

Baseline

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Neglia D, et al. J Hypertens. 2011;29:364-372.

Minimal(dipyridamole)

Coronary

resistance (mmHg/ml/min/g)

Myocardial

Blood Flow (ml/min/g)

*P < 0.05, **P < 0.01 M0 vs M6

Coronary flow in SHR

Placebo Per + Ind0

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Neglia D, et al. J Hypertens. 2011;29:364-372.

Baseline Hyperaemia

Coronary

flow (ml/min/g)

Coronary

resistance (mmHg/ml/min/g)

**P < 0.01 placebo vs perindopril/indapamide

Correlation between microvascularremodelling and coronary flow

Placebo Per/ind0

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10µm

Perindopril/indapamide

10µm

Neglia D, et al. J Hypertens. 2011;29:364-372.

Medial area (µm2)

Peak/baseline coronary flow

**P < 0.001

H. Yazawa, et al. J Cardiac Fail. 2011;17:1041-1050.

Perindopril promotes Bradykinin and NO production

Symptoms associated with Coronary Microvascular Dysfunction

Symptoms of myocardial ischemia

a. Effort and rest anginab. Angina equivalents (i.e. shortness of breath)c. Predominantly rest angina

Functional changes

Mechanisms of Coronary Microvascular Dysfunction“Vascular”

Camici PG, d'Amati G, Rimoldi O Nat Rev Cardiol. 2015 Jan;12(1):48-62

Baseline

ACH – 20µg

No symptoms

No ECG changes

ACH – 100µg

Typical chest pain

Flat T waves

ACH – 200µg

Microvascular SpasmTypical chest pain

ST depression

3731745-09

Anginal symptoms and documented myocardial ischemia*

Coronary stenosis**

FFR

Absent Severe >70%

Acetylcholine test

<0.80≥0.80

• No or <90% diameter reduction

• No angina• No ischemic ECG changes

• No or <90% diameter reduction

• + angina• + ischemic ECG changes

• ≥90% diameter reduction• + angina• + ischemic ECG changes

Adenosine testMicrovascular spasm Epicardial coronary

artery spasm Ischemia likely due to severe atherosclerotic

coronary artery disease

Investigate abnormal nociception

Microvascular anginaEndothelium independent

dysfunction

Likely false positive tests for ischemia

*As assessed by ECG, SPECT, ECHO, Cardiac MRI

Moderate 50-70%

Mild<50%

CFR≥2.5IMR<25

CFR<2.5IMR ≥ 25

Assess CFR non-invasively (PET, ECHO, CMRI)

CFR≥2.5

Microvascular angina

Previous coronary angiogram showing

normal coronary arteries or non-

obstructive coronary artery disease

Coronary Angiography

** Coronary diameter reduction

CFR<2.5

ConclusionsMyocardial ischemia can be due to a number of

different mechanisms that act alone or in combination

• Each mechanism can be investigated using a combination of invasive and non invasive tests

• Understanding the underlying mechanism is the pre-requisite for the choiceof the most appropriate therapeutic strategy